Metabolic Dysfunction-Associated Steatotic Liver Disease

Complex MONDO:0013209 Pathograph 30 Show in embeddings browser Hepatic Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD) is hepatic steatosis occurring in the presence of at least one cardiometabolic risk factor and in the absence of another identified cause of steatosis. It is the most prevalent chronic liver disease worldwide. Adipose-tissue insulin resistance and overnutrition deliver free fatty acids to the liver and drive de novo lipogenesis, so that hepatocyte lipid inflow exceeds the capacity for fatty acid oxidation and very-low-density lipoprotein export. Accumulating toxic lipid species, together with impaired mitochondrial quality control (mitophagy), provoke endoplasmic reticulum and oxidative stress, hepatocyte death, Kupffer-cell and macrophage inflammatory activation (metabolic dysfunction-associated steatohepatitis, MASH), hepatic stellate cell activation, and progressive fibrosis that can culminate in cirrhosis and hepatocellular carcinoma. Fibrosis stage, not steatosis or inflammation grade, is the histologic feature that tracks long-term outcome. Management centres on weight loss and cardiometabolic risk reduction, with resmetirom the first agent approved specifically for MASH with fibrosis.

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Subtypes

Metabolic dysfunction-associated steatotic liver (isolated steatosis)

Hepatic steatosis with a cardiometabolic risk factor but without the necessary histologic features of steatohepatitis. Progression risk is lower than in MASH, but this is a stage of the same disease rather than a distinct entity.

Show evidence (1 reference)

PMID:37363821 SUPPORT Other

"Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis."

The consensus statement establishes steatotic liver disease as the overarching term under which the bland-steatosis stage sits.

Metabolic dysfunction-associated steatohepatitis (MASH/NASH) MONDO:0007027

The inflammatory subtype, defined histologically by steatosis with lobular inflammation and hepatocellular ballooning. MASH is the stage from which progressive fibrosis, cirrhosis, and hepatocellular carcinoma most often arise, and is the target population of the current approved and investigational drug therapies.

Show evidence (1 reference)

PMID:37363821 SUPPORT Other

"The term steatohepatitis was felt to be an important pathophysiological concept that should be retained."

The nomenclature consensus retains steatohepatitis as a distinct pathophysiological stage within steatotic liver disease.

Comorbidities

Metabolic Dysfunction-Associated Steatotic Liver Disease <-> Coronary Artery Disease

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Mechanistic Hypotheses

Canonical lipid-overload and lipotoxicity model

canonical_lipotoxic_multihit_masld CANONICAL

Evidence balance 1 support

Insulin resistance and overnutrition drive hepatocyte lipid overload from adipose-derived free fatty acids and de novo lipogenesis. Toxic lipid species then produce organelle stress, hepatocyte death, macrophage inflammation, stellate-cell activation, and fibrosis. This is the established backbone of the MASLD pathograph and is shared with the hepatic_steatosis_lipotoxicity module.

Show evidence (1 reference)

PMID:15864352 SUPPORT Human Clinical

"These quantitative metabolic data document that both elevated peripheral fatty acids and DNL contribute to the accumulation of hepatic and lipoprotein fat in NAFLD."

Stable-isotope quantification in patients establishes the two lipid inflow routes that begin the canonical chain.

Impaired mitophagy as an amplifier of MASLD progression

impaired_mitophagy_amplifier EMERGING

Evidence balance 2 support

Failure of selective autophagic clearance of damaged mitochondria (mitophagy) is proposed to amplify the transition from bland steatosis to steatohepatitis by allowing dysfunctional, reactive-oxygen-species-producing mitochondria to persist and by licensing inflammasome activation. The human evidence is largely correlative; the causal experiments are in cultured hepatocytes and rodent models, so this is modeled as an emerging amplifier rather than an established requirement for human disease progression.

Pathograph links

Hepatocyte Lipid Overload -> Impaired Hepatocyte Mitophagy INDIRECT UNKNOWN INTERMEDIATES Lipid overload and the associated mitochondrial workload are proposed to overwhelm and then suppress mitochondrial quality control.

Impaired Hepatocyte Mitophagy -> Lipotoxic Stress and Organelle Dysfunction DIRECT Failure to clear damaged mitochondria sustains reactive oxygen species production and organelle stress in the steatotic hepatocyte.

Impaired Hepatocyte Mitophagy -> Hepatocyte Injury and Inflammatory Activation INDIRECT KNOWN INTERMEDIATES Suppressed PINK1-mediated mitophagy permits NLRP3 inflammasome activation and pyroptotic hepatocyte death, an inflammatory route that bypasses the generic lipotoxic-stress step. Intermediates: NLRP3 inflammasome activation

Show evidence (2 references)

PMID:42412329 SUPPORT Other

"We then discuss how impaired mitophagy drives the disease progression of MASLD from the perspective of different hepatic cell types."

The review frames impaired mitophagy as a driver of MASLD progression while presenting it as a synthesis of mechanistic rather than clinical outcome data.

PMID:34674097 SUPPORT In Vitro

"our data showed that DCA-induced pyroptosis involves the inhibition of PINK1-mediated mitophagy and the activation of the NLRP3 inflammasome."

A cell-culture model supports the mitophagy-to-inflammation link but does not establish it in human liver, bounding the hypothesis as emerging.

Liver sinusoidal endothelial dysfunction as an early driver

sinusoidal_endothelial_dysfunction_masld EMERGING

Evidence balance 2 support

An endothelium-first model in which loss of the liver sinusoidal endothelial cell (LSEC) phenotype — capillarization (loss of fenestrae) and loss of shear-responsive vasodilator production — occurs early, before overt steatohepatitis, and then licenses inflammatory-cell recruitment and hepatic stellate cell activation rather than merely following hepatocyte injury. This is deliberately modeled as a parallel arm of the pathograph, not a replacement for the canonical lipotoxic backbone: the human data are cross-sectional histology, and the causal experiments are endothelium-specific mouse models. The same endothelial lesion has been proposed as the axis shared with atherosclerosis, where vascular endothelial dysfunction initiates lipoprotein retention and leukocyte recruitment; whether dismech should represent that shared axis as a cross-disease module or a comorbidity entry is an open scope question (issue #6352), so no cross-disease structure is asserted here.

Pathograph links

Cardiometabolic Dysfunction and Adipose Insulin Resistance -> Liver Sinusoidal Endothelial Cell Dysfunction and Capillarization DIRECT The same cardiometabolic state that drives hepatocyte lipid loading also acts on the sinusoidal endothelium: insulin resistance and dyslipidaemia exacerbate endothelial activation and lipid handling across vascular and hepatic beds. This edge is what makes the endothelial arm a branch of the shared cardiometabolic trigger rather than a second, unexplained initiating step.

Liver Sinusoidal Endothelial Cell Dysfunction and Capillarization -> Hepatocyte Lipid Overload DIRECT The defining endothelium-first claim of this arm: capillarization and loss of shear-responsive vasodilator output occur early in the disease and themselves favour steatosis, rather than arising as a consequence of established hepatocyte injury. This is the edge that orders the endothelial lesion ahead of, not alongside, the steatohepatitis events below.

Liver Sinusoidal Endothelial Cell Dysfunction and Capillarization -> Hepatocyte Injury and Inflammatory Activation DIRECT Capillarized LSECs switch from restraining to recruiting: they release inflammatory mediators and support leukocyte adhesion and transmigration, adding an endothelial source to the macrophage-driven inflammation of MASH.

Liver Sinusoidal Endothelial Cell Dysfunction and Capillarization -> Hepatic Stellate Cell Activation and Fibrosis DIRECT Healthy LSECs actively maintain stellate-cell quiescence; the capillarized endothelium withdraws that restraint and adds fibrogenic signals, giving a route to fibrosis that does not require hepatocyte death as the intermediate.

Show evidence (2 references)

PMID:30797053 SUPPORT Other

"Capillarization, namely the loss of LSEC fenestrae, and LSEC dysfunction, namely the loss of the ability of LSECs to generate vasodilator agents in response to increased shear stress both occur early in NAFLD."

States the temporal claim the hypothesis rests on — that the endothelial lesion is early rather than a downstream consequence of steatohepatitis.

PMID:31726115 SUPPORT Model Organism

"In mice fed a high-fat diet, deficiency in endothelial autophagy induced liver expression of inflammatory markers (Ccl2, Ccl5, Cd68, Vcam-1), liver cell apoptosis (cleaved caspase-3) and perisinusoidal fibrosis."

An endothelium-specific mouse model supplies the causal direction, but the corresponding human data are observational, which is why this is modeled as emerging rather than canonical.

Obstructive sleep apnea-associated chronic intermittent hypoxia as a progression driver

osa_intermittent_hypoxia_masld EMERGING

Evidence balance 2 support

Chronic intermittent hypoxia (CIH) — the cyclical desaturation-reoxygenation of obstructive sleep apnea — is proposed to act on the liver as a second hit that is separable from adiposity, upregulating SREBP-1/SCD-1-dependent hepatic lipogenesis and generating hepatic lipid peroxidation, and thereby accelerating the transition from steatosis to steatohepatitis and fibrosis. This is deliberately modeled as a parallel arm of the pathograph rather than a replacement for the canonical lipotoxic backbone, and as EMERGING rather than CANONICAL, for three reasons that the curated evidence states directly. (1) The human data are observational, and they do not agree with each other endpoint by endpoint: the largest individual-participant meta-analysis attributes the fibrosis association mainly to body mass index by causal mediation analysis while finding apnea severity an independent risk factor for steatosis, whereas the one cohort scored on liver biopsy inverts that pattern, finding an obesity-adjusted fibrosis association but no association with steatosis or steatohepatitis. Each edge therefore carries both the supporting and the refuting human result. (2) The causal, dose-controlled experiments — including the HIF-1 dependence of the triglyceride response — are five-day murine intermittent-hypoxia exposures in lean mice, a model that produced no additional effect in already-obese mice. (3) Correcting the exposure does not correct the liver: randomized trials of CPAP monotherapy show no change in steatosis, fibrosis or aminotransferases. A curator extending this arm should preserve that asymmetry rather than resolving it, and should not curate CPAP as a MASLD therapy.

Pathograph links

Obstructive Sleep Apnea-Associated Chronic Intermittent Hypoxia -> Hypoxia-Driven Hepatic Lipogenesis and Oxidative Stress DIRECT Cyclical desaturation-reoxygenation is the upstream exposure that drives the hepatic lipogenic and oxidative response.

Hypoxia-Driven Hepatic Lipogenesis and Oxidative Stress -> Hepatocyte Lipid Overload INDIRECT KNOWN INTERMEDIATES SREBP-1/SCD-1 upregulation adds a hypoxia-driven de novo lipogenesis inflow on top of the adipose-derived and dietary inflows of the canonical model. As on the fibrosis edge, the human results are curated in disagreement rather than chosen between, but the disagreement runs the opposite way here: the largest individual-participant dataset finds apnea severity an independent risk factor for steatosis after adjustment, while the small biopsy-scored cohort finds no association with histological steatosis. The two measure steatosis differently (a noninvasive hepatic steatosis index in 2120 patients versus liver histology in 97), which is the most likely source of the discrepancy and is itself unresolved. Intermediates: Hepatic SREBP-1 induction; Stearoyl-CoA desaturase 1 upregulation

Hypoxia-Driven Hepatic Lipogenesis and Oxidative Stress -> Hepatocyte Injury and Inflammatory Activation INDIRECT UNKNOWN INTERMEDIATES Cyclical reoxygenation generates hepatic lipid peroxidation, which is associated with lobular inflammation and steatohepatitis severity. The association is with the oxidative readout rather than with the OSA diagnosis: the biopsy-scored cohort that graded steatohepatitis directly found no association between moderate to severe apnea and NASH, so this edge rests on the measured peroxidation rather than on the exposure label.

Hypoxia-Driven Hepatic Lipogenesis and Oxidative Stress -> Hepatic Stellate Cell Activation and Fibrosis INDIRECT UNKNOWN INTERMEDIATES Whether the hypoxic exposure drives fibrosis independently of adiposity is contested: biopsy-based cohorts report an association surviving adjustment for obesity, while individual-participant meta-analysis assigns it to body mass index. The edge is curated with both results attached rather than chosen between.

Show evidence (2 references)

PMID:32843301 SUPPORT Human Clinical

"This meta-analysis confirms the strong association between steatosis and the severity of OSA. The relation between OSA and fibrosis is mainly due to BMI as shown by causal mediation analysis."

PARTIAL, and it is the sentence that bounds the hypothesis: 2120-patient individual-participant data support the steatosis limb while assigning the fibrosis limb to adiposity rather than to the hypoxic exposure.

PMID:16507783 SUPPORT Model Organism

"We conclude that 1) the effect of IH on serum TG levels is mediated through HIF-1, 2) HIF-1 may impact on posttranscriptional regulation of SREBP-1"

Supplies the causal molecular direction the observational human data cannot — a HIF-1alpha heterozygous-null comparison showing the triglyceride response to intermittent hypoxia is HIF-1-dependent. Murine, which is why the hypothesis stays EMERGING.

Transporter-mediated hepatic fatty acid uptake as a rate-limiting, druggable step

hepatic_fatty_acid_uptake_masld EMERGING

Evidence balance 3 support

The canonical model treats the hepatocyte as a passive sink for the non-esterified fatty acid load that adipose insulin resistance releases. This hypothesis holds instead that entry into the hepatocyte is itself protein-mediated and rate-limiting, so that the fatty acid transport proteins on the basolateral hepatocyte membrane — FATP5 (SLC27A5), which is expressed exclusively by liver, and FATP2 (SLC27A2) — set how much of that load actually reaches the hepatic lipid pool, and blocking them reverses steatosis that is already established. The strong form of the claim is therapeutic: hepatic fatty acid uptake is a target in its own right, upstream of and separable from the lipogenic and oxidative arms the approved agents act on. It is modeled as EMERGING, not canonical, for two reasons the curated evidence states directly. First, every causal experiment is murine knockdown or knockout; no FATP-directed agent has been tested in human MASLD, and no human genetic evidence linking SLC27A5 or SLC27A2 variation to MASLD is curated here. Second, hepatic FATP5 knockdown also reduced whole-animal caloric uptake, so the reported protection is not cleanly attributable to the hepatic uptake step alone — a confound the source paper reports rather than one imputed to it. A curator strengthening this arm should look for the human evidence that is missing, not for more rodent replication.

Pathograph links

Cardiometabolic Dysfunction and Adipose Insulin Resistance -> Transporter-Mediated Hepatic Fatty Acid Uptake DIRECT Unrestrained adipose lipolysis raises the non-esterified fatty acid load presented to the liver, and the transporters at the hepatocyte basal membrane are what convert that circulating load into hepatocellular fatty acid entry. The edge asserts substrate delivery to the transport step, not upregulation of the transporters themselves.

Transporter-Mediated Hepatic Fatty Acid Uptake -> Hepatocyte Lipid Overload DIRECT Fatty acids entering through this transport step are the substrate for the hepatocyte triglyceride pool. On the emerging hypothesis this step is rate-limiting, so reducing it lowers hepatic triglyceride even while fatty acid inflow to the liver and dietary fat intake continue.

Deep research

OpenScientist citations 12 citations 2026-10-07T01:05:45.358047

Show evidence (3 references)

PMID:16618416 SUPPORT Model Organism

"Our findings support the hypothesis that efficient hepatocellular uptake of LCFAs, and thus liver lipid homeostasis in general, is largely a protein-mediated process requiring FATP5."

States the core premise of this hypothesis — that hepatocellular long-chain fatty acid entry is protein-mediated rather than passive — from a whole-animal knockout.

PMID:18524776 SUPPORT Model Organism

"knockdown of fatty acid transport protein 5 was also able to reverse already established non-alcoholic fatty liver disease, resulting in significantly improved whole-body glucose homeostasis."

Supplies the therapeutic form of the claim — reversal of established disease, not just prevention — which is what makes the uptake step worth modeling separately from lipid overload. Murine, which is why the hypothesis stays emerging.

PMID:18524776 SUPPORT INDIRECT Model Organism

"resulting in a marked reduction of hepatic dietary fatty acid uptake, reduced caloric uptake, and concomitant protection from diet-induced non-alcoholic fatty liver disease."

Retained deliberately as the bounding quote: the same sentence that reports protection also reports reduced caloric uptake, so the hepatic effect is confounded with a whole-animal energy-intake effect. Graded INDIRECT because the protection follows from the uptake block only through that unresolved intermediate.

A weight-independent hepatic component of GLP-1 receptor agonist benefit

semaglutide_weight_independent_hepatic_effect EMERGING

Evidence balance 2 support 4 refute

Semaglutide improves MASH histology, and this hypothesis asks what carries that benefit: weight loss and its metabolic sequelae, or an effect of GLP-1 receptor agonism that survives at matched weight loss. The question matters for the pathograph because the two readings place the drug's action on different nodes — the upstream cardiometabolic trigger in the first case, the hepatic and fibrogenic arm in the second. The strong form of the hypothesis, a cell-autonomous action on hepatocytes or hepatic stellate cells, is close to excluded rather than merely unproven. Pyke's extensively validated monoclonal antibody found no GLP-1 receptor in primate liver and confirmed the negative by in-situ ligand binding rather than immunostaining alone, and incretin agonists applied to primary human hepatocytes and stellate cells changed neither lipid content nor fibrotic markers nor CREB phosphorylation. Against that, Armstrong reports a 24.6% fall in lipogenesis in primary human hepatocytes, so the in-vitro literature is genuinely contradictory; the negatives are the better-controlled side, resting on knockout-validated reagents and an orthogonal binding assay. What remains live is a weight-independent effect routed through tissues other than the liver. The one randomised matched-weight-loss experiment in humans found liver outcomes equal between a GLP-1 receptor agonist and lifestyle, with suppression of de novo lipogenesis the one measure that separated the arms — so DNL is currently the best-evidenced weight-independent hepatic effect, and it produced no measurable difference in steatosis or disease activity over twelve weeks. It is modeled as EMERGING, and the honest reading of the present evidence favours the weight-mediated account. Two cautions bound any attempt to settle it. The only numerically reported mediation analysis in the class covers survodutide, a GLP-1/glucagon dual agonist whose hepatic glucagon receptor is expressed in human liver and which therefore has a direct route semaglutide lacks; its larger direct component for fibrosis cannot be transferred to semaglutide. And the ESSENCE weight-loss strata are post-randomisation, so conditioning on achieved weight loss compares non-comparable groups and does not yield a causal mediated fraction.

Deep research

OpenScientist citations 9 citations 2026-10-07T13:34:01.215728

Show evidence (6 references)

PMID:24467746 REFUTE In Vitro

"No GLP-1R was seen in primate liver and thyroid."

Refutes the strong, cell-autonomous form of the hypothesis by removing its anatomical substrate. The same study confirms its immunohistochemistry with in-situ ligand binding, which is why this negative outweighs antibody-only positive reports. Graded IN_VITRO because the method is immunohistochemistry and in-situ ligand binding on tissue specimens rather than any observation in patients; the quoted sentence says "primate" because the survey covers monkey and human tissue, so the hepatic negative rests on specimens of both.

PMID:39607493 REFUTE In Vitro

"These findings indicate that incretin agonists have no direct actions in human hepatocytes or hepatic stellate cells, suggesting that their beneficial effects in patients with MASH are likely mediated indirectly, potentially through improvements in body weight, insulin resistance and glycemic control."

The functional counterpart of the expression negative: no lipid, fibrotic or CREB response in primary human hepatocytes and stellate cells. The absent CREB phosphorylation is the load-bearing part, because it says the receptor-effector coupling a direct effect would need is not present. Tests liraglutide, acyl-GIP and MAR709 rather than semaglutide itself, so the extension to semaglutide is a class inference.

PMID:26394161 SUPPORT INDIRECT In Vitro

"a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p<0.01)"

Retained as the contradicting result rather than omitted: a direct functional effect in the same cell type where the study above found none. The quote is carried far enough back to name the agent and the cell type, since "primary human hepatocytes" is what puts this result in direct conflict with the negative above rather than merely near it. Graded INDIRECT because a lipogenesis change in culture reaches the histologic claim only through several unestablished steps, and because the measurement sits in the in-vitro arm of a trial whose patients also lost weight.

+ 3 more references

Discussions and Knowledge Gaps

If chronic intermittent hypoxia is a genuine driver of MASLD progression, why does correcting it with CPAP not improve the liver — and is the hypoxic exposure therefore a causal driver, a marker of adiposity, or a driver whose damage is not reversible on trial timescales?

KNOWLEDGE GAP OPEN kgap_masld_osa_cpap_hepatic_benefit

Attached to

pathophysiology#Obstructive Sleep Apnea-Associated Chronic Intermittent Hypoxia pathophysiology#Hypoxia-Driven Hepatic Lipogenesis and Oxidative Stress

The observational and mechanistic arms of this hypothesis point one way and the interventional arm points the other, and the disagreement is the gap. Observationally, hypoxia metrics track hepatic severity after adjustment for obesity in biopsy-based cohorts; mechanistically, controlled murine intermittent hypoxia raises hepatic SREBP-1/SCD-1 and liver triglyceride, and the triglyceride response is HIF-1-dependent. Yet randomized trials of CPAP monotherapy show no change in steatosis, fibrosis or aminotransferases, and a 2026 scoping review of 74 studies reports that what hepatic improvement does occur in CPAP trials tracks weight change rather than correction of sleep-disordered breathing. At least four readings remain open and the curated evidence does not discriminate between them: the association is residual confounding by adiposity that adjustment did not remove; CPAP adherence in the trials was too low or the follow-up too short to register a histological change; hypoxia contributes to establishing steatosis but not to sustaining it once the metabolic state exists; or the hepatic lesion is real but not reversible without concurrent weight loss. Until one of these is settled, CPAP must not be curated as a MASLD treatment, and the hypoxia arm must not be promoted out of EMERGING.

Proposed experiments

Adherence-stratified CPAP trial with MRI-PDFF and hypoxic-burden endpoints

adherence-stratified randomized sham-controlled trial

exp_masld_cpap_adherence_stratified_pdff

Randomize CPAP-naive patients with biopsy- or MRI-confirmed MASLD and moderate-to-severe OSA to CPAP versus sham, with telemonitored objective adherence, weight held as a prespecified covariate rather than an outcome, and MRI proton density fat fraction plus liver stiffness at 12 months. Test whether a hepatic effect emerges above an adherence threshold and above a hypoxic-burden threshold, both of which prior trials averaged below.

Decision criterion

A dose-response between nightly CPAP hours (or reduction in time below 90% saturation) and fall in MRI-PDFF, independent of weight change, supports the hypoxia arm as causal and reversible; a flat response across the adherence range with weight change explaining the variance supports adiposity as the operative variable.

Would support

pathophysiology#Obstructive Sleep Apnea-Associated Chronic Intermittent Hypoxia

Would refute

pathophysiology#Hypoxia-Driven Hepatic Lipogenesis and Oxidative Stress

Weight-clamped intermittent hypoxia exposure in diet-induced steatohepatitis

pair-fed intermittent-hypoxia exposure with conditional knockout

exp_masld_ih_weight_clamped_rodent

Expose mice with established diet-induced steatohepatitis to intermittent hypoxia versus normoxia under pair-feeding so body weight and adiposity are matched between arms, then measure hepatic SREBP-1/SCD-1, 4-hydroxynonenal adducts, NAFLD activity score and fibrosis stage, with a hepatocyte-specific Hif1a deletion arm. This separates the hypoxic signal from the adiposity it is confounded with in every human cohort, and tests whether the effect exists on an already-steatotic background rather than only in the lean state where it was first shown.

Decision criterion

Higher activity score or fibrosis stage in the hypoxia arm at matched body weight, abolished by hepatocyte Hif1a deletion, establishes a weight-independent hepatic effect of intermittent hypoxia; no difference at matched weight argues the human association is adiposity-mediated.

Would support

pathophysiology#Hypoxia-Driven Hepatic Lipogenesis and Oxidative Stress

Show evidence (2 references)

PMID:29151428 SUPPORT Human Clinical

"After CPAP treatment, no changes in liver steatosis, liver fibrosis, and aminotransferase levels (alanine aminotransferase and aspartate aminotransferase) were found."

Five randomized controlled trials pooled; the null interventional result that creates the gap. The authors grade the evidence low to very low, which is itself part of why the question stays open rather than being answered negatively.

PPR:PPR1293874 Preprint · not peer-reviewed SUPPORT Other

"RCTs demonstrated limited hepatic benefit from CPAP monotherapy, with improvements more closely related to weight change than correction of OSA alone."

A 74-study scoping review that states the weight-versus-airway attribution explicitly. Cited as a non-peer-reviewed preprint and deliberately not the sole support for any claim here — the same null result is carried by the peer-reviewed randomized-trial meta-analysis above.

Is transporter-mediated hepatic fatty acid uptake rate-limiting in human MASLD, or is the reversal of steatosis on FATP5/FATP2 knockdown a property of the diet-induced mouse — and why has the one human system that can measure hepatic fatty acid uptake never been used to perturb the transporters?

HUMAN MODEL MISMATCH OPEN hmm_masld_hepatic_fatp_uptake_human_translation

Attached to

pathophysiology#Transporter-Mediated Hepatic Fatty Acid Uptake mechanistic_hypotheses#hepatic_fatty_acid_uptake_masld

This is a model-fidelity question rather than an absence of evidence, which is why it is curated as HUMAN_MODEL_MISMATCH and not as a knowledge gap. The rodent evidence is strong and internally replicated: hepatocyte long-chain fatty acid entry is protein-mediated, silencing FATP5 reverses established diet-induced fatty liver and improves glucose homeostasis, and liver-specific FATP2 knockdown reproduces the steatosis result through a different gene while high-fat feeding continues. What is missing is not another mouse. Three things bound the translation. First, the FATP5 knockdown reduced whole-animal caloric uptake as well as hepatic fatty acid uptake, so the published protection is not cleanly attributable to the hepatic step — the confound is in the source paper's own summary sentence. Second, no human genetic evidence links SLC27A5 or SLC27A2 variation to MASLD in this entry, in contrast to the PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 signals that anchor the other hepatocyte-intrinsic arms, and no FATP-directed agent has entered human testing. Third — and this is what makes the mismatch actionable rather than merely noted — the human iPSC adipose-liver microphysiological system curated in this entry already measures hepatocyte fatty acid uptake as a primary endpoint and already shows that uptake rises when the connected adipose compartment is inflamed. It has the readout. It has never been reported with the transporters knocked down, so the human system that could adjudicate the hypothesis has been used to observe the flux and not to test what gates it. A curator should not resolve this by promoting the uptake hypothesis on the strength of additional rodent replication, and should not retire it on the absence of human data: the discriminating experiment has not been done.

Proposed experiments

FATP5 and FATP2 knockdown in the human iPSC adipose-liver microphysiological system under adipose inflammation

transporter knockdown in a human multi-tissue microphysiological system

exp_masld_fatp_knockdown_in_human_adipose_liver_mps

Take the isogenic iPSC adipose-liver chip in its inflamed configuration, in which hepatocyte fatty acid uptake and lipid accumulation are already elevated, and silence SLC27A5 and SLC27A2 in the hepatocyte compartment singly and together, with a non-targeting control. Measure hepatocyte fatty acid uptake and lipid content as the primary endpoints, and hepatic glucose production under insulin as the secondary endpoint. The design is what the whole-animal experiments cannot supply: the adipose fatty acid supply is fixed by the chip rather than varying with the animal's feeding behaviour, so a fall in hepatocyte lipid can be attributed to the transport step and not to reduced caloric intake. Running the knockdown after inflammation is established tests reversal rather than prevention, matching the design of the murine knockdown.

Perturbations

Hepatocyte-compartment SLC27A5 and SLC27A2 silencing

pathophysiology#Transporter-Mediated Hepatic Fatty Acid Uptake

RNA-interference or CRISPR-interference knockdown of each transporter alone and in combination in the iPSC-derived hepatocyte compartment only, leaving the adipocyte and macrophage compartments unmodified.

SLC27A5 hgnc:10999 SLC27A2 hgnc:10996

Readouts

Hepatocyte fatty acid uptake after transporter knockdown

pathophysiology#Transporter-Mediated Hepatic Fatty Acid Uptake

long-chain fatty acid import into hepatocytes GO:0044539

Direction: DECREASED

Interpretation: On-target confirmation. If uptake does not fall, the human hepatocyte does not depend on these transporters in the way the mouse liver does, and that is itself the answer.

Hepatocyte lipid content at fixed adipose fatty acid supply

pathophysiology#Hepatocyte Lipid Overload

lipid storage GO:0019915

Direction: DECREASED

Interpretation: The discriminating measurement. Because substrate delivery is held constant by the chip, a fall here isolates the contribution of the transport step in a way the murine caloric-uptake confound prevents.

Controls

Non-targeting knockdown construct

Scrambled or non-targeting construct delivered to the hepatocyte compartment on the same schedule, controlling for the delivery vehicle and the knockdown procedure rather than for the transporters.

Uninflamed (M0 macrophage) chip

The same chip with non-activated macrophages, in which hepatocyte fatty acid uptake is not elevated. Sets the floor against which a knockdown effect in the inflamed arm is measured.

Knockdown before versus after adipose inflammation

Two timing arms, so prevention of hepatocyte lipid accumulation is separated from reversal of accumulation that has already occurred — the distinction that made the murine FATP5 knockdown result stronger than a prevention-only design.

Decision criterion

A fall in hepatocyte lipid content on transporter knockdown, at unchanged adipose fatty acid release and unchanged media fatty acid concentration, supports the uptake step as rate-limiting in human hepatocytes and would move the hypothesis toward canonical. Confirmed on-target knockdown with no change in hepatocyte lipid content refutes the rate-limiting claim for human cells and reassigns the murine result to a whole-animal energy-balance effect.

Would support

pathophysiology#Transporter-Mediated Hepatic Fatty Acid Uptake mechanistic_hypotheses#hepatic_fatty_acid_uptake_masld

Would refute

mechanistic_hypotheses#hepatic_fatty_acid_uptake_masld

Supporting outcome

Hepatocyte fatty acid uptake and lipid content both fall on knockdown while adipose fatty acid release and circulating fatty acid levels are unchanged, with the combined SLC27A5/SLC27A2 knockdown exceeding either alone.
The fall in hepatocyte lipid content is present in the arm where knockdown follows established inflammation, showing reversal rather than prevention only.

Refuting outcome

Transporter transcript and protein fall as intended but hepatocyte fatty acid uptake and lipid content are unchanged, indicating that human hepatocyte fatty acid entry in this system is not gated by these transporters.
Hepatocyte lipid content falls only alongside a fall in circulating fatty acid availability in the chip, which would place the effect on supply rather than on the hepatocyte transport step.

Show evidence (3 references)

PMID:18524776 SUPPORT Model Organism

"resulting in a marked reduction of hepatic dietary fatty acid uptake, reduced caloric uptake, and concomitant protection from diet-induced non-alcoholic fatty liver disease."

The murine result and its confound in one sentence: hepatic uptake and whole-animal caloric uptake both fall, so the model cannot attribute the protection to the hepatic transport step alone.

PMID:39266553 SUPPORT In Vitro

"Consequently, the iHEP-MPS showed increased fatty acid uptake and lipid accumulation under inflamed iADIPO-MPS conditions"

Establishes that the human non-animal system has the hepatocyte fatty acid uptake readout this question needs, which is what makes the missing transporter perturbation a specific and reachable experiment rather than an open-ended wish for human data.

PMID:39266553 SUPPORT In Vitro

"Whether WAT expansion or its inflammation is the main trigger in WAT-driven MASLD and hepatic insulin resistance (HIR) has been difficult to address in animal models because lipid accumulation and lipotoxic events often go hand in hand with inflammation of WAT and liver"

The authors state the general form of this mismatch for a neighbouring question — that variables which can be separated in a microphysiological system are confounded in animal models — which is the same structural argument that applies to the caloric-uptake confound in the FATP5 experiment.

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Pathophysiology

Cardiometabolic Dysfunction and Adipose Insulin Resistance

MASLD is defined by hepatic steatosis in the presence of at least one cardiometabolic risk factor (overweight/obesity, dysglycaemia or type 2 diabetes, hypertension, hypertriglyceridaemia, or low HDL cholesterol). Adipose-tissue insulin resistance fails to restrain lipolysis, so non-esterified fatty acids flood the portal circulation, while hyperinsulinaemia and carbohydrate surplus drive hepatic de novo lipogenesis. This cardiometabolic state is the initiating context that distinguishes MASLD from other steatotic liver diseases.

Liver sinusoidal endothelial dysfunction as an early driver Transporter-mediated hepatic fatty acid uptake as a rate-limiting, druggable step

adipocyte CL:0000136 hepatocyte CL:0000182

cellular response to insulin stimulus GO:0032869 ↓ DECREASED

Experimental models

Isogenic iPSC adipocyte-hepatocyte-macrophage microphysiological system (M1-iADIPO-iHEP-MPS) ORGAN ON CHIP Reconstructs the initiating cardiometabolic state of the pathograph in human cells — inflamed, insulin-resistant white adipose tissue releasing fatty acids and TNF-alpha into a circulation shared with the liver — and separates adipose inflammation from adipose expansion as candidate causes, which the trigger node's description leaves bundled.

Isogenic iPSC macrophage-adipocyte microphysiological system (iMAC-iADIPO-MPS) ORGAN ON CHIP Reproduces the adipose limb of the trigger node in human cells, including the crown-like structures that are its histologic signature, and shows that macrophage polarization state rather than macrophage presence produces adipocyte insulin resistance and dysregulated lipolysis.

Metabolically competent iPSC white adipose tissue microphysiological system (iADIPO-MPS) ORGAN ON CHIP Provides the calibrated human assay for the adipose insulin-sensitivity variable this node turns on, with a dynamic range the authors report as competent against in vivo and ex vivo comparators.

Heterochronic-serum iPSC white adipose tissue-liver aging microphysiological system ORGAN ON CHIP Reads out how the state of the adipose compartment propagates to the liver compartment under an aging stimulus, on the same axis this trigger node describes. Curated as measuring, not recapitulating, because the manipulated variable is serum age rather than cardiometabolic dysfunction.

Downstream

Hepatocyte Lipid Overload Adipose insulin resistance and overnutrition supply the fatty acid inflow and lipogenic drive that produce hepatocyte lipid accumulation.

Transporter-Mediated Hepatic Fatty Acid Uptake Unrestrained adipose lipolysis raises the non-esterified fatty acid load presented to the liver, and the transporters at the hepatocyte basal membrane are what convert that circulating load into hepatocellular fatty acid entry. The edge asserts substrate delivery to the transport step, not upregulation of the transporters themselves.

Liver Sinusoidal Endothelial Cell Dysfunction and Capillarization The same cardiometabolic state that drives hepatocyte lipid loading also acts on the sinusoidal endothelium: insulin resistance and dyslipidaemia exacerbate endothelial activation and lipid handling across vascular and hepatic beds. This edge is what makes the endothelial arm a branch of the shared cardiometabolic trigger rather than a second, unexplained initiating step.

Show evidence (2 references)

PMID:37363821 SUPPORT Other

"There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors."

The nomenclature consensus makes cardiometabolic dysfunction a definitional requirement of MASLD, establishing it as the entry point of the pathograph.

PMID:42412329 SUPPORT Other

"Metabolic dysfunction-associated fatty liver disease (MASLD) represents the most prevalent chronic liver disorder globally, with pathogenesis closely linked to insulin resistance, obesity, and gut microbiota dysbiosis."

Ties MASLD pathogenesis to insulin resistance and obesity, the substrate of this trigger node.

Transporter-Mediated Hepatic Fatty Acid Uptake

Long-chain fatty acids delivered to the liver do not enter hepatocytes by passive diffusion alone. Uptake is largely protein-mediated, through fatty acid transport proteins at the basal plasma membrane of the hepatocyte. FATP5 (SLC27A5) is expressed exclusively by liver and localizes to that membrane; FATP2 (SLC27A2) accounts for a further large share of hepatic long-chain fatty acid uptake while also serving as a peroxisomal very-long-chain acyl-CoA synthetase. This node is deliberately kept separate from Hepatocyte Lipid Overload because it is the step at which the circulating non-esterified fatty acid load is gated, and because it is where the two rodent interventions that reverse established steatosis act. What is increased in the high-fat state is the flux through this step rather than, on the curated evidence, transporter expression: the murine experiments show that continued transporter activity is required to sustain fatty acid entry, not that the transporters are upregulated by disease. The node carries the emerging hepatic-uptake hypothesis and is not asserted as a required step in human disease.

Transporter-mediated hepatic fatty acid uptake as a rate-limiting, druggable step

hepatocyte CL:0000182

SLC27A5 hgnc:10999 SLC27A2 hgnc:10996

long-chain fatty acid import into hepatocytes GO:0044539 ↑ INCREASED

FATP5/FATP2 long-chain fatty acid transport activity GO:0005324

liver UBERON:0002107

Experimental models

Isogenic iPSC adipocyte-hepatocyte-macrophage microphysiological system (M1-iADIPO-iHEP-MPS) ORGAN ON CHIP Fatty acid entry into hepatocytes is measured directly in the chip as accumulation of fluorescent fatty acids, and rises when the connected adipose compartment is inflamed. This is a human read on the uptake step whose causal evidence is otherwise entirely murine.

Animal models

AAV8-shRNA hepatic FATP5 knockdown mouse on high-fat diet Mouse perturbs Directly and specifically removes the transport step this node represents, in the intact liver, and reads out the resulting change in hepatic fatty acid entry.

FATP5 (Slc27a5) knockout mouse Mouse perturbs Removes the transporter genetically and shows the predicted loss of long-chain fatty acid uptake in hepatocytes isolated from the null animals.

AAV8-shRNA hepatic FATP2 knockdown mouse on high-fat diet Mouse perturbs A second, independent genetic route to the same transport step, which is what distinguishes a transporter-specific result from a general hepatic lipid-handling effect.

Downstream

Hepatocyte Lipid Overload Fatty acids entering through this transport step are the substrate for the hepatocyte triglyceride pool. On the emerging hypothesis this step is rate-limiting, so reducing it lowers hepatic triglyceride even while fatty acid inflow to the liver and dietary fat intake continue.

Show evidence (2 references)

PMID:16618416 SUPPORT Model Organism

"FATP5 is exclusively expressed by the liver and localized to the basal plasma membrane of hepatocytes, congruent with a role in LCFA uptake from the circulation."

Establishes the expression and subcellular localization that make this a hepatocyte-membrane transport step rather than a generic lipid-handling claim.

PMID:20530735 SUPPORT Model Organism

"total hepatic (V)LACS activity was not significantly affected by loss of FATP2, while LCFA uptake was reduced by 40%, indicating a more prominent role in hepatic LCFA uptake."

Quantifies the second transporter's contribution and separates its transport role from its peroxisomal synthetase role, which is why both genes are bound on this node.

Hepatocyte Lipid Overload

Hepatocyte triglyceride accumulates when fatty acid inflow from adipose lipolysis and diet, plus de novo lipogenesis, exceeds fatty acid oxidation and very-low-density lipoprotein export. In MASLD the disorder-specific inflow is metabolic (adipose insulin resistance and carbohydrate surplus) rather than ethanol-driven, but the resulting lipid-droplet overload is the conserved module state.

Impaired mitophagy as an amplifier of MASLD progression

hepatocyte CL:0000182

triglyceride biosynthetic process GO:0019432 ↑ INCREASED lipid storage GO:0019915 ↑ INCREASED fatty acid beta-oxidation GO:0006635 ↓ DECREASED

Experimental models

Isogenic iPSC adipocyte-hepatocyte-macrophage microphysiological system (M1-iADIPO-iHEP-MPS) ORGAN ON CHIP Hepatocyte lipid accumulation arises in the chip as a consequence of inflammation in the connected adipose compartment, not from direct fatty acid loading of the hepatocytes, so the model reproduces the causal route into this node rather than only its end state.

Animal models

AAV8-shRNA hepatic FATP5 knockdown mouse on high-fat diet Mouse rescues Silencing the transporter after fatty liver is already established reverses it, placing the uptake step causally upstream of the hepatic lipid pool rather than merely correlated with it.

AAV8-shRNA hepatic FATP2 knockdown mouse on high-fat diet Mouse rescues Reducing the transport step lowers hepatic steatosis while dietary fat intake is held high, replicating the FATP5 result through a different gene.

Downstream

Impaired Hepatocyte Mitophagy Lipid overload and the associated mitochondrial workload are proposed to overwhelm and then suppress mitochondrial quality control.

Lipotoxic Stress and Organelle Dysfunction Continued lipid loading generates toxic non-triglyceride lipid species that stress the endoplasmic reticulum and mitochondria.

Show evidence (1 reference)

PMID:15864352 SUPPORT Human Clinical

"Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess liver triacylglycerol (TAG), inflammation, and liver damage."

Defines the hepatocyte triglyceride-overload state that this node represents.

Impaired Hepatocyte Mitophagy

Mitophagy is the selective autophagic clearance of damaged mitochondria, executed through ubiquitin-dependent (PINK1/Parkin) and ubiquitin-independent receptor pathways. In steatotic hepatocytes this quality-control step is suppressed, so depolarized, reactive-oxygen-species-producing mitochondria persist and NLRP3 inflammasome activation and pyroptotic hepatocyte death are licensed. This node carries the emerging mitophagy hypothesis and is not asserted as a required step in every case.

Impaired mitophagy as an amplifier of MASLD progression

hepatocyte CL:0000182

mitophagy GO:0000423 ↓ DECREASED

Downstream

Lipotoxic Stress and Organelle Dysfunction Failure to clear damaged mitochondria sustains reactive oxygen species production and organelle stress in the steatotic hepatocyte.

Hepatocyte Injury and Inflammatory Activation Suppressed PINK1-mediated mitophagy permits NLRP3 inflammasome activation and pyroptotic hepatocyte death, an inflammatory route that bypasses the generic lipotoxic-stress step.

Show evidence (2 references)

PMID:42412329 SUPPORT Other

"Mitochondrial dysfunction is central to MASLD progression, and mitophagy"

The review establishes mitochondrial dysfunction and mitophagy as central to MASLD progression, the substrate of this node.

PMID:34674097 SUPPORT In Vitro

"Expression levels of the mitophagy markers PTEN-induced kinase 1 (PINK1) and E3 ubiquitin ligase Parkin were significantly diminished by DCA"

In free-fatty-acid-loaded HepG2 cells, a bile acid relevant to steatohepatitis suppresses the PINK1/Parkin mitophagy machinery.

Lipotoxic Stress and Organelle Dysfunction

Toxic non-triglyceride lipid species (diacylglycerols, ceramides, free fatty acid metabolites) accumulate alongside stored triglyceride and induce endoplasmic reticulum stress, mitochondrial dysfunction, and reactive oxygen species accumulation. This is the amplification step that converts bland steatosis (MASL) toward steatohepatitis (MASH).

hepatocyte CL:0000182

response to endoplasmic reticulum stress GO:0034976 ↑ INCREASED response to oxidative stress GO:0006979 ↑ INCREASED

Downstream

Hepatocyte Injury and Inflammatory Activation Organelle stress sensitizes the hepatocyte to lipoapoptosis and other regulated cell death, which releases damage signals to resident macrophages.

Show evidence (2 references)

PMID:42412329 SUPPORT Other

"Mitochondrial dysfunction is central to MASLD progression"

Establishes organelle (mitochondrial) dysfunction as a central step in MASLD progression.

PMID:20427778 SUPPORT Human Clinical

"Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P=0.001)"

Benefit from an antioxidant in a randomized trial is indirect human support for oxidative stress as a modifiable amplifier, not proof of the mechanism.

Hepatocyte Injury and Inflammatory Activation

Stressed hepatocytes undergo apoptosis and pyroptosis, releasing damage signals that activate Kupffer cells and recruited macrophages, with inflammasome activation and pro-inflammatory cytokine release. Steatosis with lobular inflammation and hepatocellular ballooning defines MASH, the inflammatory subtype from which progressive disease arises.

hepatocyte CL:0000182 Kupffer cell CL:0000091 macrophage CL:0000235

apoptotic process GO:0006915 ↑ INCREASED inflammatory response GO:0006954 ↑ INCREASED

Downstream

Hepatic Stellate Cell Activation and Fibrosis Sustained hepatocyte death and macrophage activation provide the cytokine and damage-signal milieu that activates hepatic stellate cells.

Show evidence (1 reference)

PMID:34674097 SUPPORT In Vitro

"Nonalcoholic steatohepatitis (NASH) is the inflammatory subtype of nonalcoholic fatty liver disease (NAFLD), which can lead to liver fibrosis and cirrhosis."

Defines steatohepatitis as the inflammatory stage that connects hepatocyte injury to downstream fibrosis.

Liver Sinusoidal Endothelial Cell Dysfunction and Capillarization

Liver sinusoidal endothelial cells (LSECs) are the fenestrated gatekeepers between portal blood and the hepatocyte, and in health they hold Kupffer cells and hepatic stellate cells quiescent. In MASLD they capillarize — losing their fenestrae and their shear-responsive vasodilator output — and lose autophagic capacity, converting them from a restraining influence into a source of inflammatory and fibrogenic mediators. This node is the hepatic limb of the endothelial arm; it is not on the canonical lipotoxic backbone and is grouped under the emerging sinusoidal_endothelial_dysfunction_masld hypothesis.

Liver sinusoidal endothelial dysfunction as an early driver

liver sinusoidal endothelial cell CL:1000398

macroautophagy GO:0016236 ↓ DECREASED leukocyte migration GO:0050900 ↑ INCREASED nitric oxide biosynthetic process GO:0006809 ↓ DECREASED

Downstream

Hepatocyte Lipid Overload The defining endothelium-first claim of this arm: capillarization and loss of shear-responsive vasodilator output occur early in the disease and themselves favour steatosis, rather than arising as a consequence of established hepatocyte injury. This is the edge that orders the endothelial lesion ahead of, not alongside, the steatohepatitis events below.

Hepatocyte Injury and Inflammatory Activation Capillarized LSECs switch from restraining to recruiting: they release inflammatory mediators and support leukocyte adhesion and transmigration, adding an endothelial source to the macrophage-driven inflammation of MASH.

Hepatic Stellate Cell Activation and Fibrosis Healthy LSECs actively maintain stellate-cell quiescence; the capillarized endothelium withdraws that restraint and adds fibrogenic signals, giving a route to fibrosis that does not require hepatocyte death as the intermediate.

Show evidence (2 references)

PMID:31726115 SUPPORT Human Clinical

"Patients with NASH had half as many LSECs containing autophagic vacuoles as patients without liver histological abnormalities, or with simple steatosis."

Transmission electron microscopy in patient liver establishes the autophagy defect in LSECs as a human, not merely a model-system, finding.

PMID:42430855 SUPPORT Other

"Similarly, in MASLD, liver sinusoidal endothelial cells lose their capacity to regulate lipid trafficking, immune tolerance, and hepatic homeostasis, thereby promoting steatosis, inflammation, and fibrosis."

Names the three functions this node loses and the downstream states they permit — steatosis, inflammation, and fibrosis — which are the three edges below.

Hepatic Stellate Cell Activation and Fibrosis

Hepatic stellate cells transdifferentiate into myofibroblast-like cells and deposit excessive extracellular matrix. Fibrosis stage is the histologic feature that determines long-term outcome in MASLD, independent of steatohepatitis activity, which makes this node the principal prognostic and therapeutic target.

hepatic stellate cell CL:0000632 myofibroblast CL:0000186

extracellular matrix organization GO:0030198 ↑ INCREASED

Downstream

Hepatic Steatosis Progressing to Steatohepatitis and Fibrosis Progressive matrix deposition distorts hepatic architecture and yields cirrhosis, portal hypertension, hepatic decompensation, and hepatocellular carcinoma.

Show evidence (1 reference)

PMID:25935633 SUPPORT Human Clinical

"Patients with fibrosis, regardless of steatohepatitis or NAFLD activity score, had shorter survival times than patients without fibrosis."

A 619-patient longitudinal cohort establishes fibrosis, and not inflammatory activity, as the outcome-determining lesion.

Hepatic Steatosis Progressing to Steatohepatitis and Fibrosis

The convergent clinical outcome: bland steatosis advancing through steatohepatitis to bridging fibrosis, cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Most people with MASLD never reach this end of the spectrum, but fibrosis stage stratifies who will.

hepatocyte CL:0000182

Show evidence (1 reference)

PMID:25935633 SUPPORT Human Clinical

"In a longitudinal study of patients with NAFLD, fibrosis stage, but no other histologic features of steatohepatitis, were associated independently with long-term overall mortality, liver transplantation, and liver-related events."

Defines the clinical consequence set (mortality, transplantation, liver-related events) and its histologic determinant.

PNPLA3 rs738409 Genetic Susceptibility

The PNPLA3 rs738409 (I148M) allele increases hepatic triglyceride content and hepatic inflammation, and accounts for much of the ancestry-related variation in susceptibility to fatty liver. It is a susceptibility modifier of lipid retention rather than a necessary or sufficient cause of MASLD.

PNPLA3 hgnc:18590

Downstream

Hepatocyte Lipid Overload Carriage of the 148M allele raises steady-state hepatic triglyceride content, shifting the lipid-overload node toward disease.

Show evidence (1 reference)

PMID:18820647 SUPPORT Human Clinical

"strongly associated with increased hepatic fat levels (P = 5.9 x 10(-10)) and with hepatic inflammation (P = 3.7 x 10(-4))."

The genome-wide association scan establishes the rs738409 allele as associated with both hepatic fat and inflammation.

TM6SF2 p.Glu167Lys Genetic Susceptibility

The TM6SF2 p.Glu167Lys variant reduces TM6SF2 protein levels and impairs hepatic very-low-density lipoprotein export, raising liver triglyceride while lowering circulating LDL cholesterol and triglycerides. It is the prototypical example of the discordance between hepatic fat accumulation and cardiovascular lipid risk in MASLD.

TM6SF2 hgnc:11861

Downstream

Hepatocyte Lipid Overload Reduced TM6SF2 protein impairs very-low-density lipoprotein export, so triglyceride is retained in the hepatocyte.

Show evidence (1 reference)

PMID:24531328 SUPPORT Human Clinical

"The TM6SF2 variant encoding p.Glu167Lys was also associated with higher circulating levels of alanine transaminase, a marker of liver injury, and with lower levels of low-density lipoprotein-cholesterol (LDL-C), triglycerides and alkaline phosphatase in 3 independent populations"

Establishes the variant's paired hepatic-injury and lipid-lowering signature across three independent cohorts.

Obstructive Sleep Apnea-Associated Chronic Intermittent Hypoxia

Obstructive sleep apnea imposes repeated nocturnal desaturation-reoxygenation cycles on the liver. The exposure is quantified clinically by the apnea-hypopnea index, the oxygen desaturation index, and the proportion of sleep time spent below 90% saturation, and it is these hypoxia metrics rather than the arousal burden that track hepatic severity. The node is curated as a comorbid, potentially modifiable initiating context that sits alongside — not inside — the cardiometabolic trigger, because the two are strongly correlated through obesity and the curated evidence disagrees about how much survives adjustment for it. Sleep fragmentation is deliberately not modeled here: the studies that separate the two attribute the hepatic signal to the hypoxic component.

Obstructive sleep apnea-associated chronic intermittent hypoxia as a progression driver

response to hypoxia GO:0001666 ↑ INCREASED Temporal: RECURRENT

Downstream

Hypoxia-Driven Hepatic Lipogenesis and Oxidative Stress Cyclical desaturation-reoxygenation is the upstream exposure that drives the hepatic lipogenic and oxidative response.

Show evidence (2 references)

PMID:21703181 SUPPORT Human Clinical

"In multivariate analysis, after adjustment for age, obesity, and insulin resistance status, CIH remained independently associated with hepatic fibrosis, fibroinflammation, and NAS."

101 prospectively recruited morbidly obese patients with intraoperative liver biopsy and desaturation-index-graded hypoxia. This is the strongest curated statement that the hypoxic exposure carries hepatic signal after adjustment for the adiposity it travels with.

PMID:40884485 SUPPORT Human Clinical

"Similar association was found with nocturnal hypoxia markers (oxygen desaturation index and the time spent under 90% of saturation)."

Biopsy-proven cohort with in-lab polysomnography; establishes that the hypoxia metrics, not merely the OSA label, are what carry the association, which is why this node is named for the hypoxic exposure.

Hypoxia-Driven Hepatic Lipogenesis and Oxidative Stress

Intermittent hypoxia raises hepatic SREBP-1 and its target stearoyl-CoA desaturase 1, increasing triglyceride and phospholipid biosynthesis, and the reoxygenation half of each cycle generates reactive oxygen species so that the hepatocyte experiences a repeated ischemia-reperfusion-like insult. The lipogenic limb is HIF-1-dependent in mice; the oxidative limb is the one measured directly in human liver, as in-situ 4-hydroxynonenal staining and urinary F2-isoprostanes that scale with the nocturnal hypoxia metrics. The node therefore feeds both the lipid-overload state and the injury state of the canonical backbone rather than substituting for either.

Obstructive sleep apnea-associated chronic intermittent hypoxia as a progression driver

hepatocyte CL:0000182

cellular response to hypoxia GO:0071456 ↑ INCREASED triglyceride biosynthetic process GO:0019432 ↑ INCREASED response to oxidative stress GO:0006979 ↑ INCREASED

Downstream

Hepatocyte Lipid Overload SREBP-1/SCD-1 upregulation adds a hypoxia-driven de novo lipogenesis inflow on top of the adipose-derived and dietary inflows of the canonical model. As on the fibrosis edge, the human results are curated in disagreement rather than chosen between, but the disagreement runs the opposite way here: the largest individual-participant dataset finds apnea severity an independent risk factor for steatosis after adjustment, while the small biopsy-scored cohort finds no association with histological steatosis. The two measure steatosis differently (a noninvasive hepatic steatosis index in 2120 patients versus liver histology in 97), which is the most likely source of the discrepancy and is itself unresolved.

Hepatocyte Injury and Inflammatory Activation Cyclical reoxygenation generates hepatic lipid peroxidation, which is associated with lobular inflammation and steatohepatitis severity. The association is with the oxidative readout rather than with the OSA diagnosis: the biopsy-scored cohort that graded steatohepatitis directly found no association between moderate to severe apnea and NASH, so this edge rests on the measured peroxidation rather than on the exposure label.

Hepatic Stellate Cell Activation and Fibrosis Whether the hypoxic exposure drives fibrosis independently of adiposity is contested: biopsy-based cohorts report an association surviving adjustment for obesity, while individual-participant meta-analysis assigns it to body mass index. The edge is curated with both results attached rather than chosen between.

Show evidence (2 references)

PMID:27501738 SUPPORT Human Clinical

"These data support the role of nocturnal hypoxia as a trigger for localized hepatic oxidative stress, an important factor associated with the progression of NASH and hepatic fibrosis in obese pediatric patients."

The human measurement behind the oxidative limb — urinary F2-isoprostanes and hepatic 4-hydroxynonenal immunostaining in biopsy-proven NAFLD, both correlating with the polysomnographic hypoxia metrics. Paediatric, so the age generalization is not asserted.

PMID:16123334 SUPPORT Model Organism

"In lean mice, exposure to IH increased fasting serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, phospholipids (PLs), and triglycerides (TGs), as well as liver TG content."

Supplies the lipogenic limb, including the liver triglyceride readout, in an exposure-controlled model.

✶

Histopathology

Macrovesicular Steatosis

Large-droplet triglyceride accumulation displacing the hepatocyte nucleus, the defining lesion of the disease and the entry criterion for any steatotic liver disease diagnosis. Graded 0-3 as the first component of the NAFLD activity score.

Show evidence (2 references)

PMID:28585211 SUPPORT Other

"NAFLD is characterized by excess accumulation of triglyceride in the hepatocyte due to both increased inflow of free fatty acids and de novo hepatic lipogenesis."

Identifies intrahepatocellular triglyceride accumulation as the defining histologic lesion.

PMID:38324483 SUPPORT Human Clinical

"the components of this measure are steatosis (assessed on a scale of 0 to 3), lobular inflammation (assessed on a scale of 0 to 3), and hepatocellular ballooning (assessed on a scale of 0 to 2)."

Steatosis is the first of the three graded histologic components of the NAFLD activity score used in the registrational trial.

Lobular Inflammation

Mixed inflammatory cell infiltration of the hepatic lobule, the inflammatory component that distinguishes steatohepatitis (MASH) from bland steatosis (MASL). Graded 0-3 within the NAFLD activity score.

Show evidence (1 reference)

PMID:38324483 SUPPORT Human Clinical

"the components of this measure are steatosis (assessed on a scale of 0 to 3), lobular inflammation (assessed on a scale of 0 to 3), and hepatocellular ballooning (assessed on a scale of 0 to 2)."

Establishes lobular inflammation as a separately graded histologic component of the activity score.

Hepatocellular Ballooning

Swollen hepatocytes with rarefied, wispy cytoplasm and loss of the normal polygonal outline - the morphologic signature of lipotoxic hepatocyte injury and the feature whose disappearance defines histologic MASH resolution in trials. Graded 0-2 within the NAFLD activity score. No NCIT morphologic-finding term exists for this lesion (NCIT:C181484 codes the grading assessment, not the finding), so this descriptor is deliberately left unbound.

Show evidence (2 references)

PMID:38324483 SUPPORT Human Clinical

"the components of this measure are steatosis (assessed on a scale of 0 to 3), lobular inflammation (assessed on a scale of 0 to 3), and hepatocellular ballooning (assessed on a scale of 0 to 2)."

Establishes ballooning as the third separately graded histologic component of the activity score.

PMID:38324483 SUPPORT Human Clinical

"NAFLD activity scores of 4 or more are considered to indicate at-risk nonalcoholic steatohepatitis (NASH)."

Ties the composite activity score, of which ballooning is a required component, to the at-risk steatohepatitis designation.

Perisinusoidal Fibrosis Progressing to Bridging Fibrosis and Cirrhosis

Collagen deposition beginning in the perisinusoidal space of zone 3 and progressing through periportal and bridging fibrosis to cirrhosis. Staged F0-F4; this is the histologic feature that determines outcome, and unlike the activity components it is not captured by the NAFLD activity score.

Show evidence (2 references)

PMID:38324483 SUPPORT Human Clinical

"Fibrosis stages range from F0 (no fibrosis) to F4 (cirrhosis). A stage of F1B indicates moderate fibrosis, pericentral area only."

Defines the fibrosis staging scale, including the pericentral (perisinusoidal, zone 3) pattern characteristic of early MASH.

PMID:25935633 SUPPORT Human Clinical

"Patients with fibrosis, regardless of steatohepatitis or NAFLD activity score, had shorter survival times than patients without fibrosis."

Establishes fibrosis - not the activity components - as the outcome-determining histologic feature.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Digestive 4

Hepatic steatosis HP:0001397

Show evidence (1 reference)

PMID:15864352 SUPPORT Human Clinical

"Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess liver triacylglycerol (TAG), inflammation, and liver damage."

Identifies hepatic triacylglycerol accumulation as the characteristic lesion.

Hepatic fibrosis HP:0001395

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:25935633 SUPPORT Human Clinical

"stage 2 (HR, 2.89; 95% CI, 1.93-4.33), stage 3 (HR, 3.76; 95% CI, 2.40-5.89), and stage 4 (HR, 10.9; 95% CI, 6.06-19.62) compared with stage 0"

Documents fibrosis across histologic stages in a MASLD cohort together with its prognostic gradient.

Cirrhosis HP:0001394

Show evidence (1 reference)

PMID:25935633 SUPPORT Human Clinical

"Twenty-six patients (4.2%) developed liver-related events; fibrosis stage 3 (HR, 14.2; 95% CI, 3.38-59.68) and stage 4 (HR, 51.5; 95% CI, 9.87-269.2) compared with stage 0, were associated significantly with the events."

Stage 4 fibrosis is cirrhosis; in a 619-patient longitudinal MASLD cohort it carried by far the highest hazard of liver-related events, establishing cirrhosis as a human clinical endpoint of the disease.

Hepatocellular carcinoma HP:0001402

Show evidence (1 reference)

PMID:33989548 SUPPORT Other

"Its more advanced subtype, nonalcoholic steatohepatitis (NASH), connotes progressive liver injury that can lead to cirrhosis and hepatocellular carcinoma."

The review identifies hepatocellular carcinoma as a distal outcome of progressive steatohepatitis.

Metabolism 2

Elevated serum alanine aminotransferase Elevated circulating alanine aminotransferase concentration HP:0031964

Show evidence (1 reference)

PMID:24531328 SUPPORT Human Clinical

"higher circulating levels of alanine transaminase, a marker of liver injury"

Links raised circulating alanine transaminase to liver injury in fatty liver disease cohorts.

Insulin resistance HP:0000855

Show evidence (1 reference)

PMID:42412329 SUPPORT Other

"with pathogenesis closely linked to insulin resistance, obesity, and gut microbiota dysbiosis"

Places insulin resistance among the core metabolic features of MASLD.

Growth 1

Obesity HP:0001513

Show evidence (1 reference)

PMID:32553765 SUPPORT Human Clinical

"We performed a prospective study of 180 severely obese patients with biopsy-proven NASH"

A biopsy-proven steatohepatitis cohort recruited on the basis of severe obesity documents the association.

🧬

Genetic Associations

PNPLA3 rs738409 susceptibility (The rs738409 (I148M) allele increases hepatic fat content and hepatic inflammation and accounts for a large fraction of ancestry-related variation in fatty liver susceptibility. It is neither necessary nor sufficient for MASLD.)

Gene: PNPLA3 hgnc:18590 gene page relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (1 reference)

PMID:18820647 SUPPORT Human Clinical

"The allele was most common in Hispanics, the group most susceptible to NAFLD"

Documents the ancestry-patterned allele frequency underlying differential susceptibility, consistent with a modifier rather than a monogenic cause.

TM6SF2 p.Glu167Lys susceptibility (The p.Glu167Lys (rs58542926) variant reduces TM6SF2 protein and hepatic very-low-density lipoprotein export, raising liver fat and alanine transaminase while lowering plasma LDL cholesterol and triglycerides.)

Gene: TM6SF2 hgnc:11861 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (1 reference)

PMID:24531328 SUPPORT Human Clinical

"Three variants were associated with higher liver fat levels at the exome-wide significance level of 3.6 × 10(-7): two in PNPLA3, an established locus for NAFLD, and one (encoding p.Glu167Lys) in TM6SF2, a gene of unknown function."

The exome-wide association study identifies the variant at exome-wide significance for liver fat content.

GCKR common-variant susceptibility (GCKR variation is a replicated common-variant susceptibility locus for MASLD.)

Gene: GCKR hgnc:4196 gene page relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (1 reference)

PMID:32145256 SUPPORT Other

"reproducible associations between variations in genes such as PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13"

The genetics review lists GCKR among reproducibly associated NAFLD/MASLD loci.

MBOAT7 common-variant susceptibility (MBOAT7 variation is a replicated common-variant susceptibility locus for MASLD.)

Gene: MBOAT7 hgnc:15505 gene page relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (1 reference)

PMID:32145256 SUPPORT Other

"reproducible associations between variations in genes such as PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13"

The genetics review lists MBOAT7 among reproducibly associated NAFLD/MASLD loci.

HSD17B13 rs72613567 protective variant (The protein-truncating rs72613567:TA variant reduces progression from steatosis to steatohepatitis without preventing steatosis itself.)

Gene: HSD17B13 hgnc:18685 relationship_type: PROTECTIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:29562163 SUPPORT Human Clinical

"The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis"

The human association separates protection from steatohepatitis progression from susceptibility to steatosis.

Variants (1)

rs72613567:TA

Protein-truncating splice variant associated with reduced steatohepatitis risk.

💊

Medical Actions

Weight loss through lifestyle modification

Category: Therapeutic Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Hypocaloric diet and increased physical activity, targeting sustained weight loss. The histologic benefit is dose-dependent: 7-10% loss improves steatohepatitis and 10% or more is associated with the highest rates of MASH resolution and fibrosis regression. This remains the foundational intervention for all disease stages.

Mechanism Target:

INHIBITS Hepatocyte Lipid Overload — Negative energy balance reduces adipose lipolytic flux and de novo lipogenesis, lowering hepatocyte lipid loading.

Show evidence (1 reference)

PMID:25865049 SUPPORT Human Clinical

"Degree of weight loss was independently associated with improvements in all NASH-related histologic parameters"

Shows a dose-response between weight loss and improvement of the histologic features driven by hepatic lipid loading.

Show evidence (1 reference)

PMID:25865049 SUPPORT Human Clinical

"A greater extent of weight loss, induced by lifestyle changes, is associated with the level of improvement in histologic features of NASH."

The trial conclusion establishing the dose-dependent histologic benefit of lifestyle-induced weight loss.

Resmetirom

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: resmetirom NCIT:C170368

Platform: Small molecule

An oral, liver-directed, thyroid hormone receptor beta-selective agonist that increases hepatic fatty acid oxidation. In the MAESTRO-NASH phase 3 trial it was superior to placebo for both MASH resolution and fibrosis improvement in patients with F1B-F3 fibrosis, and it is the first agent approved specifically for this indication.

Mechanism Target:

INHIBITS Hepatocyte Lipid Overload — Hepatic thyroid hormone receptor beta agonism increases fatty acid oxidation and lowers hepatic lipid content.

Show evidence (1 reference)

PMID:38324483 SUPPORT Human Clinical

"Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist in development for the treatment of NASH with liver fibrosis."

Identifies the liver-directed receptor target through which the drug acts on hepatic lipid handling.

Show evidence (1 reference)

PMID:38324483 SUPPORT Human Clinical

"Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage."

The phase 3 primary-endpoint result supporting the indication in MASH with fibrosis.

Semaglutide

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: semaglutide NCIT:C152328

Platform: Peptide

A glucagon-like peptide-1 receptor agonist that produces substantial weight loss and improves glycaemia. A 72-week phase 2 trial increased MASH resolution relative to placebo but found no significant fibrosis-stage benefit; that null result has since been superseded by the phase 3 ESSENCE trial, whose week-72 interim analysis in 800 patients with MASH and F2-F3 fibrosis met both primary endpoints, including reduction in liver fibrosis. Its modeled effect therefore runs through both the upstream cardiometabolic driver and the fibrogenic arm.

Mechanism Target:

INHIBITS Cardiometabolic Dysfunction and Adipose Insulin Resistance — Weight loss and improved insulin sensitivity reduce the adipose lipolytic and lipogenic drive that initiates the pathograph.

Show evidence (2 references)

PMID:33185364 SUPPORT Human Clinical

"The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group."

Documents the weight-loss magnitude that underlies the effect on the cardiometabolic trigger node.

PMID:39266553 SUPPORT INDIRECT In Vitro

"These findings show that semaglutide prevents lipid accumulation and insulin resistance in hepatocytes by reducing WAT inflammation."

Localizes the drug's action to the adipose compartment specifically, which is why the modeled effect is placed on this cardiometabolic node rather than on a hepatocyte node. In an isogenic human iPSC adipose-liver chip, semaglutide delivered only to the adipocyte compartment reproduced the whole-system benefit while delivery only to the hepatocyte compartment did not. Graded INDIRECT because the mechanism is established in a non-animal human model system, not in the patients whose histologic benefit the trial evidence above records.

INHIBITS Hepatic Stellate Cell Activation and Fibrosis — The phase 3 ESSENCE interim analysis showed a significant reduction in fibrosis stage without worsening of steatohepatitis, so the fibrogenic arm improves under treatment. Whether the drug acts directly on that arm is a separate question this edge deliberately leaves open: the reduction is equally consistent with fibrosis regressing once the lipotoxic and inflammatory drive upstream is removed. Two observations favour the downstream reading. In the phase 2 trial a 13% weight loss and a large resolution effect bought no significant fibrosis benefit at 72 weeks, and in MASH-related cirrhosis — where fibrosis is established and no longer coupled to steatohepatitis activity — fibrosis improvement was numerically lower on semaglutide than on placebo. Human stellate cells also carry no demonstrated GLP-1 receptor and do not respond to receptor agonism in culture, so a direct action on this node has no established substrate. See the semaglutide_weight_independent_hepatic_effect hypothesis.

Show evidence (2 references)

PMID:36934740 REFUTE Human Clinical

"five [11%] of 47 patients in the semaglutide group vs seven [29%] of 24 in the placebo group; odds ratio 0·28 [95% CI 0·06-1·24; p=0·087)"

Bounds this edge rather than removing it. In established cirrhosis a direct antifibrotic action should still be visible, and fibrosis improvement was numerically lower on semaglutide. Not significant, and in a later disease stage than the F2-F3 population the edge is drawn for, so it argues against reading the edge as a direct action without refuting the fibrosis benefit itself.

PMID:40305708 SUPPORT Human Clinical

"A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of the patients in the semaglutide group and in 22.4% of those in the placebo group"

Quantifies the fibrosis-stage benefit that justifies modeling an effect on the fibrogenic node.

Show evidence (4 references)

PMID:40305708 SUPPORT Human Clinical

"Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group"

The phase 3 primary endpoint for steatohepatitis resolution, superseding the phase 2 estimate.

PMID:40305708 SUPPORT Human Clinical

"In patients with MASH and moderate or advanced liver fibrosis, once-weekly semaglutide at a dose of 2.4 mg improved liver histologic results."

The trial's own conclusion, covering both histologic endpoints in F2-F3 disease.

PMID:33185364 SUPPORT Human Clinical

"This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo."

The earlier phase 2 trial that first established the steatohepatitis resolution benefit later confirmed in phase 3.

+ 1 more reference

Vitamin E

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: vitamin E CHEBI:33234

Platform: Small molecule

High-dose alpha-tocopherol improved steatohepatitis histology relative to placebo in the PIVENS trial in adults with MASH without diabetes, but did not improve fibrosis scores. Its modeled action is on the oxidative-stress amplifier node.

Mechanism Target:

INHIBITS Lipotoxic Stress and Organelle Dysfunction — Antioxidant activity is proposed to blunt the reactive-oxygen-species arm of lipotoxic organelle stress.

Show evidence (1 reference)

PMID:20427778 SUPPORT Human Clinical

"both agents were associated with reductions in hepatic steatosis (P=0.005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P=0.02 for vitamin E and P=0.004 for pioglitazone) but not with improvement in fibrosis scores"

Supports an effect on steatosis and inflammation while explicitly excluding a fibrosis benefit.

Show evidence (1 reference)

PMID:20427778 SUPPORT Human Clinical

"Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes."

The trial conclusion, including its restriction to adults without diabetes.

Pioglitazone

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: pioglitazone CHEBI:8228

Platform: Small molecule

A PPAR-gamma agonist insulin sensitizer. In PIVENS it reduced steatosis, inflammation, and aminotransferases but did not meet the primary histologic endpoint in adults without diabetes, and caused weight gain. Modeled as acting on the cardiometabolic trigger.

Mechanism Target:

INHIBITS Cardiometabolic Dysfunction and Adipose Insulin Resistance — Insulin sensitization restrains adipose lipolysis and reduces fatty acid delivery to the liver.

Show evidence (1 reference)

PMID:20427778 SUPPORT Human Clinical

"Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P<0.001 for both comparisons)"

Documents a biochemical treatment effect for the insulin sensitizer without asserting a histologic primary-endpoint benefit.

Show evidence (1 reference)

PMID:20427778 SUPPORT Human Clinical

"the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P=0.04)"

The primary histologic comparison for pioglitazone did not reach the prespecified significance threshold, bounding the claim.

Bariatric surgery

Category: Therapeutic Action: bariatric surgery Ontology label: Bariatric Surgery NCIT:C84399

Platform: Surgery

Metabolic (bariatric) surgery in people with severe obesity and biopsy-proven MASH produced resolution of steatohepatitis in most patients at five years, with progressive fibrosis regression. Evidence is from a prospective cohort with paired biopsies rather than a randomized trial.

Mechanism Target:

INHIBITS Hepatic Stellate Cell Activation and Fibrosis — Sustained large-magnitude weight loss removes the upstream metabolic drive and permits regression of established fibrosis.

Show evidence (1 reference)

PMID:32553765 SUPPORT Human Clinical

"Fibrosis began to decrease by 1 year after surgery and continued to decrease until 5 years"

Documents progressive regression of the fibrotic effector lesion after surgery.

Show evidence (1 reference)

PMID:32553765 SUPPORT Human Clinical

"At 5 years after bariatric surgery, NASH was resolved, without worsening fibrosis, in samples from 84% of patients"

Gives the five-year steatohepatitis-resolution rate from the paired-biopsy cohort.

🔬

Diagnosis

Positive cardiometabolic criteria alongside hepatic steatosis

MASLD is diagnosed positively rather than by exclusion: hepatic steatosis on imaging or histology plus at least one of five cardiometabolic risk factors (overweight/obesity, dysglycaemia or type 2 diabetes, hypertension, hypertriglyceridaemia, low HDL cholesterol). This replaces the old NAFLD definition, which required excluding other causes of steatosis. Steatosis with no cardiometabolic parameter and no identified cause is classified instead as cryptogenic steatotic liver disease.

clinical assessment NCIT:C124351

Results: Hepatic steatosis plus at least one of five cardiometabolic risk factors establishes MASLD; steatosis with no metabolic parameter and no known cause is cryptogenic SLD.

Show evidence (2 references)

PMID:37363821 SUPPORT Other

"There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors."

The multisociety Delphi consensus establishes the cardiometabolic-criteria basis of the current positive case definition.

PMID:37363821 SUPPORT Other

"Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease."

Defines the residual category that the cardiometabolic criteria separate MASLD from.

Alcohol-intake assessment to separate MASLD from MetALD

Weekly alcohol intake must be quantified, because metabolic dysfunction and greater alcohol consumption together define MetALD, a category outside pure MASLD with different management. The consensus thresholds are 140-350 g/week for females and 210-420 g/week for males.

clinical assessment NCIT:C124351

Results: Intake above the sex-specific weekly threshold reclassifies the patient as MetALD rather than MASLD.

Show evidence (1 reference)

PMID:37363821 SUPPORT Other

"termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively)."

Gives the sex-specific weekly alcohol thresholds that bound the MASLD category.

Ultrasound with controlled attenuation parameter for steatosis detection

Ultrasound-based controlled attenuation parameter (CAP), measured on the same device as transient elastography, non-invasively detects and grades hepatic steatosis by the increased attenuation of ultrasound in fat-laden liver. Used in the resmetirom phase 3 trial with a threshold of more than 280 dB/m.

ultrasound imaging NCIT:C17230

Results: A controlled attenuation parameter above roughly 280 dB/m supports significant hepatic steatosis.

Show evidence (1 reference)

PMID:38324483 SUPPORT Human Clinical

"Controlled attenuation parameter is a method for the noninvasive assessment of steatosis"

Establishes CAP as the non-invasive steatosis measure used for trial eligibility.

Vibration-controlled transient elastography for fibrosis risk stratification

Liver stiffness measured by vibration-controlled transient elastography is the principal non-invasive test for identifying clinically significant fibrosis and is the gateway to specialist referral in MASLD care pathways.

elastography NCIT:C106517

Results: Liver stiffness above 8.5 kPa indicates fibrosis stage F2 or higher.

Show evidence (1 reference)

PMID:38324483 SUPPORT Human Clinical

"Liver stiffness was measured by means of vibration-controlled transient elastography. Values of more than 8.5 are considered to be indicative of fibrosis of stage F2 or higher."

Gives the liver-stiffness threshold used to identify clinically significant fibrosis.

MRI proton density fat fraction for liver fat quantification

MRI-PDFF is the quantitative reference standard for non-invasive liver fat measurement and is the standard steatosis endpoint in MASH trials.

magnetic resonance imaging NCIT:C16809

Results: An MRI-PDFF above 5% indicates hepatic steatosis.

Show evidence (1 reference)

PMID:38324483 SUPPORT Human Clinical

"quantitative biomarker to assess liver fat content. A reading of more than 5% is considered to be high."

Gives the MRI-PDFF threshold for high liver fat content.

FIB-4 index for advanced fibrosis triage

The Fibrosis-4 index is a serum-based score derived from platelet count, AST, ALT and age. It is the recommended first-line triage test in primary care because it uses routinely available results and identifies people who need elastography or specialist referral.

clinical assessment NCIT:C124351

Results: A FIB-4 score above 2.67 indicates advanced fibrosis and an elevated risk of liver-related events.

Show evidence (1 reference)

PMID:38324483 SUPPORT Human Clinical

"Scores of more than 2.67 are considered to be indicative of advanced fibrosis and an elevated risk of liver-related events."

Gives the FIB-4 threshold for advanced fibrosis and its prognostic significance.

Liver biopsy for steatohepatitis activity grading and fibrosis staging

Percutaneous liver biopsy remains the only test that separates MASH from bland steatosis and stages fibrosis directly. It grades the three NAFLD activity score components and assigns a fibrosis stage F0-F4, and remains the required endpoint measure in registrational MASH trials despite its sampling variability and procedural risk.

liver biopsy NCIT:C51677

Results: An activity score of 4 or more with at least 1 point for each component indicates at-risk MASH; fibrosis is staged F0-F4.

Show evidence (2 references)

PMID:38324483 SUPPORT Human Clinical

"NAFLD activity scores of 4 or more are considered to indicate at-risk nonalcoholic steatohepatitis (NASH)."

Gives the biopsy-derived activity threshold defining at-risk steatohepatitis.

PMID:38324483 SUPPORT Human Clinical

"Fibrosis stages range from F0 (no fibrosis) to F4 (cirrhosis). A stage of F1B indicates moderate fibrosis, pericentral area only."

Gives the biopsy fibrosis staging scale that determines prognosis and treatment eligibility.

📊

Prevalence

Worldwide, general adult population (imaging-diagnosed NAFLD)

Point Prevalence 32400.0 per 100,000 (29900.0–34900.0) >1 in 1,000

Meta-analysis of 72 publications and 1,030,160 individuals from 17 countries. The estimate predates the MASLD nomenclature change and uses the exclusion-based NAFLD case definition, so it approximates rather than exactly measures MASLD prevalence.

Show evidence (1 reference)

PMID:35798021 SUPPORT Human Clinical

"The overall prevalence of NAFLD worldwide was estimated to be 32·4% (95% CI 29·9-34·9)."

Provides the pooled worldwide adult prevalence estimate with its confidence interval.

Worldwide, general adult population (imaging-diagnosed NAFLD)

Annual Incidence 4690.0 per 100,000 (3640.0–5750.0) >1 in 1,000 per year

46.9 cases per 1000 person-years, converted to 4,690 per 100,000 person-years. Reported separately from prevalence and not comparable to it.

Show evidence (1 reference)

PMID:35798021 SUPPORT Human Clinical

"The overall incidence of NAFLD was estimated to be 46·9 cases per 1000 person-years (36·4-57·5)"

Provides the pooled worldwide incidence estimate used for the normalized rate.

🧫

Experimental Models

Isogenic iPSC adipocyte-hepatocyte-macrophage microphysiological system (M1-iADIPO-iHEP-MPS) ORGAN_ON_CHIP namo:OrganOnChip

A fluidically interconnected multi-tissue New Approach Methodology for the adipose tissue-liver axis, built entirely from one human induced pluripotent stem cell line so that adipocytes, hepatocytes and macrophages are isogenic and donor genotype is not a confounder. White adipocyte and hepatocyte chambers are linked by circulating media at 20 microlitres per hour; proinflammatory (M1) macrophages are added to the adipocyte chamber to impose white adipose tissue inflammation. Because adipose expansion (set by the adipocyte-to-hepatocyte ratio) and adipose inflammation (set by macrophage polarization) are controlled independently, the system can do what whole-animal models cannot: ask which of the two drives hepatic steatosis and hepatic insulin resistance. In this system inflammation, not expansion, is the driver, and the GLP-1 receptor agonist semaglutide improves hepatocyte lipid content and insulin response by acting on the adipocyte compartment rather than on the hepatocyte.

Organism

human NCBITaxon:9606

Tissue

liver UBERON:0002107

Cell source

Isogenic human induced pluripotent stem cell-derived white adipocytes, hepatocytes and macrophages from a single donor line

Culture

Interconnected two-chamber microphysiological system with circulating media at 20 microlitres per hour, and a non-circulating flow-through configuration for compartment-selective drug exposure

Publication

PMID:39266553

Pathograph links

Cardiometabolic Dysfunction and Adipose Insulin Resistance recapitulates fidelity: moderate Reconstructs the initiating cardiometabolic state of the pathograph in human cells — inflamed, insulin-resistant white adipose tissue releasing fatty acids and TNF-alpha into a circulation shared with the liver — and separates adipose inflammation from adipose expansion as candidate causes, which the trigger node's description leaves bundled.

Limitations: The system carries no vasculature, no immune trafficking beyond the added macrophages, no gut and no central control of feeding, so it models the adipose-to-liver limb of a state that is whole-body in patients. Insulin resistance is imposed over days by macrophage polarization rather than arising from years of overnutrition, and the iPSC-derived cells retain a fetal-like maturation state.

Readouts

Insulin-stimulated glucose uptake in the adipocyte compartment

cellular response to insulin stimulus GO:0032869

Direction: DECREASED

Interpretation: Loss of insulin-stimulated glucose uptake is the functional definition of adipose insulin resistance and is what the trigger node asserts.

Show evidence (1 reference)

PMID:39266553 SUPPORT In Vitro

"nor disrupted insulin-mediated regulation of glucose uptake in the iADIPO-MPS or HGP in the iHEP-MPS, similar to control conditions without iMACs"

The M0 control arm establishes that the loss of insulin-regulated glucose uptake requires proinflammatory polarization specifically, rather than the presence of macrophages.

Insulin suppression of hepatic glucose production

gluconeogenesis GO:0006094

Direction: DECREASED

Interpretation: Failure of insulin to suppress hepatic glucose production is the hepatic limb of the same insulin-resistant state, read out across the fluidic link rather than in the tissue that was manipulated.

Show evidence (1 reference)

PMID:39266553 SUPPORT In Vitro

"Analysis of insulin regulation of HGP after 48 h of iADIPO-iHEP-MPS interconnection showed insulin resistance only at the highest iADIPO-iHEP ratio of 30:1"

Records the expansion arm as the weaker of the two: mass alone produced hepatic insulin resistance only at an extreme ratio, which is the comparison that makes inflammation the primary driver.

Show evidence (1 reference)

PMID:39266553 SUPPORT In Vitro

"we establish an interconnected microphysiological system (MPS) containing white adipocytes, hepatocytes and proinflammatory macrophages derived from isogenic human induced pluripotent stem cells."

Establishes that the model contains the adipose, hepatic and inflammatory compartments this trigger node describes, in human cells of a single genotype.

Hepatocyte Lipid Overload recapitulates fidelity: moderate Hepatocyte lipid accumulation arises in the chip as a consequence of inflammation in the connected adipose compartment, not from direct fatty acid loading of the hepatocytes, so the model reproduces the causal route into this node rather than only its end state.

Limitations: The readout is intracellular fluorescent fatty acid and lipid content over days, not histologic macrovesicular steatosis; the chip has no stellate cells or Kupffer cells, so nothing downstream of this node — inflammation resolution, ballooning, fibrosis — can be assessed in it.

Readouts

Hepatocyte fatty acid uptake and lipid accumulation under adipose inflammation

lipid storage GO:0019915

Direction: INCREASED

Interpretation: The defining measurement of this node, produced in human cells by a purely upstream adipose manipulation.

Show evidence (1 reference)

PMID:39266553 SUPPORT In Vitro

"Consequently, the iHEP-MPS showed increased fatty acid uptake and lipid accumulation under inflamed iADIPO-MPS conditions"

Reports both the uptake and the accumulation limbs of the hepatocyte response to adipose inflammation.

Show evidence (1 reference)

PMID:39266553 SUPPORT In Vitro

"macrophage-induced adipocyte inflammation causes lipid accumulation in hepatocytes and MPS-wide insulin resistance, corresponding to initiation of metabolic dysfunction-associated steatotic liver disease."

The authors' own mapping of the chip's end state onto MASLD initiation, which is what licenses linking it to this node.

Transporter-Mediated Hepatic Fatty Acid Uptake measures fidelity: unknown Fatty acid entry into hepatocytes is measured directly in the chip as accumulation of fluorescent fatty acids, and rises when the connected adipose compartment is inflamed. This is a human read on the uptake step whose causal evidence is otherwise entirely murine.

Limitations: The measurement is of net fatty acid entry, not of transporter activity: no FATP5 or FATP2 knockdown, inhibition or expression measurement is reported in this system, so the model quantifies the flux this node carries without attributing it to the transporters the node names. Fluorescent fatty acid analogues are also a proxy for physiological long-chain fatty acids.

Readouts

Fluorescent fatty acid accumulation in the hepatocyte compartment

long-chain fatty acid import into hepatocytes GO:0044539

Direction: INCREASED

Interpretation: Establishes that hepatic fatty acid uptake is a measurable, modifiable variable in a human system, which is the precondition for testing the rodent-derived uptake hypothesis in human cells.

Show evidence (1 reference)

PMID:39266553 SUPPORT In Vitro

"Consequently, the iHEP-MPS showed increased fatty acid uptake and lipid accumulation under inflamed iADIPO-MPS conditions"

The uptake limb of the same measurement, cited here for the transport step rather than for the resulting lipid pool.

Show evidence (1 reference)

PMID:39266553 SUPPORT In Vitro

"To reliably quantify lipid accumulation in iHEPs, we first analyzed absorption of fluorescent fatty acids by the PDMS used to build the iHEP-MPS and iADIPO-MPS, which showed no bias for up to 4 days"

Documents the device-absorption control that makes the fatty acid uptake measurement in this chip interpretable, which is why the model is curated as measuring rather than recapitulating this node.

Notes

The compartment-selective result is the part hardest to obtain any other way: using a non-circulating flow-through configuration, semaglutide applied only to the adipocyte compartment reproduced the whole-system benefit, while semaglutide applied only to the hepatocyte compartment did not. The authors note that the same question is confounded in mice by semaglutide's effects on feeding and body weight and by GLP-1 receptor expression across several cell types. This is curated as evidence on the Semaglutide treatment's adipose target_mechanisms edge rather than as a separate mechanism node.

Isogenic iPSC macrophage-adipocyte microphysiological system (iMAC-iADIPO-MPS) ORGAN_ON_CHIP namo:OrganOnChip

The adipose half of the platform, used on its own to model chronic white adipose tissue inflammation. iPSC-derived macrophages migrate into three-dimensional adipocyte clusters and form crown-like structures around damaged adipocytes, reproducing the defining histology of obese human adipose tissue; the number of such structures rises with adipocyte age and with palmitic acid exposure, so inflammatory severity is gradable. Polarization is the operative variable: M1 but not M2 macrophages induce adipocyte insulin resistance and dysregulated lipolysis, and transcriptomics and cytokine profiling identify a reciprocal proinflammatory loop between the two cell types.

Organism

human NCBITaxon:9606

Tissue

white adipose tissue UBERON:0001347

Cell source

Isogenic human induced pluripotent stem cell-derived macrophages and adipocytes

Culture

Microphysiological system supporting three-dimensional adipocyte clusters with macrophage infiltration

Publication

PMID:37104853

Pathograph links

Cardiometabolic Dysfunction and Adipose Insulin Resistance recapitulates fidelity: moderate Reproduces the adipose limb of the trigger node in human cells, including the crown-like structures that are its histologic signature, and shows that macrophage polarization state rather than macrophage presence produces adipocyte insulin resistance and dysregulated lipolysis.

Limitations: Adipose tissue only: there is no liver in this configuration, so the effect on the hepatic nodes is inferred rather than measured, and the interconnected system (PMID:39266553) is the model that closes that gap. Inflammation is imposed by adding pre-polarized macrophages rather than arising from resident immune recruitment.

Readouts

Crown-like structure formation around damaged adipocytes

Direction: INCREASED

Interpretation: The histologic hallmark of inflamed human adipose tissue, reproduced in a non-animal system and gradable with exposure severity.

Show evidence (1 reference)

PMID:37104853 SUPPORT In Vitro

"iMACs migrate toward and infiltrate into the 3D iADIPOs cluster to form crown-like structures (CLSs)-like morphology around damaged iADIPOs, recreating classic histological features of WAT inflammation seen in obesity."

States the structural correspondence between the model and obese human adipose tissue.

Dysregulated adipocyte lipolysis under proinflammatory macrophage co-culture

triglyceride catabolic process GO:0019433

Direction: INCREASED

Interpretation: Dysregulated lipolysis is the step that supplies fatty acids to the liver in this node, and the M1-versus-M2 contrast is the internal control showing it is inflammation-specific.

Show evidence (1 reference)

PMID:37104853 SUPPORT In Vitro

"M1 (proinflammatory) but not M2 (tissue repair) iMACs induced insulin resistance and dysregulated lipolysis in iADIPOs."

The polarization-controlled comparison that grounds this readout.

Show evidence (1 reference)

PMID:37104853 SUPPORT In Vitro

"This iMAC-iADIPO-MPS thus successfully recreates pathological conditions of chronically inflamed human WAT"

The authors' summary claim about what the model reproduces, which is the adipose content of this trigger node.

Metabolically competent iPSC white adipose tissue microphysiological system (iADIPO-MPS) ORGAN_ON_CHIP namo:OrganOnChip

The platform-qualification model underlying the two systems above, and the reason they can be read as models of insulin resistance at all. Standard adipose differentiation protocols were found to yield already insulin-resistant tissue, which cannot report a further loss of insulin sensitivity; new differentiation conditions plus chip optimization produced hormonally responsive adipose tissue with larger, more unilocular lipid droplets and a dynamic range wide enough to detect insulin sensitizers and desensitizers in both directions. Three independent insulin-sensitivity assays are used: glucose uptake, fatty acid uptake, and suppression of stimulated lipolysis.

Organism

human NCBITaxon:9606

Tissue

white adipose tissue UBERON:0001347

Cell source

Human pluripotent stem cell-derived white adipocytes

Culture

Three-dimensional adipose tissue in a microphysiological system, benchmarked against two-dimensional culture

Publication

PMID:34761526

Pathograph links

Cardiometabolic Dysfunction and Adipose Insulin Resistance measures fidelity: moderate Provides the calibrated human assay for the adipose insulin-sensitivity variable this node turns on, with a dynamic range the authors report as competent against in vivo and ex vivo comparators.

Limitations: A healthy-tissue platform rather than a disease model: no inflammatory, lipotoxic or hepatic component, so it bounds what the derived MASLD models can measure without itself modeling MASLD. It also documents a defect in prior protocols rather than in patients.

Readouts

Insulin-stimulated glucose uptake, fatty acid uptake and lipolysis suppression

cellular response to insulin stimulus GO:0032869

Direction: INCREASED

Interpretation: Direction is relative to conventional two-dimensional culture, not to a disease state: the readouts record restored insulin responsiveness in the chip, which is what makes a subsequent loss of that responsiveness interpretable.

Show evidence (1 reference)

PMID:34761526 SUPPORT In Vitro

"Using three independent insulin sensitivity assays, i.e., glucose and fatty acid uptake and suppression of lipolysis, as the functional readouts new differentiation conditions yielding hormonally responsive iADIPO are derived."

Names the three functional readouts and the fact that they are what the differentiation conditions were selected against.

Show evidence (1 reference)

PMID:34761526 SUPPORT In Vitro

"Surprisingly, previously reported WAT differentiation approaches create insulin resistant WAT ill-suited for type-2 diabetes mellitus drug discovery."

The negative platform result that makes this model informative for the node: an adipose model must be shown insulin-sensitive at baseline before a loss of insulin sensitivity can be attributed to a disease manipulation.

Heterochronic-serum iPSC white adipose tissue-liver aging microphysiological system ORGAN_ON_CHIP namo:OrganOnChip

The same adipose-liver axis chip run as an aging model, perfused with heterochronic human serum. Over four days it reproduces hallmarks that take decades in people, including gerontic shifts in gene expression and oxidative DNA damage, and it reports knock-on effects of aging in the fat compartment on the liver compartment, sexual dimorphism of aging, and tissue memory of donor age. It is curated here for the adipose-to-liver limb rather than for MASLD endpoints, which it does not report.

Organism

human NCBITaxon:9606

Tissue

liver UBERON:0002107

Cell source

Human induced pluripotent stem cell-derived adipocytes and hepatocytes perfused with young or aged human serum

Culture

Interconnected adipose tissue-liver microphysiological chip under heterochronic serum perfusion

Publication

PMID:41882175

Pathograph links

Cardiometabolic Dysfunction and Adipose Insulin Resistance measures fidelity: unknown Reads out how the state of the adipose compartment propagates to the liver compartment under an aging stimulus, on the same axis this trigger node describes. Curated as measuring, not recapitulating, because the manipulated variable is serum age rather than cardiometabolic dysfunction.

Limitations: No steatosis, insulin-resistance or histologic endpoint for MASLD is reported, so this model supports the existence and directionality of the fat-to-liver limb rather than any MASLD-specific claim. Fidelity is left UNKNOWN deliberately: the correspondence between four days of heterochronic serum and decades of human aging is the model's own open question. A curator should not promote this link without a MASLD-relevant readout.

Readouts

Aging hallmarks in the adipose-liver chip under heterochronic serum

Direction: ALTERED

Interpretation: Establishes that the chip registers a systemic humoral input as coordinated change across both tissues, which is the property that would let it carry a cardiometabolic exposure in future work.

Show evidence (1 reference)

PMID:41882175 SUPPORT In Vitro

"The microphysiological chip recapitulates, in 4 days, aging-associated hallmarks that occur after decades of aging in people, including gerontic shifts in gene expression and oxidative DNA damage."

States what the model reproduces and on what timescale, which is the basis for the readout and for the fidelity caveat recorded on this link.

Show evidence (1 reference)

PMID:41882175 SUPPORT In Vitro

"We uncover unknown signalling networks in human aging, knock-on effects of aging in fat on liver, sexual polymorphisms of aging and tissue memory of age"

The fat-to-liver propagation claim, which is the only reason this aging model is linked to a MASLD node at all.

🐁

Animal Models

AAV8-shRNA hepatic FATP5 knockdown mouse on high-fat diet

A therapeutic-direction rather than an etiologic model: a single adeno-associated virus injection delivers shRNA that persistently silences FATP5 in mouse liver, applied either before or after diet-induced fatty liver is established. Its value is that it tests reversal of existing disease, which a germline knockout cannot do, and it does so while high-fat feeding continues.

Species

Mouse

Genotype

Wild-type C57BL/6 with adeno-associated virus-delivered shRNA silencing hepatic Slc27a5 (FATP5)

Background

Diet-induced obesity, high-fat feeding

Genes

SLC27A5 hgnc:10999

Publication

PMID:18524776

Pathograph links

Transporter-Mediated Hepatic Fatty Acid Uptake perturbs fidelity: moderate Directly and specifically removes the transport step this node represents, in the intact liver, and reads out the resulting change in hepatic fatty acid entry.

Limitations: Knockdown reduced whole-animal caloric uptake as well as hepatic fatty acid uptake, so the two cannot be fully separated in this design. Mouse FATP5 biology is also assumed rather than shown to match human SLC27A5, and no human FATP5-directed agent exists against which to calibrate the model.

Readouts

Hepatic dietary fatty acid uptake

long-chain fatty acid import into hepatocytes GO:0044539

Direction: DECREASED

Interpretation: Confirms the intended on-target effect: the perturbation reaches the transport step rather than acting elsewhere in hepatic lipid metabolism.

Show evidence (1 reference)

PMID:18524776 SUPPORT Model Organism

"resulting in a marked reduction of hepatic dietary fatty acid uptake, reduced caloric uptake, and concomitant protection from diet-induced non-alcoholic fatty liver disease."

Reports the measured fall in hepatic dietary fatty acid uptake, and in the same sentence the caloric-uptake confound recorded in this link's limitations.

Show evidence (1 reference)

PMID:18524776 SUPPORT Model Organism

"continued activity of hepatic fatty acid transport protein 5 is required to sustain caloric uptake and fatty acid flux into the liver during high fat feeding"

States that the transport step is required to sustain hepatic fatty acid flux, which is what makes this model informative for the uptake node.

Hepatocyte Lipid Overload rescues fidelity: moderate Silencing the transporter after fatty liver is already established reverses it, placing the uptake step causally upstream of the hepatic lipid pool rather than merely correlated with it.

Limitations: Reversal was measured in diet-induced murine fatty liver, which models steatosis and metabolic dysfunction but not the fibrotic progression that determines human outcome. The concurrent fall in caloric uptake means the rescue is not attributable to the hepatic step alone.

Readouts

Established diet-induced fatty liver after knockdown

lipid storage GO:0019915

Direction: RESTORED

Interpretation: Reversal of an already-established lesion, which is the stronger of the two possible results and the one that motivates treating hepatic uptake as a therapeutic target.

Show evidence (1 reference)

PMID:18524776 SUPPORT Model Organism

"knockdown of fatty acid transport protein 5 was also able to reverse already established non-alcoholic fatty liver disease, resulting in significantly improved whole-body glucose homeostasis."

The reversal-of-established-disease result this link asserts, together with the glycaemic improvement that accompanied it.

Show evidence (1 reference)

PMID:18524776 SUPPORT Model Organism

"knockdown of fatty acid transport protein 5 was also able to reverse already established non-alcoholic fatty liver disease, resulting in significantly improved whole-body glucose homeostasis."

Supports treating this intervention model as informative for the hepatic lipid-overload node.

FATP5 (Slc27a5) knockout mouse

Germline deletion of the liver-exclusive fatty acid transport protein. Isolated hepatocytes show reduced long-chain fatty acid uptake and the liver holds less triglyceride and free fatty acid, with lipid redistributed to other fatty-acid-metabolizing tissues. This is the loss-of-function evidence that hepatocellular fatty acid entry is protein-mediated; it is a protection model, not a model of MASLD itself.

Species

Mouse

Genotype

Slc27a5 (FATP5) targeted deletion, homozygous null

Background

C57BL/6

Genes

SLC27A5 hgnc:10999

Publication

PMID:16618416

Pathograph links

Transporter-Mediated Hepatic Fatty Acid Uptake perturbs fidelity: moderate Removes the transporter genetically and shows the predicted loss of long-chain fatty acid uptake in hepatocytes isolated from the null animals.

Limitations: A germline null cannot separate developmental adaptation from the acute requirement for transport, and FATP5 also carries bile acid/coenzyme A ligase activity, so the hepatic phenotype is not attributable to lipid transport alone. Lipid is redistributed to other tissues rather than simply not absorbed, so the model protects the liver at a whole-body cost that a hepatocyte-level reading would miss.

Readouts

Long-chain fatty acid uptake by isolated hepatocytes

long-chain fatty acid import into hepatocytes GO:0044539

Direction: DECREASED

Interpretation: Measured in hepatocytes removed from the animal, so it isolates the cell-autonomous transport defect from whole-body energy balance.

Show evidence (1 reference)

PMID:16618416 SUPPORT Model Organism

"FATP5 deletion significantly reduced LCFA uptake by hepatocytes isolated from FATP5 knockout animals."

The cell-autonomous uptake measurement that grounds this readout.

Show evidence (1 reference)

PMID:16618416 SUPPORT Model Organism

"Our findings support the hypothesis that efficient hepatocellular uptake of LCFAs, and thus liver lipid homeostasis in general, is largely a protein-mediated process requiring FATP5."

The authors' own conclusion, which is the claim this node makes and this model supports.

AAV8-shRNA hepatic FATP2 knockdown mouse on high-fat diet

Liver-specific knockdown of the second hepatic fatty acid transporter. Included because it makes the uptake claim independent of any single transporter: FATP2 loss reduces hepatic long-chain fatty acid uptake by about 40% without materially changing total hepatic acyl-CoA synthetase activity, and knockdown reduces steatosis while high-fat feeding continues.

Species

Mouse

Genotype

Wild-type mouse with adeno-associated virus 8-delivered shRNA silencing hepatic Slc27a2 (FATP2)

Background

High-fat feeding

Genes

SLC27A2 hgnc:10996

Publication

PMID:20530735

Pathograph links

Transporter-Mediated Hepatic Fatty Acid Uptake perturbs fidelity: moderate A second, independent genetic route to the same transport step, which is what distinguishes a transporter-specific result from a general hepatic lipid-handling effect.

Limitations: FATP2 is bifunctional — a minor peroxisomal pool contributes roughly half of peroxisomal very-long-chain acyl-CoA synthetase activity — so knockdown is not a clean transport-only perturbation, even though total hepatic synthetase activity was unchanged. Murine, and the effect size on uptake is partial.

Readouts

Hepatic long-chain fatty acid uptake after FATP2 loss

long-chain fatty acid import into hepatocytes GO:0044539

Direction: DECREASED

Interpretation: A partial (40%) reduction, consistent with several transporters sharing the step rather than one accounting for all of it.

Show evidence (1 reference)

PMID:20530735 SUPPORT Model Organism

"total hepatic (V)LACS activity was not significantly affected by loss of FATP2, while LCFA uptake was reduced by 40%, indicating a more prominent role in hepatic LCFA uptake."

Gives both the magnitude of the uptake readout and the internal control separating transport from synthetase activity.

Show evidence (1 reference)

PMID:20530735 SUPPORT Model Organism

"This suggests FATP2 as a potential target for a therapeutic intervention of hepatosteatosis."

States the authors' framing of the transporter as an intervention point, the claim this model is curated to support.

Hepatocyte Lipid Overload rescues fidelity: moderate Reducing the transport step lowers hepatic steatosis while dietary fat intake is held high, replicating the FATP5 result through a different gene.

Limitations: Steatosis, fasting glucose and insulin are the endpoints; no fibrosis or histologic activity endpoint is reported, so the model speaks to the lipid-overload node and not to progression.

Readouts

Hepatosteatosis under continued high-fat feeding

lipid storage GO:0019915

Direction: DECREASED

Interpretation: Because fat intake is unchanged, the fall in hepatic lipid is attributable to the transport step rather than to reduced substrate supply.

Show evidence (1 reference)

PMID:20530735 SUPPORT Model Organism

"liver-specific FATP2 knockdown, which significantly reduced hepatosteatosis in the face of continued high-fat feeding, concomitant with improvements in liver physiology, fasting glucose, and insulin levels."

The steatosis readout together with the metabolic improvements that accompanied it.

Show evidence (1 reference)

PMID:20530735 SUPPORT Model Organism

"liver-specific FATP2 knockdown, which significantly reduced hepatosteatosis in the face of continued high-fat feeding"

Supports treating this knockdown model as informative for the hepatic lipid-overload node.

{ }

Source YAML

click to show

name: Metabolic Dysfunction-Associated Steatotic Liver Disease
creation_date: '2026-08-01T00:00:00Z'
description: >-
  Metabolic dysfunction-associated steatotic liver disease (MASLD) is hepatic
  steatosis occurring in the presence of at least one cardiometabolic risk
  factor and in the absence of another identified cause of steatosis. It is the
  most prevalent chronic liver disease worldwide. Adipose-tissue insulin
  resistance and overnutrition deliver free fatty acids to the liver and drive
  de novo lipogenesis, so that hepatocyte lipid inflow exceeds the capacity for
  fatty acid oxidation and very-low-density lipoprotein export. Accumulating
  toxic lipid species, together with impaired mitochondrial quality control
  (mitophagy), provoke endoplasmic reticulum and oxidative stress, hepatocyte
  death, Kupffer-cell and macrophage inflammatory activation
  (metabolic dysfunction-associated steatohepatitis, MASH), hepatic stellate
  cell activation, and progressive fibrosis that can culminate in cirrhosis and
  hepatocellular carcinoma. Fibrosis stage, not steatosis or inflammation grade,
  is the histologic feature that tracks long-term outcome. Management centres on
  weight loss and cardiometabolic risk reduction, with resmetirom the first
  agent approved specifically for MASH with fibrosis.
synonyms:
- MASLD
- Nonalcoholic fatty liver disease
- NAFLD
- Non-alcoholic fatty liver disease
- Metabolic dysfunction-associated fatty liver disease
category: Complex
parents:
- Hepatic Disease
disease_term:
  preferred_term: metabolic dysfunction-associated steatotic liver disease
  term:
    id: MONDO:0013209
    label: metabolic dysfunction-associated steatotic liver disease
has_subtypes:
- name: MASL
  display_name: Metabolic dysfunction-associated steatotic liver (isolated steatosis)
  description: >-
    Hepatic steatosis with a cardiometabolic risk factor but without the
    necessary histologic features of steatohepatitis. Progression risk is lower
    than in MASH, but this is a stage of the same disease rather than a distinct
    entity.
  evidence:
  - reference: PMID:37363821
    reference_title: A multisociety Delphi consensus statement on new fatty liver disease nomenclature.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Steatotic liver disease was chosen as an overarching term to encompass the
      various aetiologies of steatosis.
    explanation: >-
      The consensus statement establishes steatotic liver disease as the
      overarching term under which the bland-steatosis stage sits.
- name: MASH
  display_name: Metabolic dysfunction-associated steatohepatitis (MASH/NASH)
  description: >-
    The inflammatory subtype, defined histologically by steatosis with lobular
    inflammation and hepatocellular ballooning. MASH is the stage from which
    progressive fibrosis, cirrhosis, and hepatocellular carcinoma most often
    arise, and is the target population of the current approved and
    investigational drug therapies.
  subtype_term:
    preferred_term: metabolic dysfunction-associated steatohepatitis
    term:
      id: MONDO:0007027
      label: metabolic dysfunction-associated steatohepatitis
  evidence:
  - reference: PMID:37363821
    reference_title: A multisociety Delphi consensus statement on new fatty liver disease nomenclature.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The term steatohepatitis was felt to be an important pathophysiological
      concept that should be retained.
    explanation: >-
      The nomenclature consensus retains steatohepatitis as a distinct
      pathophysiological stage within steatotic liver disease.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_lipotoxic_multihit_masld
  hypothesis_label: Canonical lipid-overload and lipotoxicity model
  status: CANONICAL
  description: >-
    Insulin resistance and overnutrition drive hepatocyte lipid overload from
    adipose-derived free fatty acids and de novo lipogenesis. Toxic lipid
    species then produce organelle stress, hepatocyte death, macrophage
    inflammation, stellate-cell activation, and fibrosis. This is the
    established backbone of the MASLD pathograph and is shared with the
    hepatic_steatosis_lipotoxicity module.
  evidence:
  - reference: PMID:15864352
    reference_title: Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These quantitative metabolic data document that both elevated peripheral
      fatty acids and DNL contribute to the accumulation of hepatic and
      lipoprotein fat in NAFLD.
    explanation: >-
      Stable-isotope quantification in patients establishes the two lipid inflow
      routes that begin the canonical chain.
- hypothesis_group_id: impaired_mitophagy_amplifier
  hypothesis_label: Impaired mitophagy as an amplifier of MASLD progression
  status: EMERGING
  description: >-
    Failure of selective autophagic clearance of damaged mitochondria
    (mitophagy) is proposed to amplify the transition from bland steatosis to
    steatohepatitis by allowing dysfunctional, reactive-oxygen-species-producing
    mitochondria to persist and by licensing inflammasome activation. The human
    evidence is largely correlative; the causal experiments are in cultured
    hepatocytes and rodent models, so this is modeled as an emerging amplifier
    rather than an established requirement for human disease progression.
  evidence:
  - reference: PMID:42412329
    reference_title: 'Mitophagy in Metabolic Dysfunction-Associated Fatty Liver Disease: Mechanisms, Regulatory Networks, and Therapeutic Perspectives.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We then discuss how impaired mitophagy drives the disease progression of
      MASLD from the perspective of different hepatic cell types.
    explanation: >-
      The review frames impaired mitophagy as a driver of MASLD progression
      while presenting it as a synthesis of mechanistic rather than clinical
      outcome data.
  - reference: PMID:34674097
    reference_title: Deoxycholic Acid Promotes Pyroptosis in Free Fatty Acid-Induced Steatotic Hepatocytes by Inhibiting PINK1-Mediated Mitophagy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      our data showed that DCA-induced pyroptosis involves the inhibition of
      PINK1-mediated mitophagy and the activation of the NLRP3 inflammasome.
    explanation: >-
      A cell-culture model supports the mitophagy-to-inflammation link but does
      not establish it in human liver, bounding the hypothesis as emerging.
- hypothesis_group_id: sinusoidal_endothelial_dysfunction_masld
  hypothesis_label: Liver sinusoidal endothelial dysfunction as an early driver
  status: EMERGING
  description: >-
    An endothelium-first model in which loss of the liver sinusoidal endothelial
    cell (LSEC) phenotype — capillarization (loss of fenestrae) and loss of
    shear-responsive vasodilator production — occurs early, before overt
    steatohepatitis, and then licenses inflammatory-cell recruitment and hepatic
    stellate cell activation rather than merely following hepatocyte injury.
    This is deliberately modeled as a parallel arm of the pathograph, not a
    replacement for the canonical lipotoxic backbone: the human data are
    cross-sectional histology, and the causal experiments are
    endothelium-specific mouse models. The same endothelial lesion has been
    proposed as the axis shared with atherosclerosis, where vascular endothelial
    dysfunction initiates lipoprotein retention and leukocyte recruitment;
    whether dismech should represent that shared axis as a cross-disease module
    or a comorbidity entry is an open scope question (issue #6352), so no
    cross-disease structure is asserted here.
  evidence:
  - reference: PMID:30797053
    reference_title: Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Capillarization, namely the loss of LSEC fenestrae, and LSEC dysfunction,
      namely the loss of the ability of LSECs to generate vasodilator agents in
      response to increased shear stress both occur early in NAFLD.
    explanation: >-
      States the temporal claim the hypothesis rests on — that the endothelial
      lesion is early rather than a downstream consequence of steatohepatitis.
  - reference: PMID:31726115
    reference_title: A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In mice fed a high-fat diet, deficiency in endothelial autophagy induced
      liver expression of inflammatory markers (Ccl2, Ccl5, Cd68, Vcam-1), liver
      cell apoptosis (cleaved caspase-3) and perisinusoidal fibrosis.
    explanation: >-
      An endothelium-specific mouse model supplies the causal direction, but the
      corresponding human data are observational, which is why this is modeled
      as emerging rather than canonical.
- hypothesis_group_id: osa_intermittent_hypoxia_masld
  hypothesis_label: Obstructive sleep apnea-associated chronic intermittent hypoxia
    as a progression driver
  status: EMERGING
  description: >-
    Chronic intermittent hypoxia (CIH) — the cyclical desaturation-reoxygenation
    of obstructive sleep apnea — is proposed to act on the liver as a second hit
    that is separable from adiposity, upregulating SREBP-1/SCD-1-dependent
    hepatic lipogenesis and generating hepatic lipid peroxidation, and thereby
    accelerating the transition from steatosis to steatohepatitis and fibrosis.
    This is deliberately modeled as a parallel arm of the pathograph rather than
    a replacement for the canonical lipotoxic backbone, and as EMERGING rather
    than CANONICAL, for three reasons that the curated evidence states directly.
    (1) The human data are observational, and they do not agree with each other
    endpoint by endpoint: the largest individual-participant meta-analysis
    attributes the fibrosis association mainly to body mass index by causal
    mediation analysis while finding apnea severity an independent risk factor
    for steatosis, whereas the one cohort scored on liver biopsy inverts that
    pattern, finding an obesity-adjusted fibrosis association but no association
    with steatosis or steatohepatitis. Each edge therefore carries both the
    supporting and the refuting human result. (2) The causal, dose-controlled
    experiments — including the
    HIF-1 dependence of the triglyceride response — are five-day murine
    intermittent-hypoxia exposures in lean mice, a model that produced no
    additional effect in already-obese mice. (3) Correcting the exposure does
    not correct the liver: randomized trials of CPAP monotherapy show no change
    in steatosis, fibrosis or aminotransferases. A curator extending this arm
    should preserve that asymmetry rather than resolving it, and should not
    curate CPAP as a MASLD therapy.
  evidence:
  - reference: PMID:32843301
    reference_title: 'Obstructive sleep apnea, chronic obstructive pulmonary disease
      and NAFLD: an individual participant data meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This meta-analysis confirms the strong association between steatosis and
      the severity of OSA. The relation between OSA and fibrosis is mainly due to
      BMI as shown by causal mediation analysis.
    explanation: >-
      PARTIAL, and it is the sentence that bounds the hypothesis: 2120-patient
      individual-participant data support the steatosis limb while assigning the
      fibrosis limb to adiposity rather than to the hypoxic exposure.
  - reference: PMID:16507783
    reference_title: Altered metabolic responses to intermittent hypoxia in mice with
      partial deficiency of hypoxia-inducible factor-1alpha.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We conclude that 1) the effect of IH on serum TG levels is mediated through
      HIF-1, 2) HIF-1 may impact on posttranscriptional regulation of SREBP-1
    explanation: >-
      Supplies the causal molecular direction the observational human data cannot
      — a HIF-1alpha heterozygous-null comparison showing the triglyceride
      response to intermittent hypoxia is HIF-1-dependent. Murine, which is why
      the hypothesis stays EMERGING.
- hypothesis_group_id: hepatic_fatty_acid_uptake_masld
  hypothesis_label: Transporter-mediated hepatic fatty acid uptake as a rate-limiting,
    druggable step
  status: EMERGING
  description: >-
    The canonical model treats the hepatocyte as a passive sink for the
    non-esterified fatty acid load that adipose insulin resistance releases. This
    hypothesis holds instead that entry into the hepatocyte is itself
    protein-mediated and rate-limiting, so that the fatty acid transport proteins
    on the basolateral hepatocyte membrane — FATP5 (SLC27A5), which is expressed
    exclusively by liver, and FATP2 (SLC27A2) — set how much of that load actually
    reaches the hepatic lipid pool, and blocking them reverses steatosis that is
    already established. The strong form of the claim is therapeutic: hepatic
    fatty acid uptake is a target in its own right, upstream of and separable from
    the lipogenic and oxidative arms the approved agents act on.
    It is modeled as EMERGING, not canonical, for two reasons the curated evidence
    states directly. First, every causal experiment is murine knockdown or
    knockout; no FATP-directed agent has been tested in human MASLD, and no human
    genetic evidence linking SLC27A5 or SLC27A2 variation to MASLD is curated
    here. Second, hepatic FATP5 knockdown also reduced whole-animal caloric
    uptake, so the reported protection is not cleanly attributable to the hepatic
    uptake step alone — a confound the source paper reports rather than one
    imputed to it. A curator strengthening this arm should look for the human
    evidence that is missing, not for more rodent replication.
  evidence:
  - reference: PMID:16618416
    reference_title: 'Targeted deletion of FATP5 reveals multiple functions in liver
      metabolism: alterations in hepatic lipid homeostasis.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our findings support the hypothesis that efficient hepatocellular uptake of
      LCFAs, and thus liver lipid homeostasis in general, is largely a
      protein-mediated process requiring FATP5.
    explanation: >-
      States the core premise of this hypothesis — that hepatocellular long-chain
      fatty acid entry is protein-mediated rather than passive — from a
      whole-animal knockout.
  - reference: PMID:18524776
    reference_title: Silencing of hepatic fatty acid transporter protein 5 in vivo
      reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      knockdown of fatty acid transport protein 5 was also able to reverse already
      established non-alcoholic fatty liver disease, resulting in significantly
      improved whole-body glucose homeostasis.
    explanation: >-
      Supplies the therapeutic form of the claim — reversal of established
      disease, not just prevention — which is what makes the uptake step worth
      modeling separately from lipid overload. Murine, which is why the hypothesis
      stays emerging.
  - reference: PMID:18524776
    reference_title: Silencing of hepatic fatty acid transporter protein 5 in vivo
      reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      resulting in a marked reduction of hepatic dietary fatty acid uptake,
      reduced caloric uptake, and concomitant protection from diet-induced
      non-alcoholic fatty liver disease.
    explanation: >-
      Retained deliberately as the bounding quote: the same sentence that reports
      protection also reports reduced caloric uptake, so the hepatic effect is
      confounded with a whole-animal energy-intake effect. Graded INDIRECT because
      the protection follows from the uptake block only through that unresolved
      intermediate.
- hypothesis_group_id: semaglutide_weight_independent_hepatic_effect
  hypothesis_label: A weight-independent hepatic component of GLP-1 receptor agonist
    benefit
  status: EMERGING
  description: >-
    Semaglutide improves MASH histology, and this hypothesis asks what carries
    that benefit: weight loss and its metabolic sequelae, or an effect of GLP-1
    receptor agonism that survives at matched weight loss. The question matters
    for the pathograph because the two readings place the drug's action on
    different nodes — the upstream cardiometabolic trigger in the first case,
    the hepatic and fibrogenic arm in the second.
    The strong form of the hypothesis, a cell-autonomous action on hepatocytes
    or hepatic stellate cells, is close to excluded rather than merely
    unproven. Pyke's extensively validated monoclonal antibody found no GLP-1
    receptor in primate liver and confirmed the negative by in-situ ligand
    binding rather than immunostaining alone, and incretin agonists applied to
    primary human hepatocytes and stellate cells changed neither lipid content
    nor fibrotic markers nor CREB phosphorylation. Against that, Armstrong
    reports a 24.6% fall in lipogenesis in primary human hepatocytes, so the
    in-vitro literature is genuinely contradictory; the negatives are the
    better-controlled side, resting on knockout-validated reagents and an
    orthogonal binding assay.
    What remains live is a weight-independent effect routed through tissues
    other than the liver. The one randomised matched-weight-loss experiment in
    humans found liver outcomes equal between a GLP-1 receptor agonist and
    lifestyle, with suppression of de novo lipogenesis the one measure that
    separated the arms — so DNL is currently the best-evidenced
    weight-independent hepatic effect, and it produced no measurable difference
    in steatosis or disease activity over twelve weeks.
    It is modeled as EMERGING, and the honest reading of the present evidence
    favours the weight-mediated account. Two cautions bound any attempt to
    settle it. The only numerically reported mediation analysis in the class
    covers survodutide, a GLP-1/glucagon dual agonist whose hepatic glucagon
    receptor is expressed in human liver and which therefore has a direct route
    semaglutide lacks; its larger direct component for fibrosis cannot be
    transferred to semaglutide. And the ESSENCE weight-loss strata are
    post-randomisation, so conditioning on achieved weight loss compares
    non-comparable groups and does not yield a causal mediated fraction.
  evidence:
  - reference: PMID:24467746
    reference_title: 'GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody.'
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      No GLP-1R was seen in primate liver and thyroid.
    explanation: >-
      Refutes the strong, cell-autonomous form of the hypothesis by removing its
      anatomical substrate. The same study confirms its immunohistochemistry
      with in-situ ligand binding, which is why this negative outweighs
      antibody-only positive reports. Graded IN_VITRO because the method is
      immunohistochemistry and in-situ ligand binding on tissue specimens rather
      than any observation in patients; the quoted sentence says "primate"
      because the survey covers monkey and human tissue, so the hepatic negative
      rests on specimens of both.
  - reference: PMID:39607493
    reference_title: GLP-1 and GIP agonism has no direct actions in human hepatocytes or hepatic stellate cells.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      These findings indicate that incretin agonists have no direct actions in
      human hepatocytes or hepatic stellate cells, suggesting that their
      beneficial effects in patients with MASH are likely mediated indirectly,
      potentially through improvements in body weight, insulin resistance and
      glycemic control.
    explanation: >-
      The functional counterpart of the expression negative: no lipid, fibrotic
      or CREB response in primary human hepatocytes and stellate cells. The
      absent CREB phosphorylation is the load-bearing part, because it says the
      receptor-effector coupling a direct effect would need is not present.
      Tests liraglutide, acyl-GIP and MAR709 rather than semaglutide itself, so
      the extension to semaglutide is a class inference.
  - reference: PMID:26394161
    reference_title: Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      a finding endorsed by the effect of GLP-1 receptor agonist on primary human
      hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p<0.01)
    explanation: >-
      Retained as the contradicting result rather than omitted: a direct
      functional effect in the same cell type where the study above found none.
      The quote is carried far enough back to name the agent and the cell type,
      since "primary human hepatocytes" is what puts this result in direct
      conflict with the negative above rather than merely near it.
      Graded INDIRECT because a lipogenesis change in culture reaches the
      histologic claim only through several unestablished steps, and because
      the measurement sits in the in-vitro arm of a trial whose patients also
      lost weight.
  - reference: PMID:40342635
    reference_title: Randomised trial comparing weight loss through lifestyle and GLP-1 receptor agonist therapy in people with MASLD.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Matched weight loss was achieved in both arms. Body composition changes,
      reductions in alanine aminotransferase, liver steatosis, and disease
      activity were similar following both treatments.
    explanation: >-
      The designed test of the hypothesis, and it is negative on the liver
      endpoints: at matched weight loss the drug did not beat lifestyle. Bounded
      rather than decisive — 29 participants, twelve weeks, and imaging and
      biochemistry rather than histology, so it cannot see fibrosis.
  - reference: PMID:42545725
    reference_title: 'Weight reduction-dependent/-independent effects of survodutide on liver endpoints: Mediation analysis of a phase 2 trial in MASH.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the percentage of the total treatment effect mediated by weight reduction
      (indirect effect) was estimated at 66.7% for resolution of MASH without
      worsening of fibrosis, 71.8% for improvement in MASH without worsening of
      fibrosis, and 36.3% for improvement in fibrosis without worsening of MASH
      (suggesting a greater direct effect)
    explanation: >-
      The only numerically reported mediation analysis in the class, and the
      source of the claim that a weight-independent component exists and is
      concentrated on fibrosis. Graded INDIRECT for the reason the description
      states: survodutide is a GLP-1/glucagon dual agonist engaging a hepatic
      receptor semaglutide does not, so its direct component may be carried by
      a mechanism absent from the drug this entry curates.
  - reference: PMID:36934740
    reference_title: 'Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      five [11%] of 47 patients in the semaglutide group vs seven [29%] of 24 in
      the placebo group; odds ratio 0·28 [95% CI 0·06-1·24; p=0·087)
    explanation: >-
      Tests the hypothesis where it is most separable: in established cirrhosis
      the steatohepatitis-to-fibrosis coupling is broken, so a direct
      antifibrotic action would still show. Fibrosis improvement was
      numerically lower on semaglutide than placebo. Not statistically
      significant and in a different disease stage, so it bounds the claim
      rather than refuting it outright.
prevalence:
- population: Worldwide, general adult population (imaging-diagnosed NAFLD)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 32400.0
  rate_low: 29900.0
  rate_high: 34900.0
  notes: >-
    Meta-analysis of 72 publications and 1,030,160 individuals from 17
    countries. The estimate predates the MASLD nomenclature change and uses the
    exclusion-based NAFLD case definition, so it approximates rather than
    exactly measures MASLD prevalence.
  evidence:
  - reference: PMID:35798021
    reference_title: 'The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The overall prevalence of NAFLD worldwide was estimated to be 32·4% (95%
      CI 29·9-34·9).
    explanation: >-
      Provides the pooled worldwide adult prevalence estimate with its
      confidence interval.
- population: Worldwide, general adult population (imaging-diagnosed NAFLD)
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 4690.0
  rate_low: 3640.0
  rate_high: 5750.0
  notes: >-
    46.9 cases per 1000 person-years, converted to 4,690 per 100,000
    person-years. Reported separately from prevalence and not comparable to it.
  evidence:
  - reference: PMID:35798021
    reference_title: 'The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The overall incidence of NAFLD was estimated to be 46·9 cases per 1000
      person-years (36·4-57·5)
    explanation: >-
      Provides the pooled worldwide incidence estimate used for the normalized
      rate.
pathophysiology:
- name: Cardiometabolic Dysfunction and Adipose Insulin Resistance
  biological_scale: ORGANISM
  role: trigger
  description: >-
    MASLD is defined by hepatic steatosis in the presence of at least one
    cardiometabolic risk factor (overweight/obesity, dysglycaemia or type 2
    diabetes, hypertension, hypertriglyceridaemia, or low HDL cholesterol).
    Adipose-tissue insulin resistance fails to restrain lipolysis, so
    non-esterified fatty acids flood the portal circulation, while
    hyperinsulinaemia and carbohydrate surplus drive hepatic de novo
    lipogenesis. This cardiometabolic state is the initiating context that
    distinguishes MASLD from other steatotic liver diseases.
  cell_types:
  - preferred_term: adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: cellular response to insulin stimulus
    term:
      id: GO:0032869
      label: cellular response to insulin stimulus
    modifier: DECREASED
  evidence:
  - reference: PMID:37363821
    reference_title: A multisociety Delphi consensus statement on new fatty liver disease nomenclature.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There was consensus to change the definition to include the presence of at
      least 1 of 5 cardiometabolic risk factors.
    explanation: >-
      The nomenclature consensus makes cardiometabolic dysfunction a definitional
      requirement of MASLD, establishing it as the entry point of the pathograph.
  - reference: PMID:42412329
    reference_title: 'Mitophagy in Metabolic Dysfunction-Associated Fatty Liver Disease: Mechanisms, Regulatory Networks, and Therapeutic Perspectives.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Metabolic dysfunction-associated fatty liver disease (MASLD) represents the
      most prevalent chronic liver disorder globally, with pathogenesis closely
      linked to insulin resistance, obesity, and gut microbiota dysbiosis.
    explanation: >-
      Ties MASLD pathogenesis to insulin resistance and obesity, the substrate of
      this trigger node.
  downstream:
  - target: Hepatocyte Lipid Overload
    description: >-
      Adipose insulin resistance and overnutrition supply the fatty acid inflow
      and lipogenic drive that produce hepatocyte lipid accumulation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:15864352
      reference_title: Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Of the TAG accounted for in liver, 59.0% +/- 9.9% of TAG arose from
        NEFAs; 26.1% +/- 6.7%, from DNL; and 14.9% +/- 7.0%, from the diet.
      explanation: >-
        Directly quantifies adipose-derived non-esterified fatty acids and de novo
        lipogenesis as the dominant sources of stored hepatic triglyceride.
  - target: Transporter-Mediated Hepatic Fatty Acid Uptake
    description: >-
      Unrestrained adipose lipolysis raises the non-esterified fatty acid load
      presented to the liver, and the transporters at the hepatocyte basal membrane
      are what convert that circulating load into hepatocellular fatty acid entry.
      The edge asserts substrate delivery to the transport step, not upregulation of
      the transporters themselves.
    causal_link_type: DIRECT
    hypothesis_groups:
    - hepatic_fatty_acid_uptake_masld
    evidence:
    - reference: PMID:16618416
      reference_title: 'Targeted deletion of FATP5 reveals multiple functions in liver
        metabolism: alterations in hepatic lipid homeostasis.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        FATP5 is exclusively expressed by the liver and localized to the basal
        plasma membrane of hepatocytes, congruent with a role in LCFA uptake from
        the circulation.
      explanation: >-
        Places the transport step at the interface between the circulating fatty
        acid load this trigger node generates and the hepatocyte, which is the
        junction this edge represents.
    - reference: PMID:39266553
      reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
        resistance in a human iPSC-based microphysiological system.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Consequently, the iHEP-MPS showed increased fatty acid uptake and lipid
        accumulation under inflamed iADIPO-MPS conditions
      explanation: >-
        The human counterpart of the same edge: manipulating only the adipose
        compartment of an isogenic iPSC adipose-liver chip raises hepatocyte fatty
        acid uptake, so the delivery relationship is demonstrated in human cells and
        not only inferred from rodent transporter biology.
  - target: Liver Sinusoidal Endothelial Cell Dysfunction and Capillarization
    description: >-
      The same cardiometabolic state that drives hepatocyte lipid loading also
      acts on the sinusoidal endothelium: insulin resistance and dyslipidaemia
      exacerbate endothelial activation and lipid handling across vascular and
      hepatic beds. This edge is what makes the endothelial arm a branch of the
      shared cardiometabolic trigger rather than a second, unexplained
      initiating step.
    causal_link_type: DIRECT
    hypothesis_groups:
    - sinusoidal_endothelial_dysfunction_masld
    evidence:
    - reference: PMID:42430855
      reference_title: 'Endothelial Cells at the Crossroad of Atherosclerosis and Metabolic Dysfunction-Associated Steatotic Liver Disease: A Unifying Target for Dual Treatment.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        We further discuss how metabolic disturbances including insulin
        resistance and dyslipidemia exacerbate endothelial activation, lipid
        accumulation, and immune cell responses across vascular and hepatic
        beds.
      explanation: >-
        Names insulin resistance and dyslipidaemia — the content of this trigger
        node — as what exacerbates endothelial activation in the hepatic bed.

- name: Transporter-Mediated Hepatic Fatty Acid Uptake
  biological_scale: MOLECULAR
  role: amplifier
  description: >-
    Long-chain fatty acids delivered to the liver do not enter hepatocytes by
    passive diffusion alone. Uptake is largely protein-mediated, through fatty
    acid transport proteins at the basal plasma membrane of the hepatocyte. FATP5
    (SLC27A5) is expressed exclusively by liver and localizes to that membrane;
    FATP2 (SLC27A2) accounts for a further large share of hepatic long-chain fatty
    acid uptake while also serving as a peroxisomal very-long-chain acyl-CoA
    synthetase. This node is deliberately kept separate from Hepatocyte Lipid
    Overload because it is the step at which the circulating non-esterified fatty
    acid load is gated, and because it is where the two rodent interventions that
    reverse established steatosis act. What is increased in the high-fat state is
    the flux through this step rather than, on the curated evidence, transporter
    expression: the murine experiments show that continued transporter activity is
    required to sustain fatty acid entry, not that the transporters are
    upregulated by disease. The node carries the emerging hepatic-uptake
    hypothesis and is not asserted as a required step in human disease.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  genes:
  - preferred_term: SLC27A5
    term:
      id: hgnc:10999
      label: SLC27A5
  - preferred_term: SLC27A2
    term:
      id: hgnc:10996
      label: SLC27A2
  biological_processes:
  - preferred_term: long-chain fatty acid import into hepatocytes
    term:
      id: GO:0044539
      label: long-chain fatty acid import into cell
    modifier: INCREASED
  molecular_functions:
  - preferred_term: FATP5/FATP2 long-chain fatty acid transport activity
    term:
      id: GO:0005324
      label: long-chain fatty acid transmembrane transporter activity
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:16618416
    reference_title: 'Targeted deletion of FATP5 reveals multiple functions in liver
      metabolism: alterations in hepatic lipid homeostasis.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      FATP5 is exclusively expressed by the liver and localized to the basal
      plasma membrane of hepatocytes, congruent with a role in LCFA uptake from
      the circulation.
    explanation: >-
      Establishes the expression and subcellular localization that make this a
      hepatocyte-membrane transport step rather than a generic lipid-handling
      claim.
  - reference: PMID:20530735
    reference_title: FATP2 is a hepatic fatty acid transporter and peroxisomal very
      long-chain acyl-CoA synthetase.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      total hepatic (V)LACS activity was not significantly affected by loss of
      FATP2, while LCFA uptake was reduced by 40%, indicating a more prominent
      role in hepatic LCFA uptake.
    explanation: >-
      Quantifies the second transporter's contribution and separates its transport
      role from its peroxisomal synthetase role, which is why both genes are bound
      on this node.
  downstream:
  - target: Hepatocyte Lipid Overload
    description: >-
      Fatty acids entering through this transport step are the substrate for the
      hepatocyte triglyceride pool. On the emerging hypothesis this step is
      rate-limiting, so reducing it lowers hepatic triglyceride even while fatty
      acid inflow to the liver and dietary fat intake continue.
    causal_link_type: DIRECT
    hypothesis_groups:
    - hepatic_fatty_acid_uptake_masld
    evidence:
    - reference: PMID:16618416
      reference_title: 'Targeted deletion of FATP5 reveals multiple functions in liver
        metabolism: alterations in hepatic lipid homeostasis.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        FATP5 deletion resulted in lower hepatic triglyceride and free fatty acid
        content despite increased expression of fatty acid synthetase
      explanation: >-
        Removing the transporter lowers the hepatic triglyceride pool even against
        a compensatory rise in lipogenic enzyme expression, which is the causal
        direction this edge asserts.
    - reference: PMID:20530735
      reference_title: FATP2 is a hepatic fatty acid transporter and peroxisomal very
        long-chain acyl-CoA synthetase.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        liver-specific FATP2 knockdown, which significantly reduced hepatosteatosis
        in the face of continued high-fat feeding
      explanation: >-
        Independent replication through a second transporter, and the phrase "in
        the face of continued high-fat feeding" is what licenses calling the
        uptake step rate-limiting rather than merely permissive.
- name: Hepatocyte Lipid Overload
  conforms_to: 'hepatic_steatosis_lipotoxicity#Hepatocyte Lipid Overload'
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    Hepatocyte triglyceride accumulates when fatty acid inflow from adipose
    lipolysis and diet, plus de novo lipogenesis, exceeds fatty acid oxidation
    and very-low-density lipoprotein export. In MASLD the disorder-specific
    inflow is metabolic (adipose insulin resistance and carbohydrate surplus)
    rather than ethanol-driven, but the resulting lipid-droplet overload is the
    conserved module state.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: triglyceride biosynthetic process
    term:
      id: GO:0019432
      label: triglyceride biosynthetic process
    modifier: INCREASED
  - preferred_term: lipid storage
    term:
      id: GO:0019915
      label: lipid storage
    modifier: INCREASED
  - preferred_term: fatty acid beta-oxidation
    term:
      id: GO:0006635
      label: fatty acid beta-oxidation
    modifier: DECREASED
  evidence:
  - reference: PMID:15864352
    reference_title: Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nonalcoholic fatty liver disease (NAFLD) is characterized by the
      accumulation of excess liver triacylglycerol (TAG), inflammation, and liver
      damage.
    explanation: >-
      Defines the hepatocyte triglyceride-overload state that this node
      represents.
  downstream:
  - target: Impaired Hepatocyte Mitophagy
    description: >-
      Lipid overload and the associated mitochondrial workload are proposed to
      overwhelm and then suppress mitochondrial quality control.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - impaired_mitophagy_amplifier
    evidence:
    - reference: PMID:42412329
      reference_title: 'Mitophagy in Metabolic Dysfunction-Associated Fatty Liver Disease: Mechanisms, Regulatory Networks, and Therapeutic Perspectives.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Mitochondrial dysfunction is central to MASLD progression
      explanation: >-
        Supports an edge from the lipid-overloaded hepatocyte state to
        mitochondrial quality-control failure while leaving the intermediate
        steps unresolved.
  - target: Lipotoxic Stress and Organelle Dysfunction
    description: >-
      Continued lipid loading generates toxic non-triglyceride lipid species that
      stress the endoplasmic reticulum and mitochondria.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42412329
      reference_title: 'Mitophagy in Metabolic Dysfunction-Associated Fatty Liver Disease: Mechanisms, Regulatory Networks, and Therapeutic Perspectives.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Mitochondrial dysfunction is central to MASLD progression
      explanation: >-
        Places organelle dysfunction downstream of the lipid-overloaded hepatocyte
        in MASLD progression.

- name: Impaired Hepatocyte Mitophagy
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    Mitophagy is the selective autophagic clearance of damaged mitochondria,
    executed through ubiquitin-dependent (PINK1/Parkin) and
    ubiquitin-independent receptor pathways. In steatotic hepatocytes this
    quality-control step is suppressed, so depolarized,
    reactive-oxygen-species-producing mitochondria persist and NLRP3 inflammasome
    activation and
    pyroptotic hepatocyte death are licensed. This node carries the emerging
    mitophagy hypothesis and is not asserted as a required step in every case.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: mitophagy
    term:
      id: GO:0000423
      label: mitophagy
    modifier: DECREASED
  evidence:
  - reference: PMID:42412329
    reference_title: 'Mitophagy in Metabolic Dysfunction-Associated Fatty Liver Disease: Mechanisms, Regulatory Networks, and Therapeutic Perspectives.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mitochondrial dysfunction is central to MASLD progression, and mitophagy
    explanation: >-
      The review establishes mitochondrial dysfunction and mitophagy as central
      to MASLD progression, the substrate of this node.
  - reference: PMID:34674097
    reference_title: Deoxycholic Acid Promotes Pyroptosis in Free Fatty Acid-Induced Steatotic Hepatocytes by Inhibiting PINK1-Mediated Mitophagy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Expression levels of the mitophagy markers PTEN-induced kinase 1 (PINK1)
      and E3 ubiquitin ligase Parkin were significantly diminished by DCA
    explanation: >-
      In free-fatty-acid-loaded HepG2 cells, a bile acid relevant to
      steatohepatitis suppresses the PINK1/Parkin mitophagy machinery.
  downstream:
  - target: Lipotoxic Stress and Organelle Dysfunction
    description: >-
      Failure to clear damaged mitochondria sustains reactive oxygen species
      production and organelle stress in the steatotic hepatocyte.
    causal_link_type: DIRECT
    hypothesis_groups:
    - impaired_mitophagy_amplifier
    evidence:
    - reference: PMID:42412329
      reference_title: 'Mitophagy in Metabolic Dysfunction-Associated Fatty Liver Disease: Mechanisms, Regulatory Networks, and Therapeutic Perspectives.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        a selective form of autophagy that clears damaged mitochondria
      explanation: >-
        Defines the clearance function whose loss leaves damaged mitochondria in
        place as a source of organelle stress.
  - target: Hepatocyte Injury and Inflammatory Activation
    description: >-
      Suppressed PINK1-mediated mitophagy permits NLRP3 inflammasome activation
      and pyroptotic hepatocyte death, an inflammatory route that bypasses the
      generic lipotoxic-stress step.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - impaired_mitophagy_amplifier
    intermediate_mechanisms:
    - NLRP3 inflammasome activation
    evidence:
    - reference: PMID:34674097
      reference_title: Deoxycholic Acid Promotes Pyroptosis in Free Fatty Acid-Induced Steatotic Hepatocytes by Inhibiting PINK1-Mediated Mitophagy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        induction of mitophagy by CCCP prevented DCA-induced inflammatory response
      explanation: >-
        Restoring mitophagy pharmacologically blocks the inflammatory response in
        steatotic hepatocytes, supporting the edge in a cell model only.

- name: Lipotoxic Stress and Organelle Dysfunction
  conforms_to: 'hepatic_steatosis_lipotoxicity#Lipotoxic Stress and Organelle Dysfunction'
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    Toxic non-triglyceride lipid species (diacylglycerols, ceramides, free fatty
    acid metabolites) accumulate alongside stored triglyceride and induce
    endoplasmic reticulum stress, mitochondrial dysfunction, and reactive oxygen
    species accumulation. This is the amplification step that converts bland
    steatosis (MASL) toward steatohepatitis (MASH).
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    modifier: INCREASED
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  evidence:
  - reference: PMID:42412329
    reference_title: 'Mitophagy in Metabolic Dysfunction-Associated Fatty Liver Disease: Mechanisms, Regulatory Networks, and Therapeutic Perspectives.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mitochondrial dysfunction is central to MASLD progression
    explanation: >-
      Establishes organelle (mitochondrial) dysfunction as a central step in
      MASLD progression.
  - reference: PMID:20427778
    reference_title: Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vitamin E therapy, as compared with placebo, was associated with a
      significantly higher rate of improvement in nonalcoholic steatohepatitis
      (43% vs. 19%, P=0.001)
    explanation: >-
      Benefit from an antioxidant in a randomized trial is indirect human support
      for oxidative stress as a modifiable amplifier, not proof of the mechanism.
  downstream:
  - target: Hepatocyte Injury and Inflammatory Activation
    description: >-
      Organelle stress sensitizes the hepatocyte to lipoapoptosis and other
      regulated cell death, which releases damage signals to resident macrophages.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28585211
      reference_title: Non-Alcoholic Fatty Liver Disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Furthermore, hepatocyte lipoapoptosis is a critical feature of NASH.
      explanation: >-
        Places lipoapoptosis, the cell-death output of lipotoxic organelle
        stress, at the core of the steatohepatitis stage.

- name: Hepatocyte Injury and Inflammatory Activation
  conforms_to: 'hepatic_steatosis_lipotoxicity#Hepatocyte Injury and Inflammatory Activation'
  biological_scale: TISSUE
  role: central_effector
  description: >-
    Stressed hepatocytes undergo apoptosis and pyroptosis, releasing damage
    signals that activate Kupffer cells and recruited macrophages, with
    inflammasome activation and pro-inflammatory cytokine release. Steatosis with
    lobular inflammation and hepatocellular ballooning defines MASH, the
    inflammatory subtype from which progressive disease arises.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: Kupffer cell
    term:
      id: CL:0000091
      label: Kupffer cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:34674097
    reference_title: Deoxycholic Acid Promotes Pyroptosis in Free Fatty Acid-Induced Steatotic Hepatocytes by Inhibiting PINK1-Mediated Mitophagy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Nonalcoholic steatohepatitis (NASH) is the inflammatory subtype of
      nonalcoholic fatty liver disease (NAFLD), which can lead to liver fibrosis
      and cirrhosis.
    explanation: >-
      Defines steatohepatitis as the inflammatory stage that connects hepatocyte
      injury to downstream fibrosis.
  downstream:
  - target: Hepatic Stellate Cell Activation and Fibrosis
    description: >-
      Sustained hepatocyte death and macrophage activation provide the cytokine
      and damage-signal milieu that activates hepatic stellate cells.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33989548
      reference_title: Mechanisms and disease consequences of nonalcoholic fatty liver disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        bile acid toxicity, macrophage dysfunction, and hepatic stellate cell
        activation, and consider the role of genetic, epigenetic, and
        environmental factors that promote fibrosis progression
      explanation: >-
        Couples macrophage dysfunction to hepatic stellate cell activation as the
        pathogenetic route to fibrosis progression.

- name: Liver Sinusoidal Endothelial Cell Dysfunction and Capillarization
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    Liver sinusoidal endothelial cells (LSECs) are the fenestrated gatekeepers
    between portal blood and the hepatocyte, and in health they hold Kupffer
    cells and hepatic stellate cells quiescent. In MASLD they capillarize —
    losing their fenestrae and their shear-responsive vasodilator output — and
    lose autophagic capacity, converting them from a restraining influence into
    a source of inflammatory and fibrogenic mediators. This node is the hepatic
    limb of the endothelial arm; it is not on the canonical lipotoxic backbone
    and is grouped under the emerging
    sinusoidal_endothelial_dysfunction_masld hypothesis.
  cell_types:
  - preferred_term: liver sinusoidal endothelial cell
    term:
      id: CL:1000398
      label: endothelial cell of hepatic sinusoid
  biological_processes:
  - preferred_term: macroautophagy
    term:
      id: GO:0016236
      label: macroautophagy
    modifier: DECREASED
  - preferred_term: leukocyte migration
    term:
      id: GO:0050900
      label: leukocyte migration
    modifier: INCREASED
  - preferred_term: nitric oxide biosynthetic process
    term:
      id: GO:0006809
      label: nitric oxide biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:31726115
    reference_title: A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with NASH had half as many LSECs containing autophagic vacuoles
      as patients without liver histological abnormalities, or with simple
      steatosis.
    explanation: >-
      Transmission electron microscopy in patient liver establishes the
      autophagy defect in LSECs as a human, not merely a model-system, finding.
  - reference: PMID:42430855
    reference_title: 'Endothelial Cells at the Crossroad of Atherosclerosis and Metabolic Dysfunction-Associated Steatotic Liver Disease: A Unifying Target for Dual Treatment.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Similarly, in MASLD, liver sinusoidal endothelial cells lose their
      capacity to regulate lipid trafficking, immune tolerance, and hepatic
      homeostasis, thereby promoting steatosis, inflammation, and fibrosis.
    explanation: >-
      Names the three functions this node loses and the downstream states they
      permit — steatosis, inflammation, and fibrosis — which are the three edges
      below.
  downstream:
  - target: Hepatocyte Lipid Overload
    description: >-
      The defining endothelium-first claim of this arm: capillarization and loss
      of shear-responsive vasodilator output occur early in the disease and
      themselves favour steatosis, rather than arising as a consequence of
      established hepatocyte injury. This is the edge that orders the endothelial
      lesion ahead of, not alongside, the steatohepatitis events below.
    causal_link_type: DIRECT
    hypothesis_groups:
    - sinusoidal_endothelial_dysfunction_masld
    evidence:
    - reference: PMID:30797053
      reference_title: Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        These LSEC changes favour steatosis development and set the stage for
        NAFLD progression.
      explanation: >-
        States the steatosis-promoting direction of the edge, and follows
        immediately on the review's statement that both LSEC changes occur early
        in NAFLD, which is what licenses the endothelium-first ordering.
  - target: Hepatocyte Injury and Inflammatory Activation
    description: >-
      Capillarized LSECs switch from restraining to recruiting: they release
      inflammatory mediators and support leukocyte adhesion and transmigration,
      adding an endothelial source to the macrophage-driven inflammation of
      MASH.
    causal_link_type: DIRECT
    hypothesis_groups:
    - sinusoidal_endothelial_dysfunction_masld
    evidence:
    - reference: PMID:30797053
      reference_title: Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        At the stage of non-alcoholic steatohepatitis, altered LSECs release
        inflammatory mediators and contribute to the recruitment of inflammatory
        cells, thus promoting liver injury and inflammation.
      explanation: >-
        States the edge directly, and locates it at the steatohepatitis stage
        rather than in bland steatosis.
  - target: Hepatic Stellate Cell Activation and Fibrosis
    description: >-
      Healthy LSECs actively maintain stellate-cell quiescence; the capillarized
      endothelium withdraws that restraint and adds fibrogenic signals, giving a
      route to fibrosis that does not require hepatocyte death as the
      intermediate.
    causal_link_type: DIRECT
    hypothesis_groups:
    - sinusoidal_endothelial_dysfunction_masld
    evidence:
    - reference: PMID:30797053
      reference_title: Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Altered LSECs also fail to maintain hepatic stellate cell quiescence and
        release fibrogenic mediators, including Hedgehog signalling molecules,
        promoting liver fibrosis.
      explanation: >-
        Supplies both halves of the edge — loss of the quiescence-maintaining
        function and positive release of fibrogenic mediators.

- name: Hepatic Stellate Cell Activation and Fibrosis
  conforms_to: 'hepatic_steatosis_lipotoxicity#Hepatic Stellate Cell Activation and Fibrosis'
  biological_scale: TISSUE
  role: effector
  description: >-
    Hepatic stellate cells transdifferentiate into myofibroblast-like cells and
    deposit excessive extracellular matrix. Fibrosis stage is the histologic
    feature that determines long-term outcome in MASLD, independent of
    steatohepatitis activity, which makes this node the principal prognostic and
    therapeutic target.
  cell_types:
  - preferred_term: hepatic stellate cell
    term:
      id: CL:0000632
      label: hepatic stellate cell
  - preferred_term: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  evidence:
  - reference: PMID:25935633
    reference_title: Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with fibrosis, regardless of steatohepatitis or NAFLD activity
      score, had shorter survival times than patients without fibrosis.
    explanation: >-
      A 619-patient longitudinal cohort establishes fibrosis, and not
      inflammatory activity, as the outcome-determining lesion.
  downstream:
  - target: Hepatic Steatosis Progressing to Steatohepatitis and Fibrosis
    description: >-
      Progressive matrix deposition distorts hepatic architecture and yields
      cirrhosis, portal hypertension, hepatic decompensation, and hepatocellular
      carcinoma.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25935633
      reference_title: Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Twenty-six patients (4.2%) developed liver-related events; fibrosis stage
        3 (HR, 14.2; 95% CI, 3.38-59.68) and stage 4 (HR, 51.5; 95% CI,
        9.87-269.2) compared with stage 0, were associated significantly with the
        events.
      explanation: >-
        Quantifies the stage-dependent escalation from fibrosis to
        liver-related clinical events.

- name: Hepatic Steatosis Progressing to Steatohepatitis and Fibrosis
  conforms_to: 'hepatic_steatosis_lipotoxicity#Hepatic Steatosis Progressing to Steatohepatitis and Fibrosis'
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The convergent clinical outcome: bland steatosis advancing through
    steatohepatitis to bridging fibrosis, cirrhosis, hepatic decompensation, and
    hepatocellular carcinoma. Most people with MASLD never reach this end of the
    spectrum, but fibrosis stage stratifies who will.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:25935633
    reference_title: Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a longitudinal study of patients with NAFLD, fibrosis stage, but no
      other histologic features of steatohepatitis, were associated independently
      with long-term overall mortality, liver transplantation, and liver-related
      events.
    explanation: >-
      Defines the clinical consequence set (mortality, transplantation,
      liver-related events) and its histologic determinant.

- name: PNPLA3 rs738409 Genetic Susceptibility
  biological_scale: MOLECULAR
  role: susceptibility
  description: >-
    The PNPLA3 rs738409 (I148M) allele increases hepatic triglyceride content and
    hepatic inflammation, and accounts for much of the ancestry-related variation
    in susceptibility to fatty liver. It is a susceptibility modifier of lipid
    retention rather than a necessary or sufficient cause of MASLD.
  genes:
  - preferred_term: PNPLA3
    term:
      id: hgnc:18590
      label: PNPLA3
  evidence:
  - reference: PMID:18820647
    reference_title: Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      strongly associated with increased hepatic fat levels (P = 5.9 x 10(-10))
      and with hepatic inflammation (P = 3.7 x 10(-4)).
    explanation: >-
      The genome-wide association scan establishes the rs738409 allele as
      associated with both hepatic fat and inflammation.
  downstream:
  - target: Hepatocyte Lipid Overload
    description: >-
      Carriage of the 148M allele raises steady-state hepatic triglyceride
      content, shifting the lipid-overload node toward disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:18820647
      reference_title: Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        variation in PNPLA3 contributes to ancestry-related and inter-individual
        differences in hepatic fat content and susceptibility to NAFLD.
      explanation: >-
        Links the locus to hepatic fat content while leaving the molecular
        intermediates unresolved.

- name: TM6SF2 p.Glu167Lys Genetic Susceptibility
  biological_scale: MOLECULAR
  role: susceptibility
  description: >-
    The TM6SF2 p.Glu167Lys variant reduces TM6SF2 protein levels and impairs
    hepatic very-low-density lipoprotein export, raising liver triglyceride while
    lowering circulating LDL cholesterol and triglycerides. It is the
    prototypical example of the discordance between hepatic fat accumulation and
    cardiovascular lipid risk in MASLD.
  genes:
  - preferred_term: TM6SF2
    term:
      id: hgnc:11861
      label: TM6SF2
  evidence:
  - reference: PMID:24531328
    reference_title: Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The TM6SF2 variant encoding p.Glu167Lys was also associated with higher
      circulating levels of alanine transaminase, a marker of liver injury, and
      with lower levels of low-density lipoprotein-cholesterol (LDL-C),
      triglycerides and alkaline phosphatase in 3 independent populations
    explanation: >-
      Establishes the variant's paired hepatic-injury and lipid-lowering
      signature across three independent cohorts.
  downstream:
  - target: Hepatocyte Lipid Overload
    description: >-
      Reduced TM6SF2 protein impairs very-low-density lipoprotein export, so
      triglyceride is retained in the hepatocyte.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced TM6SF2 protein abundance
    - Impaired hepatic VLDL secretion
    evidence:
    - reference: PMID:24531328
      reference_title: Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        When recombinant protein was expressed in cultured hepatocytes, 50% less
        Glu167Lys TM6SF2 protein was produced relative to wild-type TM6SF2.
      explanation: >-
        Identifies reduced protein abundance as the intermediate between genotype
        and hepatic lipid retention.

- name: Obstructive Sleep Apnea-Associated Chronic Intermittent Hypoxia
  biological_scale: ORGANISM
  role: trigger
  description: >-
    Obstructive sleep apnea imposes repeated nocturnal
    desaturation-reoxygenation cycles on the liver. The exposure is quantified
    clinically by the apnea-hypopnea index, the oxygen desaturation index, and
    the proportion of sleep time spent below 90% saturation, and it is these
    hypoxia metrics rather than the arousal burden that track hepatic severity.
    The node is curated as a comorbid, potentially modifiable initiating context
    that sits alongside — not inside — the cardiometabolic trigger, because the
    two are strongly correlated through obesity and the curated evidence
    disagrees about how much survives adjustment for it. Sleep fragmentation is
    deliberately not modeled here: the studies that separate the two attribute
    the hepatic signal to the hypoxic component.
  biological_processes:
  - preferred_term: response to hypoxia
    term:
      id: GO:0001666
      label: response to hypoxia
    modifier: INCREASED
    temporality: RECURRENT
  evidence:
  - reference: PMID:21703181
    reference_title: Chronic intermittent hypoxia is a major trigger for non-alcoholic
      fatty liver disease in morbid obese.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In multivariate analysis, after adjustment for age, obesity, and insulin
      resistance status, CIH remained independently associated with hepatic
      fibrosis, fibroinflammation, and NAS.
    explanation: >-
      101 prospectively recruited morbidly obese patients with intraoperative
      liver biopsy and desaturation-index-graded hypoxia. This is the strongest
      curated statement that the hypoxic exposure carries hepatic signal after
      adjustment for the adiposity it travels with.
  - reference: PMID:40884485
    reference_title: Association between obstructive sleep apnea and liver fibrosis
      in patients with suspected nonalcoholic fatty liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Similar association was found with nocturnal hypoxia markers (oxygen
      desaturation index and the time spent under 90% of saturation).
    explanation: >-
      Biopsy-proven cohort with in-lab polysomnography; establishes that the
      hypoxia metrics, not merely the OSA label, are what carry the association,
      which is why this node is named for the hypoxic exposure.
  downstream:
  - target: Hypoxia-Driven Hepatic Lipogenesis and Oxidative Stress
    description: >-
      Cyclical desaturation-reoxygenation is the upstream exposure that drives
      the hepatic lipogenic and oxidative response.
    causal_link_type: DIRECT
    hypothesis_groups:
    - osa_intermittent_hypoxia_masld
    evidence:
    - reference: PMID:16123334
      reference_title: Intermittent hypoxia induces hyperlipidemia in lean mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In lean mice, IH increased sterol regulatory element binding protein 1
        (SREBP-1) levels in the liver, increased mRNA and protein levels of
        stearoyl-coenzyme A desaturase 1 (SCD-1), an important gene of TG and PL
        biosynthesis controlled by SREBP-1
      explanation: >-
        A controlled five-day intermittent-hypoxia exposure, which is what makes
        this an edge rather than a correlation. Murine, and the same study found
        no additional effect in already-obese mice.

- name: Hypoxia-Driven Hepatic Lipogenesis and Oxidative Stress
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    Intermittent hypoxia raises hepatic SREBP-1 and its target stearoyl-CoA
    desaturase 1, increasing triglyceride and phospholipid biosynthesis, and the
    reoxygenation half of each cycle generates reactive oxygen species so that
    the hepatocyte experiences a repeated ischemia-reperfusion-like insult. The
    lipogenic limb is HIF-1-dependent in mice; the oxidative limb is the one
    measured directly in human liver, as in-situ 4-hydroxynonenal staining and
    urinary F2-isoprostanes that scale with the nocturnal hypoxia metrics. The
    node therefore feeds both the lipid-overload state and the injury state of
    the canonical backbone rather than substituting for either.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: cellular response to hypoxia
    term:
      id: GO:0071456
      label: cellular response to hypoxia
    modifier: INCREASED
  - preferred_term: triglyceride biosynthetic process
    term:
      id: GO:0019432
      label: triglyceride biosynthetic process
    modifier: INCREASED
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  evidence:
  - reference: PMID:27501738
    reference_title: Nocturnal hypoxia-induced oxidative stress promotes progression
      of pediatric non-alcoholic fatty liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data support the role of nocturnal hypoxia as a trigger for localized
      hepatic oxidative stress, an important factor associated with the
      progression of NASH and hepatic fibrosis in obese pediatric patients.
    explanation: >-
      The human measurement behind the oxidative limb — urinary F2-isoprostanes
      and hepatic 4-hydroxynonenal immunostaining in biopsy-proven NAFLD, both
      correlating with the polysomnographic hypoxia metrics. Paediatric, so the
      age generalization is not asserted.
  - reference: PMID:16123334
    reference_title: Intermittent hypoxia induces hyperlipidemia in lean mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In lean mice, exposure to IH increased fasting serum levels of total
      cholesterol, high-density lipoprotein (HDL) cholesterol, phospholipids
      (PLs), and triglycerides (TGs), as well as liver TG content.
    explanation: >-
      Supplies the lipogenic limb, including the liver triglyceride readout, in
      an exposure-controlled model.
  downstream:
  - target: Hepatocyte Lipid Overload
    description: >-
      SREBP-1/SCD-1 upregulation adds a hypoxia-driven de novo lipogenesis inflow
      on top of the adipose-derived and dietary inflows of the canonical model.
      As on the fibrosis edge, the human results are curated in disagreement
      rather than chosen between, but the disagreement runs the opposite way
      here: the largest individual-participant dataset finds apnea severity an
      independent risk factor for steatosis after adjustment, while the small
      biopsy-scored cohort finds no association with histological steatosis. The
      two measure steatosis differently (a noninvasive hepatic steatosis index
      in 2120 patients versus liver histology in 97), which is the most likely
      source of the discrepancy and is itself unresolved.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Hepatic SREBP-1 induction
    - Stearoyl-CoA desaturase 1 upregulation
    hypothesis_groups:
    - osa_intermittent_hypoxia_masld
    evidence:
    - reference: PMID:16123334
      reference_title: Intermittent hypoxia induces hyperlipidemia in lean mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We conclude that exposure to IH for five days increases serum cholesterol
        and PL levels, upregulates pathways of TG and PL biosynthesis, and
        inhibits pathways of cholesterol uptake in the liver in the lean state
      explanation: >-
        Names the biosynthetic pathways and the hepatic compartment, supporting
        the edge into the lipid-overload node.
    - reference: PMID:32843301
      reference_title: 'Obstructive sleep apnea, chronic obstructive pulmonary disease
        and NAFLD: an individual participant data meta-analysis.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In multivariable analysis, risk factors for steatosis were an
        apnea-hypopnea index (AHI) > 5/h, body mass index (BMI) > 26 kg/m2, age,
        type 2 diabetes (all p-values <0.01) and male gender (p = 0.02).
      explanation: >-
        The strongest human result on this edge, and the reason the steatosis
        limb is the one that survives in this hypothesis: in 2120 patients apnea
        severity remains an independent risk factor for steatosis alongside BMI
        rather than being displaced by it. Steatosis was scored by the
        noninvasive Hepatic Steatosis Index, not by biopsy.
    - reference: PMID:40884485
      reference_title: Association between obstructive sleep apnea and liver fibrosis
        in patients with suspected nonalcoholic fatty liver disease.
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        No association was observed between moderate to severe OSA and steatosis
        or nonalcoholic steatohepatitis.
      explanation: >-
        The counter-result on this edge, from the same cohort whose fibrosis
        finding is curated as SUPPORT above. In 97 patients with percutaneous
        liver biopsy the hypoxic exposure tracked fibrosis but not histological
        steatosis, so the study that most directly measures the lipid-overload
        endpoint does not see the effect.
  - target: Hepatocyte Injury and Inflammatory Activation
    description: >-
      Cyclical reoxygenation generates hepatic lipid peroxidation, which is
      associated with lobular inflammation and steatohepatitis severity. The
      association is with the oxidative readout rather than with the OSA
      diagnosis: the biopsy-scored cohort that graded steatohepatitis directly
      found no association between moderate to severe apnea and NASH, so this
      edge rests on the measured peroxidation rather than on the exposure label.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - osa_intermittent_hypoxia_masld
    evidence:
    - reference: PMID:27501738
      reference_title: Nocturnal hypoxia-induced oxidative stress promotes progression
        of pediatric non-alcoholic fatty liver disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Greater oxidative stress occurred in subjects with definite NASH as
        measured by F(2)-isoprostanes (p=0.06) and hepatic 4HNE (p=0.03) compared
        to those with borderline/not NASH.
      explanation: >-
        Ties the oxidative readout to steatohepatitis rather than to steatosis
        alone. Cross-sectional, hence the unknown-intermediates link type.
    - reference: PMID:40884485
      reference_title: Association between obstructive sleep apnea and liver fibrosis
        in patients with suspected nonalcoholic fatty liver disease.
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        No association was observed between moderate to severe OSA and steatosis
        or nonalcoholic steatohepatitis.
      explanation: >-
        Graded by the NASH-CRN scoring system on percutaneous liver biopsy, so
        this is a direct negative measurement of the endpoint this edge asserts.
        Kept on the edge rather than in prose so the disagreement with the
        paediatric oxidative-stress result is visible in the graph.
  - target: Hepatic Stellate Cell Activation and Fibrosis
    description: >-
      Whether the hypoxic exposure drives fibrosis independently of adiposity is
      contested: biopsy-based cohorts report an association surviving adjustment
      for obesity, while individual-participant meta-analysis assigns it to body
      mass index. The edge is curated with both results attached rather than
      chosen between.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - osa_intermittent_hypoxia_masld
    evidence:
    - reference: PMID:40884485
      reference_title: Association between obstructive sleep apnea and liver fibrosis
        in patients with suspected nonalcoholic fatty liver disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The association between moderate to severe OSA and advanced fibrosis
        remained significant after adjustment for sex, age, diabetes and obesity
      explanation: >-
        97 patients with percutaneous liver biopsy and in-lab polysomnography;
        the adjustment for obesity is what makes this evidence for the edge
        rather than for confounding.
    - reference: PMID:32843301
      reference_title: 'Obstructive sleep apnea, chronic obstructive pulmonary disease
        and NAFLD: an individual participant data meta-analysis.'
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        AHI severity was not associated with fibrosis.
      explanation: >-
        The counter-result, kept on the edge so the disagreement is visible in
        the graph rather than only in prose: in 2218 patients the fibrosis risk
        factors were BMI, age, male gender and type 2 diabetes, not apnea
        severity.
genetic:
- name: PNPLA3 rs738409 susceptibility
  gene_term:
    preferred_term: PNPLA3
    term:
      id: hgnc:18590
      label: PNPLA3
  association: >-
    The rs738409 (I148M) allele increases hepatic fat content and hepatic
    inflammation and accounts for a large fraction of ancestry-related variation
    in fatty liver susceptibility. It is neither necessary nor sufficient for
    MASLD.
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:18820647
    reference_title: Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The allele was most common in Hispanics, the group most susceptible to
      NAFLD
    explanation: >-
      Documents the ancestry-patterned allele frequency underlying differential
      susceptibility, consistent with a modifier rather than a monogenic cause.
- name: TM6SF2 p.Glu167Lys susceptibility
  gene_term:
    preferred_term: TM6SF2
    term:
      id: hgnc:11861
      label: TM6SF2
  association: >-
    The p.Glu167Lys (rs58542926) variant reduces TM6SF2 protein and hepatic
    very-low-density lipoprotein export, raising liver fat and alanine
    transaminase while lowering plasma LDL cholesterol and triglycerides.
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:24531328
    reference_title: Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three variants were associated with higher liver fat levels at the
      exome-wide significance level of 3.6 × 10(-7): two in PNPLA3, an
      established locus for NAFLD, and one (encoding p.Glu167Lys) in TM6SF2, a
      gene of unknown function.
    explanation: >-
      The exome-wide association study identifies the variant at exome-wide
      significance for liver fat content.
- name: GCKR common-variant susceptibility
  gene_term:
    preferred_term: GCKR
    term:
      id: hgnc:4196
      label: GCKR
  association: GCKR variation is a replicated common-variant susceptibility locus for MASLD.
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:32145256
    reference_title: "Update on NAFLD genetics: From new variants to the clinic."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: reproducible associations between variations in genes such as PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13
    explanation: The genetics review lists GCKR among reproducibly associated NAFLD/MASLD loci.
- name: MBOAT7 common-variant susceptibility
  gene_term:
    preferred_term: MBOAT7
    term:
      id: hgnc:15505
      label: MBOAT7
  association: MBOAT7 variation is a replicated common-variant susceptibility locus for MASLD.
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:32145256
    reference_title: "Update on NAFLD genetics: From new variants to the clinic."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: reproducible associations between variations in genes such as PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13
    explanation: The genetics review lists MBOAT7 among reproducibly associated NAFLD/MASLD loci.
- name: HSD17B13 rs72613567 protective variant
  gene_term:
    preferred_term: HSD17B13
    term:
      id: hgnc:18685
      label: HSD17B13
  association: >-
    The protein-truncating rs72613567:TA variant reduces progression from
    steatosis to steatohepatitis without preventing steatosis itself.
  relationship_type: PROTECTIVE
  variant_origin: GERMLINE
  variants:
  - name: rs72613567:TA
    description: Protein-truncating splice variant associated with reduced steatohepatitis risk.
  evidence:
  - reference: PMID:29562163
    reference_title: "A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis
    explanation: The human association separates protection from steatohepatitis progression from susceptibility to steatosis.
phenotypes:
- category: Gastrointestinal
  name: Hepatic steatosis
  description: >-
    Excess triglyceride stored in hepatocyte lipid droplets is the defining
    lesion of MASLD and is detected by imaging or histology.
  phenotype_term:
    preferred_term: Hepatic steatosis
    term:
      id: HP:0001397
      label: Hepatic steatosis
  evidence:
  - reference: PMID:15864352
    reference_title: Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nonalcoholic fatty liver disease (NAFLD) is characterized by the
      accumulation of excess liver triacylglycerol (TAG), inflammation, and liver
      damage.
    explanation: >-
      Identifies hepatic triacylglycerol accumulation as the characteristic
      lesion.
- category: Laboratory
  name: Elevated serum alanine aminotransferase
  description: >-
    Aminotransferase elevation is a common but insensitive marker of hepatocyte
    injury in MASLD; normal values do not exclude steatohepatitis or fibrosis.
  phenotype_term:
    preferred_term: Elevated circulating alanine aminotransferase concentration
    term:
      id: HP:0031964
      label: Elevated circulating alanine aminotransferase concentration
  evidence:
  - reference: PMID:24531328
    reference_title: Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      higher circulating levels of alanine transaminase, a marker of liver injury
    explanation: >-
      Links raised circulating alanine transaminase to liver injury in fatty
      liver disease cohorts.
- category: Endocrine
  name: Insulin resistance
  description: >-
    Impaired insulin action in adipose tissue, muscle, and liver is a
    definitional cardiometabolic feature of MASLD.
  phenotype_term:
    preferred_term: Insulin resistance
    term:
      id: HP:0000855
      label: Insulin resistance
  evidence:
  - reference: PMID:42412329
    reference_title: 'Mitophagy in Metabolic Dysfunction-Associated Fatty Liver Disease: Mechanisms, Regulatory Networks, and Therapeutic Perspectives.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      with pathogenesis closely linked to insulin resistance, obesity, and gut
      microbiota dysbiosis
    explanation: >-
      Places insulin resistance among the core metabolic features of MASLD.
- category: Endocrine
  name: Obesity
  description: >-
    Overweight or obesity is the most common qualifying cardiometabolic risk
    factor, though MASLD also occurs in people with normal body mass index.
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  evidence:
  - reference: PMID:32553765
    reference_title: Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed a prospective study of 180 severely obese patients with
      biopsy-proven NASH
    explanation: >-
      A biopsy-proven steatohepatitis cohort recruited on the basis of severe
      obesity documents the association.
- category: Gastrointestinal
  name: Hepatic fibrosis
  description: >-
    Excessive extracellular matrix deposition after sustained hepatocyte injury.
    Fibrosis stage is the histologic feature most strongly tied to outcome.
  phenotype_term:
    preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:25935633
    reference_title: Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      stage 2 (HR, 2.89; 95% CI, 1.93-4.33), stage 3 (HR, 3.76; 95% CI,
      2.40-5.89), and stage 4 (HR, 10.9; 95% CI, 6.06-19.62) compared with stage
      0
    explanation: >-
      Documents fibrosis across histologic stages in a MASLD cohort together with
      its prognostic gradient.
- category: Gastrointestinal
  name: Cirrhosis
  description: >-
    Advanced, architecture-distorting fibrosis reached by a minority of people
    with MASLD, carrying the risk of decompensation and hepatocellular carcinoma.
  phenotype_term:
    preferred_term: Cirrhosis
    term:
      id: HP:0001394
      label: Cirrhosis
  evidence:
  - reference: PMID:25935633
    reference_title: Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty-six patients (4.2%) developed liver-related events; fibrosis stage 3
      (HR, 14.2; 95% CI, 3.38-59.68) and stage 4 (HR, 51.5; 95% CI, 9.87-269.2)
      compared with stage 0, were associated significantly with the events.
    explanation: >-
      Stage 4 fibrosis is cirrhosis; in a 619-patient longitudinal MASLD cohort it
      carried by far the highest hazard of liver-related events, establishing
      cirrhosis as a human clinical endpoint of the disease.
- category: Gastrointestinal
  name: Hepatocellular carcinoma
  description: Advanced steatohepatitis can progress through cirrhosis to hepatocellular carcinoma.
  phenotype_term:
    preferred_term: Hepatocellular carcinoma
    term:
      id: HP:0001402
      label: Hepatocellular carcinoma
  evidence:
  - reference: PMID:33989548
    reference_title: "Mechanisms and disease consequences of nonalcoholic fatty liver disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Its more advanced subtype, nonalcoholic steatohepatitis (NASH), connotes progressive liver injury that can lead to cirrhosis and hepatocellular carcinoma.
    explanation: The review identifies hepatocellular carcinoma as a distal outcome of progressive steatohepatitis.
histopathology:
- name: Macrovesicular Steatosis
  finding_term:
    preferred_term: Macrovesicular steatosis
    term:
      id: NCIT:C82990
      label: Macrovesicular Steatosis
  description: >-
    Large-droplet triglyceride accumulation displacing the hepatocyte nucleus, the
    defining lesion of the disease and the entry criterion for any steatotic liver
    disease diagnosis. Graded 0-3 as the first component of the NAFLD activity
    score.
  diagnostic: true
  evidence:
  - reference: PMID:28585211
    reference_title: Non-Alcoholic Fatty Liver Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      NAFLD is characterized by excess accumulation of triglyceride in the
      hepatocyte due to both increased inflow of free fatty acids and de novo
      hepatic lipogenesis.
    explanation: >-
      Identifies intrahepatocellular triglyceride accumulation as the defining
      histologic lesion.
  - reference: PMID:38324483
    reference_title: A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the components of this measure are steatosis (assessed on a scale of 0 to
      3), lobular inflammation (assessed on a scale of 0 to 3), and hepatocellular
      ballooning (assessed on a scale of 0 to 2).
    explanation: >-
      Steatosis is the first of the three graded histologic components of the
      NAFLD activity score used in the registrational trial.
- name: Lobular Inflammation
  finding_term:
    preferred_term: Lobular inflammation
    term:
      id: NCIT:C35978
      label: Inflammatory Infiltrate
  description: >-
    Mixed inflammatory cell infiltration of the hepatic lobule, the inflammatory
    component that distinguishes steatohepatitis (MASH) from bland steatosis
    (MASL). Graded 0-3 within the NAFLD activity score.
  evidence:
  - reference: PMID:38324483
    reference_title: A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the components of this measure are steatosis (assessed on a scale of 0 to
      3), lobular inflammation (assessed on a scale of 0 to 3), and hepatocellular
      ballooning (assessed on a scale of 0 to 2).
    explanation: >-
      Establishes lobular inflammation as a separately graded histologic component
      of the activity score.
- name: Hepatocellular Ballooning
  finding_term:
    preferred_term: Hepatocellular ballooning degeneration
  description: >-
    Swollen hepatocytes with rarefied, wispy cytoplasm and loss of the normal
    polygonal outline - the morphologic signature of lipotoxic hepatocyte injury
    and the feature whose disappearance defines histologic MASH resolution in
    trials. Graded 0-2 within the NAFLD activity score. No NCIT morphologic-finding
    term exists for this lesion (NCIT:C181484 codes the grading assessment, not the
    finding), so this descriptor is deliberately left unbound.
  diagnostic: true
  evidence:
  - reference: PMID:38324483
    reference_title: A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the components of this measure are steatosis (assessed on a scale of 0 to
      3), lobular inflammation (assessed on a scale of 0 to 3), and hepatocellular
      ballooning (assessed on a scale of 0 to 2).
    explanation: >-
      Establishes ballooning as the third separately graded histologic component
      of the activity score.
  - reference: PMID:38324483
    reference_title: A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NAFLD activity scores of 4 or more are considered to indicate at-risk
      nonalcoholic steatohepatitis (NASH).
    explanation: >-
      Ties the composite activity score, of which ballooning is a required
      component, to the at-risk steatohepatitis designation.
- name: Perisinusoidal Fibrosis Progressing to Bridging Fibrosis and Cirrhosis
  finding_term:
    preferred_term: Perisinusoidal (pericellular) fibrosis
    term:
      id: NCIT:C3044
      label: Fibrosis
  description: >-
    Collagen deposition beginning in the perisinusoidal space of zone 3 and
    progressing through periportal and bridging fibrosis to cirrhosis. Staged F0-F4;
    this is the histologic feature that determines outcome, and unlike the activity
    components it is not captured by the NAFLD activity score.
  evidence:
  - reference: PMID:38324483
    reference_title: A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fibrosis stages range from F0 (no fibrosis) to F4 (cirrhosis). A stage of F1B
      indicates moderate fibrosis, pericentral area only.
    explanation: >-
      Defines the fibrosis staging scale, including the pericentral
      (perisinusoidal, zone 3) pattern characteristic of early MASH.
  - reference: PMID:25935633
    reference_title: Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with fibrosis, regardless of steatohepatitis or NAFLD activity
      score, had shorter survival times than patients without fibrosis.
    explanation: >-
      Establishes fibrosis - not the activity components - as the
      outcome-determining histologic feature.
treatments:
- name: Weight loss through lifestyle modification
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: >-
    Hypocaloric diet and increased physical activity, targeting sustained weight
    loss. The histologic benefit is dose-dependent: 7-10% loss improves
    steatohepatitis and 10% or more is associated with the highest rates of MASH
    resolution and fibrosis regression. This remains the foundational
    intervention for all disease stages.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Hepatocyte Lipid Overload
    treatment_effect: INHIBITS
    description: >-
      Negative energy balance reduces adipose lipolytic flux and de novo
      lipogenesis, lowering hepatocyte lipid loading.
    evidence:
    - reference: PMID:25865049
      reference_title: Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Degree of weight loss was independently associated with improvements in
        all NASH-related histologic parameters
      explanation: >-
        Shows a dose-response between weight loss and improvement of the
        histologic features driven by hepatic lipid loading.
  evidence:
  - reference: PMID:25865049
    reference_title: Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A greater extent of weight loss, induced by lifestyle changes, is
      associated with the level of improvement in histologic features of NASH.
    explanation: >-
      The trial conclusion establishing the dose-dependent histologic benefit of
      lifestyle-induced weight loss.
- name: Resmetirom
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    An oral, liver-directed, thyroid hormone receptor beta-selective agonist that
    increases hepatic fatty acid oxidation. In the MAESTRO-NASH phase 3 trial it
    was superior to placebo for both MASH resolution and fibrosis improvement in
    patients with F1B-F3 fibrosis, and it is the first agent approved
    specifically for this indication.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: resmetirom
      term:
        id: NCIT:C170368
        label: Resmetirom
  target_mechanisms:
  - target: Hepatocyte Lipid Overload
    treatment_effect: INHIBITS
    description: >-
      Hepatic thyroid hormone receptor beta agonism increases fatty acid
      oxidation and lowers hepatic lipid content.
    evidence:
    - reference: PMID:38324483
      reference_title: A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Resmetirom is an oral, liver-directed, thyroid hormone receptor
        beta-selective agonist in development for the treatment of NASH with
        liver fibrosis.
      explanation: >-
        Identifies the liver-directed receptor target through which the drug acts
        on hepatic lipid handling.
  evidence:
  - reference: PMID:38324483
    reference_title: A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both the 80-mg dose and the 100-mg dose of resmetirom were superior to
      placebo with respect to NASH resolution and improvement in liver fibrosis
      by at least one stage.
    explanation: >-
      The phase 3 primary-endpoint result supporting the indication in MASH with
      fibrosis.
- name: Semaglutide
  action_category: THERAPEUTIC
  therapeutic_modality: PEPTIDE
  description: >-
    A glucagon-like peptide-1 receptor agonist that produces substantial weight
    loss and improves glycaemia. A 72-week phase 2 trial increased MASH resolution
    relative to placebo but found no significant fibrosis-stage benefit; that null
    result has since been superseded by the phase 3 ESSENCE trial, whose week-72
    interim analysis in 800 patients with MASH and F2-F3 fibrosis met both primary
    endpoints, including reduction in liver fibrosis. Its modeled effect therefore
    runs through both the upstream cardiometabolic driver and the fibrogenic arm.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: semaglutide
      term:
        id: NCIT:C152328
        label: Semaglutide
  target_mechanisms:
  - target: Cardiometabolic Dysfunction and Adipose Insulin Resistance
    treatment_effect: INHIBITS
    description: >-
      Weight loss and improved insulin sensitivity reduce the adipose lipolytic
      and lipogenic drive that initiates the pathograph.
    evidence:
    - reference: PMID:33185364
      reference_title: A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The mean percent weight loss was 13% in the 0.4-mg group and 1% in the
        placebo group.
      explanation: >-
        Documents the weight-loss magnitude that underlies the effect on the
        cardiometabolic trigger node.
    - reference: PMID:39266553
      reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
        resistance in a human iPSC-based microphysiological system.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        These findings show that semaglutide prevents lipid accumulation and insulin
        resistance in hepatocytes by reducing WAT inflammation.
      explanation: >-
        Localizes the drug's action to the adipose compartment specifically, which is
        why the modeled effect is placed on this cardiometabolic node rather than on
        a hepatocyte node. In an isogenic human iPSC adipose-liver chip, semaglutide
        delivered only to the adipocyte compartment reproduced the whole-system
        benefit while delivery only to the hepatocyte compartment did not. Graded
        INDIRECT because the mechanism is established in a non-animal human model
        system, not in the patients whose histologic benefit the trial evidence above
        records.
  - target: Hepatic Stellate Cell Activation and Fibrosis
    treatment_effect: INHIBITS
    description: >-
      The phase 3 ESSENCE interim analysis showed a significant reduction in
      fibrosis stage without worsening of steatohepatitis, so the fibrogenic arm
      improves under treatment. Whether the drug acts directly on that arm is a
      separate question this edge deliberately leaves open: the reduction is equally
      consistent with fibrosis regressing once the lipotoxic and inflammatory
      drive upstream is removed. Two observations favour the downstream reading.
      In the phase 2 trial a 13% weight loss and a large resolution effect bought
      no significant fibrosis benefit at 72 weeks, and in MASH-related cirrhosis
      — where fibrosis is established and no longer coupled to steatohepatitis
      activity — fibrosis improvement was numerically lower on semaglutide than
      on placebo. Human stellate cells also carry no demonstrated GLP-1 receptor
      and do not respond to receptor agonism in culture, so a direct action on
      this node has no established substrate. See the
      semaglutide_weight_independent_hepatic_effect hypothesis.
    evidence:
    - reference: PMID:36934740
      reference_title: 'Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial.'
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        five [11%] of 47 patients in the semaglutide group vs seven [29%] of 24 in
        the placebo group; odds ratio 0·28 [95% CI 0·06-1·24; p=0·087)
      explanation: >-
        Bounds this edge rather than removing it. In established cirrhosis a
        direct antifibrotic action should still be visible, and fibrosis
        improvement was numerically lower on semaglutide. Not significant, and in
        a later disease stage than the F2-F3 population the edge is drawn for, so
        it argues against reading the edge as a direct action without refuting
        the fibrosis benefit itself.
    - reference: PMID:40305708
      reference_title: Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A reduction in liver fibrosis without worsening of steatohepatitis was
        reported in 36.8% of the patients in the semaglutide group and in 22.4% of
        those in the placebo group
      explanation: >-
        Quantifies the fibrosis-stage benefit that justifies modeling an effect on
        the fibrogenic node.
  evidence:
  - reference: PMID:40305708
    reference_title: Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9%
      of the 534 patients in the semaglutide group and in 34.3% of the 266 patients
      in the placebo group
    explanation: >-
      The phase 3 primary endpoint for steatohepatitis resolution, superseding the
      phase 2 estimate.
  - reference: PMID:40305708
    reference_title: Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with MASH and moderate or advanced liver fibrosis, once-weekly
      semaglutide at a dose of 2.4 mg improved liver histologic results.
    explanation: >-
      The trial's own conclusion, covering both histologic endpoints in F2-F3
      disease.
  - reference: PMID:33185364
    reference_title: A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This phase 2 trial involving patients with NASH showed that treatment with
      semaglutide resulted in a significantly higher percentage of patients with
      NASH resolution than placebo.
    explanation: >-
      The earlier phase 2 trial that first established the steatohepatitis
      resolution benefit later confirmed in phase 3.
  - reference: PMID:33185364
    reference_title: A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, the trial did not show a significant between-group difference in
      the percentage of patients with an improvement in fibrosis stage.
    explanation: >-
      Retained for provenance: this phase 2 null result on fibrosis was the
      standing claim until the larger phase 3 trial (PMID:40305708) demonstrated a
      significant fibrosis benefit, and it is superseded by that result.
- name: Vitamin E
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    High-dose alpha-tocopherol improved steatohepatitis histology relative to
    placebo in the PIVENS trial in adults with MASH without diabetes, but did not
    improve fibrosis scores. Its modeled action is on the oxidative-stress
    amplifier node.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: vitamin E
      term:
        id: CHEBI:33234
        label: vitamin E
  target_mechanisms:
  - target: Lipotoxic Stress and Organelle Dysfunction
    treatment_effect: INHIBITS
    description: >-
      Antioxidant activity is proposed to blunt the reactive-oxygen-species arm
      of lipotoxic organelle stress.
    evidence:
    - reference: PMID:20427778
      reference_title: Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        both agents were associated with reductions in hepatic steatosis (P=0.005
        for vitamin E and P<0.001 for pioglitazone) and lobular inflammation
        (P=0.02 for vitamin E and P=0.004 for pioglitazone) but not with
        improvement in fibrosis scores
      explanation: >-
        Supports an effect on steatosis and inflammation while explicitly
        excluding a fibrosis benefit.
  evidence:
  - reference: PMID:20427778
    reference_title: Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vitamin E was superior to placebo for the treatment of nonalcoholic
      steatohepatitis in adults without diabetes.
    explanation: >-
      The trial conclusion, including its restriction to adults without diabetes.
- name: Pioglitazone
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    A PPAR-gamma agonist insulin sensitizer. In PIVENS it reduced steatosis,
    inflammation, and aminotransferases but did not meet the primary histologic
    endpoint in adults without diabetes, and caused weight gain. Modeled as
    acting on the cardiometabolic trigger.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pioglitazone
      term:
        id: CHEBI:8228
        label: pioglitazone
  target_mechanisms:
  - target: Cardiometabolic Dysfunction and Adipose Insulin Resistance
    treatment_effect: INHIBITS
    description: >-
      Insulin sensitization restrains adipose lipolysis and reduces fatty acid
      delivery to the liver.
    evidence:
    - reference: PMID:20427778
      reference_title: Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Serum alanine and aspartate aminotransferase levels were reduced with
        vitamin E and with pioglitazone, as compared with placebo (P<0.001 for
        both comparisons)
      explanation: >-
        Documents a biochemical treatment effect for the insulin sensitizer
        without asserting a histologic primary-endpoint benefit.
  evidence:
  - reference: PMID:20427778
    reference_title: Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the difference in the rate of improvement with pioglitazone as compared
      with placebo was not significant (34% and 19%, respectively; P=0.04)
    explanation: >-
      The primary histologic comparison for pioglitazone did not reach the
      prespecified significance threshold, bounding the claim.
- name: Bariatric surgery
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  description: >-
    Metabolic (bariatric) surgery in people with severe obesity and biopsy-proven
    MASH produced resolution of steatohepatitis in most patients at five years,
    with progressive fibrosis regression. Evidence is from a prospective cohort
    with paired biopsies rather than a randomized trial.
  treatment_term:
    preferred_term: bariatric surgery
    term:
      id: NCIT:C84399
      label: Bariatric Surgery
  target_mechanisms:
  - target: Hepatic Stellate Cell Activation and Fibrosis
    treatment_effect: INHIBITS
    description: >-
      Sustained large-magnitude weight loss removes the upstream metabolic drive
      and permits regression of established fibrosis.
    evidence:
    - reference: PMID:32553765
      reference_title: Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Fibrosis began to decrease by 1 year after surgery and continued to
        decrease until 5 years
      explanation: >-
        Documents progressive regression of the fibrotic effector lesion after
        surgery.
  evidence:
  - reference: PMID:32553765
    reference_title: Bariatric Surgery Provides Long-term Resolution of Nonalcoholic Steatohepatitis and Regression of Fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 5 years after bariatric surgery, NASH was resolved, without worsening
      fibrosis, in samples from 84% of patients
    explanation: >-
      Gives the five-year steatohepatitis-resolution rate from the paired-biopsy
      cohort.
diagnosis:
- name: Positive cardiometabolic criteria alongside hepatic steatosis
  description: >-
    MASLD is diagnosed positively rather than by exclusion: hepatic steatosis on
    imaging or histology plus at least one of five cardiometabolic risk factors
    (overweight/obesity, dysglycaemia or type 2 diabetes, hypertension,
    hypertriglyceridaemia, low HDL cholesterol). This replaces the old NAFLD
    definition, which required excluding other causes of steatosis. Steatosis with
    no cardiometabolic parameter and no identified cause is classified instead as
    cryptogenic steatotic liver disease.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: >-
    Hepatic steatosis plus at least one of five cardiometabolic risk factors
    establishes MASLD; steatosis with no metabolic parameter and no known cause is
    cryptogenic SLD.
  evidence:
  - reference: PMID:37363821
    reference_title: A multisociety Delphi consensus statement on new fatty liver disease nomenclature.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There was consensus to change the definition to include the presence of at
      least 1 of 5 cardiometabolic risk factors.
    explanation: >-
      The multisociety Delphi consensus establishes the cardiometabolic-criteria
      basis of the current positive case definition.
  - reference: PMID:37363821
    reference_title: A multisociety Delphi consensus statement on new fatty liver disease nomenclature.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Those with no metabolic parameters and no known cause were deemed to have
      cryptogenic steatotic liver disease.
    explanation: >-
      Defines the residual category that the cardiometabolic criteria separate
      MASLD from.
- name: Alcohol-intake assessment to separate MASLD from MetALD
  description: >-
    Weekly alcohol intake must be quantified, because metabolic dysfunction and
    greater alcohol consumption together define MetALD, a category outside pure
    MASLD with different management. The consensus thresholds are 140-350 g/week
    for females and 210-420 g/week for males.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: >-
    Intake above the sex-specific weekly threshold reclassifies the patient as
    MetALD rather than MASLD.
  evidence:
  - reference: PMID:37363821
    reference_title: A multisociety Delphi consensus statement on new fatty liver disease nomenclature.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      termed metabolic and alcohol related/associated liver disease (MetALD), was
      selected to describe those with metabolic dysfunction-associated steatotic
      liver disease, who consume greater amounts of alcohol per week (140-350 g/wk
      and 210-420 g/wk for females and males, respectively).
    explanation: >-
      Gives the sex-specific weekly alcohol thresholds that bound the MASLD
      category.
- name: Ultrasound with controlled attenuation parameter for steatosis detection
  description: >-
    Ultrasound-based controlled attenuation parameter (CAP), measured on the same
    device as transient elastography, non-invasively detects and grades hepatic
    steatosis by the increased attenuation of ultrasound in fat-laden liver. Used
    in the resmetirom phase 3 trial with a threshold of more than 280 dB/m.
  diagnosis_term:
    preferred_term: ultrasound imaging
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  results: >-
    A controlled attenuation parameter above roughly 280 dB/m supports significant
    hepatic steatosis.
  evidence:
  - reference: PMID:38324483
    reference_title: A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Controlled attenuation parameter is a method for the noninvasive assessment
      of steatosis
    explanation: >-
      Establishes CAP as the non-invasive steatosis measure used for trial
      eligibility.
- name: Vibration-controlled transient elastography for fibrosis risk stratification
  description: >-
    Liver stiffness measured by vibration-controlled transient elastography is the
    principal non-invasive test for identifying clinically significant fibrosis and
    is the gateway to specialist referral in MASLD care pathways.
  diagnosis_term:
    preferred_term: elastography
    term:
      id: NCIT:C106517
      label: Elastography
  results: >-
    Liver stiffness above 8.5 kPa indicates fibrosis stage F2 or higher.
  evidence:
  - reference: PMID:38324483
    reference_title: A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver stiffness was measured by means of vibration-controlled transient
      elastography. Values of more than 8.5 are considered to be indicative of
      fibrosis of stage F2 or higher.
    explanation: >-
      Gives the liver-stiffness threshold used to identify clinically significant
      fibrosis.
- name: MRI proton density fat fraction for liver fat quantification
  description: >-
    MRI-PDFF is the quantitative reference standard for non-invasive liver fat
    measurement and is the standard steatosis endpoint in MASH trials.
  diagnosis_term:
    preferred_term: magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  results: >-
    An MRI-PDFF above 5% indicates hepatic steatosis.
  evidence:
  - reference: PMID:38324483
    reference_title: A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      quantitative biomarker to assess liver fat content. A reading of more than 5%
      is considered to be high.
    explanation: >-
      Gives the MRI-PDFF threshold for high liver fat content.
- name: FIB-4 index for advanced fibrosis triage
  description: >-
    The Fibrosis-4 index is a serum-based score derived from platelet count, AST,
    ALT and age. It is the recommended first-line triage test in primary care
    because it uses routinely available results and identifies people who need
    elastography or specialist referral.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: >-
    A FIB-4 score above 2.67 indicates advanced fibrosis and an elevated risk of
    liver-related events.
  evidence:
  - reference: PMID:38324483
    reference_title: A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Scores of more than 2.67 are considered to be indicative of advanced fibrosis
      and an elevated risk of liver-related events.
    explanation: >-
      Gives the FIB-4 threshold for advanced fibrosis and its prognostic
      significance.
- name: Liver biopsy for steatohepatitis activity grading and fibrosis staging
  description: >-
    Percutaneous liver biopsy remains the only test that separates MASH from bland
    steatosis and stages fibrosis directly. It grades the three NAFLD activity score
    components and assigns a fibrosis stage F0-F4, and remains the required endpoint
    measure in registrational MASH trials despite its sampling variability and
    procedural risk.
  diagnosis_term:
    preferred_term: liver biopsy
    term:
      id: NCIT:C51677
      label: Liver Biopsy
  results: >-
    An activity score of 4 or more with at least 1 point for each component
    indicates at-risk MASH; fibrosis is staged F0-F4.
  evidence:
  - reference: PMID:38324483
    reference_title: A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NAFLD activity scores of 4 or more are considered to indicate at-risk
      nonalcoholic steatohepatitis (NASH).
    explanation: >-
      Gives the biopsy-derived activity threshold defining at-risk steatohepatitis.
  - reference: PMID:38324483
    reference_title: A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fibrosis stages range from F0 (no fibrosis) to F4 (cirrhosis). A stage of F1B
      indicates moderate fibrosis, pericentral area only.
    explanation: >-
      Gives the biopsy fibrosis staging scale that determines prognosis and
      treatment eligibility.
animal_models:
- name: AAV8-shRNA hepatic FATP5 knockdown mouse on high-fat diet
  species: Mouse
  genotype: Wild-type C57BL/6 with adeno-associated virus-delivered shRNA silencing
    hepatic Slc27a5 (FATP5)
  background: Diet-induced obesity, high-fat feeding
  publication: PMID:18524776
  genes:
  - preferred_term: SLC27A5
    term:
      id: hgnc:10999
      label: SLC27A5
  description: >-
    A therapeutic-direction rather than an etiologic model: a single
    adeno-associated virus injection delivers shRNA that persistently silences
    FATP5 in mouse liver, applied either before or after diet-induced fatty liver
    is established. Its value is that it tests reversal of existing disease, which
    a germline knockout cannot do, and it does so while high-fat feeding
    continues.
  modeled_mechanisms:
  - target: Transporter-Mediated Hepatic Fatty Acid Uptake
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Directly and specifically removes the transport step this node represents,
      in the intact liver, and reads out the resulting change in hepatic fatty
      acid entry.
    limitations: >-
      Knockdown reduced whole-animal caloric uptake as well as hepatic fatty acid
      uptake, so the two cannot be fully separated in this design. Mouse FATP5
      biology is also assumed rather than shown to match human SLC27A5, and no
      human FATP5-directed agent exists against which to calibrate the model.
    readouts:
    - name: Hepatic dietary fatty acid uptake
      target: Transporter-Mediated Hepatic Fatty Acid Uptake
      direction: DECREASED
      biological_processes:
      - preferred_term: long-chain fatty acid import into hepatocytes
        term:
          id: GO:0044539
          label: long-chain fatty acid import into cell
      interpretation: >-
        Confirms the intended on-target effect: the perturbation reaches the
        transport step rather than acting elsewhere in hepatic lipid metabolism.
      evidence:
      - reference: PMID:18524776
        reference_title: Silencing of hepatic fatty acid transporter protein 5 in
          vivo reverses diet-induced non-alcoholic fatty liver disease and improves
          hyperglycemia.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          resulting in a marked reduction of hepatic dietary fatty acid uptake,
          reduced caloric uptake, and concomitant protection from diet-induced
          non-alcoholic fatty liver disease.
        explanation: >-
          Reports the measured fall in hepatic dietary fatty acid uptake, and in
          the same sentence the caloric-uptake confound recorded in this link's
          limitations.
    evidence:
    - reference: PMID:18524776
      reference_title: Silencing of hepatic fatty acid transporter protein 5 in vivo
        reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        continued activity of hepatic fatty acid transport protein 5 is required
        to sustain caloric uptake and fatty acid flux into the liver during high
        fat feeding
      explanation: >-
        States that the transport step is required to sustain hepatic fatty acid
        flux, which is what makes this model informative for the uptake node.
  - target: Hepatocyte Lipid Overload
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      Silencing the transporter after fatty liver is already established reverses
      it, placing the uptake step causally upstream of the hepatic lipid pool
      rather than merely correlated with it.
    limitations: >-
      Reversal was measured in diet-induced murine fatty liver, which models
      steatosis and metabolic dysfunction but not the fibrotic progression that
      determines human outcome. The concurrent fall in caloric uptake means the
      rescue is not attributable to the hepatic step alone.
    readouts:
    - name: Established diet-induced fatty liver after knockdown
      target: Hepatocyte Lipid Overload
      direction: RESTORED
      biological_processes:
      - preferred_term: lipid storage
        term:
          id: GO:0019915
          label: lipid storage
      interpretation: >-
        Reversal of an already-established lesion, which is the stronger of the
        two possible results and the one that motivates treating hepatic uptake as
        a therapeutic target.
      evidence:
      - reference: PMID:18524776
        reference_title: Silencing of hepatic fatty acid transporter protein 5 in
          vivo reverses diet-induced non-alcoholic fatty liver disease and improves
          hyperglycemia.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          knockdown of fatty acid transport protein 5 was also able to reverse
          already established non-alcoholic fatty liver disease, resulting in
          significantly improved whole-body glucose homeostasis.
        explanation: >-
          The reversal-of-established-disease result this link asserts, together
          with the glycaemic improvement that accompanied it.
    evidence:
    - reference: PMID:18524776
      reference_title: Silencing of hepatic fatty acid transporter protein 5 in vivo
        reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        knockdown of fatty acid transport protein 5 was also able to reverse
        already established non-alcoholic fatty liver disease, resulting in
        significantly improved whole-body glucose homeostasis.
      explanation: >-
        Supports treating this intervention model as informative for the hepatic
        lipid-overload node.
- name: FATP5 (Slc27a5) knockout mouse
  species: Mouse
  genotype: Slc27a5 (FATP5) targeted deletion, homozygous null
  background: C57BL/6
  publication: PMID:16618416
  genes:
  - preferred_term: SLC27A5
    term:
      id: hgnc:10999
      label: SLC27A5
  description: >-
    Germline deletion of the liver-exclusive fatty acid transport protein. Isolated
    hepatocytes show reduced long-chain fatty acid uptake and the liver holds less
    triglyceride and free fatty acid, with lipid redistributed to other
    fatty-acid-metabolizing tissues. This is the loss-of-function evidence that
    hepatocellular fatty acid entry is protein-mediated; it is a protection model,
    not a model of MASLD itself.
  modeled_mechanisms:
  - target: Transporter-Mediated Hepatic Fatty Acid Uptake
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Removes the transporter genetically and shows the predicted loss of
      long-chain fatty acid uptake in hepatocytes isolated from the null animals.
    limitations: >-
      A germline null cannot separate developmental adaptation from the acute
      requirement for transport, and FATP5 also carries bile acid/coenzyme A ligase
      activity, so the hepatic phenotype is not attributable to lipid transport
      alone. Lipid is redistributed to other tissues rather than simply not
      absorbed, so the model protects the liver at a whole-body cost that a
      hepatocyte-level reading would miss.
    readouts:
    - name: Long-chain fatty acid uptake by isolated hepatocytes
      target: Transporter-Mediated Hepatic Fatty Acid Uptake
      direction: DECREASED
      biological_processes:
      - preferred_term: long-chain fatty acid import into hepatocytes
        term:
          id: GO:0044539
          label: long-chain fatty acid import into cell
      interpretation: >-
        Measured in hepatocytes removed from the animal, so it isolates the
        cell-autonomous transport defect from whole-body energy balance.
      evidence:
      - reference: PMID:16618416
        reference_title: 'Targeted deletion of FATP5 reveals multiple functions in
          liver metabolism: alterations in hepatic lipid homeostasis.'
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          FATP5 deletion significantly reduced LCFA uptake by hepatocytes isolated
          from FATP5 knockout animals.
        explanation: >-
          The cell-autonomous uptake measurement that grounds this readout.
    evidence:
    - reference: PMID:16618416
      reference_title: 'Targeted deletion of FATP5 reveals multiple functions in liver
        metabolism: alterations in hepatic lipid homeostasis.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our findings support the hypothesis that efficient hepatocellular uptake of
        LCFAs, and thus liver lipid homeostasis in general, is largely a
        protein-mediated process requiring FATP5.
      explanation: >-
        The authors' own conclusion, which is the claim this node makes and this
        model supports.
- name: AAV8-shRNA hepatic FATP2 knockdown mouse on high-fat diet
  species: Mouse
  genotype: Wild-type mouse with adeno-associated virus 8-delivered shRNA silencing
    hepatic Slc27a2 (FATP2)
  background: High-fat feeding
  publication: PMID:20530735
  genes:
  - preferred_term: SLC27A2
    term:
      id: hgnc:10996
      label: SLC27A2
  description: >-
    Liver-specific knockdown of the second hepatic fatty acid transporter. Included
    because it makes the uptake claim independent of any single transporter: FATP2
    loss reduces hepatic long-chain fatty acid uptake by about 40% without
    materially changing total hepatic acyl-CoA synthetase activity, and knockdown
    reduces steatosis while high-fat feeding continues.
  modeled_mechanisms:
  - target: Transporter-Mediated Hepatic Fatty Acid Uptake
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      A second, independent genetic route to the same transport step, which is what
      distinguishes a transporter-specific result from a general hepatic
      lipid-handling effect.
    limitations: >-
      FATP2 is bifunctional — a minor peroxisomal pool contributes roughly half of
      peroxisomal very-long-chain acyl-CoA synthetase activity — so knockdown is
      not a clean transport-only perturbation, even though total hepatic synthetase
      activity was unchanged. Murine, and the effect size on uptake is partial.
    readouts:
    - name: Hepatic long-chain fatty acid uptake after FATP2 loss
      target: Transporter-Mediated Hepatic Fatty Acid Uptake
      direction: DECREASED
      biological_processes:
      - preferred_term: long-chain fatty acid import into hepatocytes
        term:
          id: GO:0044539
          label: long-chain fatty acid import into cell
      interpretation: >-
        A partial (40%) reduction, consistent with several transporters sharing the
        step rather than one accounting for all of it.
      evidence:
      - reference: PMID:20530735
        reference_title: FATP2 is a hepatic fatty acid transporter and peroxisomal
          very long-chain acyl-CoA synthetase.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          total hepatic (V)LACS activity was not significantly affected by loss of
          FATP2, while LCFA uptake was reduced by 40%, indicating a more prominent
          role in hepatic LCFA uptake.
        explanation: >-
          Gives both the magnitude of the uptake readout and the internal control
          separating transport from synthetase activity.
    evidence:
    - reference: PMID:20530735
      reference_title: FATP2 is a hepatic fatty acid transporter and peroxisomal very
        long-chain acyl-CoA synthetase.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This suggests FATP2 as a potential target for a therapeutic intervention of
        hepatosteatosis.
      explanation: >-
        States the authors' framing of the transporter as an intervention point,
        the claim this model is curated to support.
  - target: Hepatocyte Lipid Overload
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      Reducing the transport step lowers hepatic steatosis while dietary fat intake
      is held high, replicating the FATP5 result through a different gene.
    limitations: >-
      Steatosis, fasting glucose and insulin are the endpoints; no fibrosis or
      histologic activity endpoint is reported, so the model speaks to the
      lipid-overload node and not to progression.
    readouts:
    - name: Hepatosteatosis under continued high-fat feeding
      target: Hepatocyte Lipid Overload
      direction: DECREASED
      biological_processes:
      - preferred_term: lipid storage
        term:
          id: GO:0019915
          label: lipid storage
      interpretation: >-
        Because fat intake is unchanged, the fall in hepatic lipid is attributable
        to the transport step rather than to reduced substrate supply.
      evidence:
      - reference: PMID:20530735
        reference_title: FATP2 is a hepatic fatty acid transporter and peroxisomal
          very long-chain acyl-CoA synthetase.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          liver-specific FATP2 knockdown, which significantly reduced hepatosteatosis
          in the face of continued high-fat feeding, concomitant with improvements
          in liver physiology, fasting glucose, and insulin levels.
        explanation: >-
          The steatosis readout together with the metabolic improvements that
          accompanied it.
    evidence:
    - reference: PMID:20530735
      reference_title: FATP2 is a hepatic fatty acid transporter and peroxisomal very
        long-chain acyl-CoA synthetase.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        liver-specific FATP2 knockdown, which significantly reduced hepatosteatosis
        in the face of continued high-fat feeding
      explanation: >-
        Supports treating this knockdown model as informative for the hepatic
        lipid-overload node.
experimental_models:
- name: Isogenic iPSC adipocyte-hepatocyte-macrophage microphysiological system (M1-iADIPO-iHEP-MPS)
  description: >-
    A fluidically interconnected multi-tissue New Approach Methodology for the
    adipose tissue-liver axis, built entirely from one human induced pluripotent
    stem cell line so that adipocytes, hepatocytes and macrophages are isogenic and
    donor genotype is not a confounder. White adipocyte and hepatocyte chambers are
    linked by circulating media at 20 microlitres per hour; proinflammatory (M1)
    macrophages are added to the adipocyte chamber to impose white adipose tissue
    inflammation. Because adipose expansion (set by the adipocyte-to-hepatocyte
    ratio) and adipose inflammation (set by macrophage polarization) are controlled
    independently, the system can do what whole-animal models cannot: ask which of
    the two drives hepatic steatosis and hepatic insulin resistance. In this system
    inflammation, not expansion, is the driver, and the GLP-1 receptor agonist
    semaglutide improves hepatocyte lipid content and insulin response by acting on
    the adipocyte compartment rather than on the hepatocyte.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  cell_types:
  - preferred_term: iPSC-derived white adipocyte (iADIPO)
    term:
      id: CL:0000448
      label: white adipocyte
  - preferred_term: iPSC-derived hepatocyte (iHEP)
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: iPSC-derived proinflammatory (M1) macrophage (iMAC)
    term:
      id: CL:0000863
      label: M1 macrophage
  conditions:
  - white adipose tissue inflammation imposed by proinflammatory macrophages
  - graded adipose expansion set by adipocyte-to-hepatocyte ratio
  - hepatic steatosis and hepatic insulin resistance
  - pharmacological intervention with semaglutide, metformin, rosiglitazone and dexamethasone
  cell_source: >-
    Isogenic human induced pluripotent stem cell-derived white adipocytes,
    hepatocytes and macrophages from a single donor line
  culture_system: >-
    Interconnected two-chamber microphysiological system with circulating media at
    20 microlitres per hour, and a non-circulating flow-through configuration for
    compartment-selective drug exposure
  publication: PMID:39266553
  modeled_mechanisms:
  - target: Cardiometabolic Dysfunction and Adipose Insulin Resistance
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reconstructs the initiating cardiometabolic state of the pathograph in human
      cells — inflamed, insulin-resistant white adipose tissue releasing fatty
      acids and TNF-alpha into a circulation shared with the liver — and separates
      adipose inflammation from adipose expansion as candidate causes, which the
      trigger node's description leaves bundled.
    limitations: >-
      The system carries no vasculature, no immune trafficking beyond the added
      macrophages, no gut and no central control of feeding, so it models the
      adipose-to-liver limb of a state that is whole-body in patients. Insulin
      resistance is imposed over days by macrophage polarization rather than
      arising from years of overnutrition, and the iPSC-derived cells retain a
      fetal-like maturation state.
    readouts:
    - name: Insulin-stimulated glucose uptake in the adipocyte compartment
      target: Cardiometabolic Dysfunction and Adipose Insulin Resistance
      direction: DECREASED
      biological_processes:
      - preferred_term: cellular response to insulin stimulus
        term:
          id: GO:0032869
          label: cellular response to insulin stimulus
      interpretation: >-
        Loss of insulin-stimulated glucose uptake is the functional definition of
        adipose insulin resistance and is what the trigger node asserts.
      evidence:
      - reference: PMID:39266553
        reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
          resistance in a human iPSC-based microphysiological system.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          nor disrupted insulin-mediated regulation of glucose uptake in the
          iADIPO-MPS or HGP in the iHEP-MPS, similar to control conditions without
          iMACs
        explanation: >-
          The M0 control arm establishes that the loss of insulin-regulated glucose
          uptake requires proinflammatory polarization specifically, rather than
          the presence of macrophages.
    - name: Insulin suppression of hepatic glucose production
      target: Cardiometabolic Dysfunction and Adipose Insulin Resistance
      direction: DECREASED
      biological_processes:
      - preferred_term: gluconeogenesis
        term:
          id: GO:0006094
          label: gluconeogenesis
      interpretation: >-
        Failure of insulin to suppress hepatic glucose production is the hepatic
        limb of the same insulin-resistant state, read out across the fluidic link
        rather than in the tissue that was manipulated.
      evidence:
      - reference: PMID:39266553
        reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
          resistance in a human iPSC-based microphysiological system.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Analysis of insulin regulation of HGP after 48 h of iADIPO-iHEP-MPS
          interconnection showed insulin resistance only at the highest
          iADIPO-iHEP ratio of 30:1
        explanation: >-
          Records the expansion arm as the weaker of the two: mass alone produced
          hepatic insulin resistance only at an extreme ratio, which is the
          comparison that makes inflammation the primary driver.
    evidence:
    - reference: PMID:39266553
      reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
        resistance in a human iPSC-based microphysiological system.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we establish an interconnected microphysiological system (MPS) containing
        white adipocytes, hepatocytes and proinflammatory macrophages derived from
        isogenic human induced pluripotent stem cells.
      explanation: >-
        Establishes that the model contains the adipose, hepatic and inflammatory
        compartments this trigger node describes, in human cells of a single
        genotype.
  - target: Hepatocyte Lipid Overload
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Hepatocyte lipid accumulation arises in the chip as a consequence of
      inflammation in the connected adipose compartment, not from direct fatty acid
      loading of the hepatocytes, so the model reproduces the causal route into
      this node rather than only its end state.
    limitations: >-
      The readout is intracellular fluorescent fatty acid and lipid content over
      days, not histologic macrovesicular steatosis; the chip has no stellate cells
      or Kupffer cells, so nothing downstream of this node — inflammation
      resolution, ballooning, fibrosis — can be assessed in it.
    readouts:
    - name: Hepatocyte fatty acid uptake and lipid accumulation under adipose inflammation
      target: Hepatocyte Lipid Overload
      direction: INCREASED
      biological_processes:
      - preferred_term: lipid storage
        term:
          id: GO:0019915
          label: lipid storage
      interpretation: >-
        The defining measurement of this node, produced in human cells by a purely
        upstream adipose manipulation.
      evidence:
      - reference: PMID:39266553
        reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
          resistance in a human iPSC-based microphysiological system.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Consequently, the iHEP-MPS showed increased fatty acid uptake and lipid
          accumulation under inflamed iADIPO-MPS conditions
        explanation: >-
          Reports both the uptake and the accumulation limbs of the hepatocyte
          response to adipose inflammation.
    evidence:
    - reference: PMID:39266553
      reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
        resistance in a human iPSC-based microphysiological system.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        macrophage-induced adipocyte inflammation causes lipid accumulation in
        hepatocytes and MPS-wide insulin resistance, corresponding to initiation of
        metabolic dysfunction-associated steatotic liver disease.
      explanation: >-
        The authors' own mapping of the chip's end state onto MASLD initiation,
        which is what licenses linking it to this node.
  - target: Transporter-Mediated Hepatic Fatty Acid Uptake
    relationship: MEASURES
    fidelity: UNKNOWN
    description: >-
      Fatty acid entry into hepatocytes is measured directly in the chip as
      accumulation of fluorescent fatty acids, and rises when the connected adipose
      compartment is inflamed. This is a human read on the uptake step whose causal
      evidence is otherwise entirely murine.
    limitations: >-
      The measurement is of net fatty acid entry, not of transporter activity: no
      FATP5 or FATP2 knockdown, inhibition or expression measurement is reported in
      this system, so the model quantifies the flux this node carries without
      attributing it to the transporters the node names. Fluorescent fatty acid
      analogues are also a proxy for physiological long-chain fatty acids.
    readouts:
    - name: Fluorescent fatty acid accumulation in the hepatocyte compartment
      target: Transporter-Mediated Hepatic Fatty Acid Uptake
      direction: INCREASED
      biological_processes:
      - preferred_term: long-chain fatty acid import into hepatocytes
        term:
          id: GO:0044539
          label: long-chain fatty acid import into cell
      interpretation: >-
        Establishes that hepatic fatty acid uptake is a measurable, modifiable
        variable in a human system, which is the precondition for testing the
        rodent-derived uptake hypothesis in human cells.
      evidence:
      - reference: PMID:39266553
        reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
          resistance in a human iPSC-based microphysiological system.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Consequently, the iHEP-MPS showed increased fatty acid uptake and lipid
          accumulation under inflamed iADIPO-MPS conditions
        explanation: >-
          The uptake limb of the same measurement, cited here for the transport
          step rather than for the resulting lipid pool.
    evidence:
    - reference: PMID:39266553
      reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
        resistance in a human iPSC-based microphysiological system.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        To reliably quantify lipid accumulation in iHEPs, we first analyzed
        absorption of fluorescent fatty acids by the PDMS used to build the
        iHEP-MPS and iADIPO-MPS, which showed no bias for up to 4 days
      explanation: >-
        Documents the device-absorption control that makes the fatty acid uptake
        measurement in this chip interpretable, which is why the model is curated
        as measuring rather than recapitulating this node.
  notes: >-
    The compartment-selective result is the part hardest to obtain any other way:
    using a non-circulating flow-through configuration, semaglutide applied only to
    the adipocyte compartment reproduced the whole-system benefit, while semaglutide
    applied only to the hepatocyte compartment did not. The authors note that the
    same question is confounded in mice by semaglutide's effects on feeding and body
    weight and by GLP-1 receptor expression across several cell types. This is
    curated as evidence on the Semaglutide treatment's adipose target_mechanisms
    edge rather than as a separate mechanism node.
- name: Isogenic iPSC macrophage-adipocyte microphysiological system (iMAC-iADIPO-MPS)
  description: >-
    The adipose half of the platform, used on its own to model chronic white adipose
    tissue inflammation. iPSC-derived macrophages migrate into three-dimensional
    adipocyte clusters and form crown-like structures around damaged adipocytes,
    reproducing the defining histology of obese human adipose tissue; the number of
    such structures rises with adipocyte age and with palmitic acid exposure, so
    inflammatory severity is gradable. Polarization is the operative variable: M1
    but not M2 macrophages induce adipocyte insulin resistance and dysregulated
    lipolysis, and transcriptomics and cytokine profiling identify a reciprocal
    proinflammatory loop between the two cell types.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: white adipose tissue
    term:
      id: UBERON:0001347
      label: white adipose tissue
  cell_types:
  - preferred_term: iPSC-derived white adipocyte (iADIPO)
    term:
      id: CL:0000448
      label: white adipocyte
  - preferred_term: iPSC-derived macrophage (iMAC), M1 and M2 polarized
    term:
      id: CL:0000235
      label: macrophage
  conditions:
  - chronic white adipose tissue inflammation
  - M1 versus M2 macrophage polarization
  - palmitic acid lipotoxic exposure
  - adipocyte aging in culture
  cell_source: >-
    Isogenic human induced pluripotent stem cell-derived macrophages and adipocytes
  culture_system: >-
    Microphysiological system supporting three-dimensional adipocyte clusters with
    macrophage infiltration
  publication: PMID:37104853
  modeled_mechanisms:
  - target: Cardiometabolic Dysfunction and Adipose Insulin Resistance
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the adipose limb of the trigger node in human cells, including the
      crown-like structures that are its histologic signature, and shows that
      macrophage polarization state rather than macrophage presence produces
      adipocyte insulin resistance and dysregulated lipolysis.
    limitations: >-
      Adipose tissue only: there is no liver in this configuration, so the effect on
      the hepatic nodes is inferred rather than measured, and the interconnected
      system (PMID:39266553) is the model that closes that gap. Inflammation is
      imposed by adding pre-polarized macrophages rather than arising from resident
      immune recruitment.
    readouts:
    - name: Crown-like structure formation around damaged adipocytes
      target: Cardiometabolic Dysfunction and Adipose Insulin Resistance
      direction: INCREASED
      interpretation: >-
        The histologic hallmark of inflamed human adipose tissue, reproduced in a
        non-animal system and gradable with exposure severity.
      evidence:
      - reference: PMID:37104853
        reference_title: Human iPSC-Derived Proinflammatory Macrophages cause Insulin
          Resistance in an Isogenic White Adipose Tissue Microphysiological System.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          iMACs migrate toward and infiltrate into the 3D iADIPOs cluster to form
          crown-like structures (CLSs)-like morphology around damaged iADIPOs,
          recreating classic histological features of WAT inflammation seen in
          obesity.
        explanation: >-
          States the structural correspondence between the model and obese human
          adipose tissue.
    - name: Dysregulated adipocyte lipolysis under proinflammatory macrophage co-culture
      target: Cardiometabolic Dysfunction and Adipose Insulin Resistance
      direction: INCREASED
      biological_processes:
      - preferred_term: triglyceride catabolic process
        term:
          id: GO:0019433
          label: triglyceride catabolic process
      interpretation: >-
        Dysregulated lipolysis is the step that supplies fatty acids to the liver in
        this node, and the M1-versus-M2 contrast is the internal control showing it
        is inflammation-specific.
      evidence:
      - reference: PMID:37104853
        reference_title: Human iPSC-Derived Proinflammatory Macrophages cause Insulin
          Resistance in an Isogenic White Adipose Tissue Microphysiological System.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          M1 (proinflammatory) but not M2 (tissue repair) iMACs induced insulin
          resistance and dysregulated lipolysis in iADIPOs.
        explanation: >-
          The polarization-controlled comparison that grounds this readout.
    evidence:
    - reference: PMID:37104853
      reference_title: Human iPSC-Derived Proinflammatory Macrophages cause Insulin
        Resistance in an Isogenic White Adipose Tissue Microphysiological System.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This iMAC-iADIPO-MPS thus successfully recreates pathological conditions of
        chronically inflamed human WAT
      explanation: >-
        The authors' summary claim about what the model reproduces, which is the
        adipose content of this trigger node.
- name: Metabolically competent iPSC white adipose tissue microphysiological system (iADIPO-MPS)
  description: >-
    The platform-qualification model underlying the two systems above, and the
    reason they can be read as models of insulin resistance at all. Standard adipose
    differentiation protocols were found to yield already insulin-resistant tissue,
    which cannot report a further loss of insulin sensitivity; new differentiation
    conditions plus chip optimization produced hormonally responsive adipose tissue
    with larger, more unilocular lipid droplets and a dynamic range wide enough to
    detect insulin sensitizers and desensitizers in both directions. Three
    independent insulin-sensitivity assays are used: glucose uptake, fatty acid
    uptake, and suppression of stimulated lipolysis.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: white adipose tissue
    term:
      id: UBERON:0001347
      label: white adipose tissue
  cell_types:
  - preferred_term: iPSC-derived white adipocyte (iADIPO)
    term:
      id: CL:0000448
      label: white adipocyte
  conditions:
  - insulin-sensitive versus insulin-resistant adipose tissue
  - insulin sensitizer and desensitizer pharmacology
  cell_source: Human pluripotent stem cell-derived white adipocytes
  culture_system: >-
    Three-dimensional adipose tissue in a microphysiological system, benchmarked
    against two-dimensional culture
  publication: PMID:34761526
  modeled_mechanisms:
  - target: Cardiometabolic Dysfunction and Adipose Insulin Resistance
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Provides the calibrated human assay for the adipose insulin-sensitivity
      variable this node turns on, with a dynamic range the authors report as
      competent against in vivo and ex vivo comparators.
    limitations: >-
      A healthy-tissue platform rather than a disease model: no inflammatory,
      lipotoxic or hepatic component, so it bounds what the derived MASLD models can
      measure without itself modeling MASLD. It also documents a defect in prior
      protocols rather than in patients.
    readouts:
    - name: Insulin-stimulated glucose uptake, fatty acid uptake and lipolysis suppression
      target: Cardiometabolic Dysfunction and Adipose Insulin Resistance
      direction: INCREASED
      biological_processes:
      - preferred_term: cellular response to insulin stimulus
        term:
          id: GO:0032869
          label: cellular response to insulin stimulus
      interpretation: >-
        Direction is relative to conventional two-dimensional culture, not to a
        disease state: the readouts record restored insulin responsiveness in the
        chip, which is what makes a subsequent loss of that responsiveness
        interpretable.
      evidence:
      - reference: PMID:34761526
        reference_title: Probing Insulin Sensitivity with Metabolically Competent Human
          Stem Cell-Derived White Adipose Tissue Microphysiological Systems.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Using three independent insulin sensitivity assays, i.e., glucose and fatty
          acid uptake and suppression of lipolysis, as the functional readouts new
          differentiation conditions yielding hormonally responsive iADIPO are
          derived.
        explanation: >-
          Names the three functional readouts and the fact that they are what the
          differentiation conditions were selected against.
    evidence:
    - reference: PMID:34761526
      reference_title: Probing Insulin Sensitivity with Metabolically Competent Human
        Stem Cell-Derived White Adipose Tissue Microphysiological Systems.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Surprisingly, previously reported WAT differentiation approaches create
        insulin resistant WAT ill-suited for type-2 diabetes mellitus drug discovery.
      explanation: >-
        The negative platform result that makes this model informative for the node:
        an adipose model must be shown insulin-sensitive at baseline before a loss of
        insulin sensitivity can be attributed to a disease manipulation.
- name: Heterochronic-serum iPSC white adipose tissue-liver aging microphysiological system
  description: >-
    The same adipose-liver axis chip run as an aging model, perfused with
    heterochronic human serum. Over four days it reproduces hallmarks that take
    decades in people, including gerontic shifts in gene expression and oxidative
    DNA damage, and it reports knock-on effects of aging in the fat compartment on
    the liver compartment, sexual dimorphism of aging, and tissue memory of donor
    age. It is curated here for the adipose-to-liver limb rather than for MASLD
    endpoints, which it does not report.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  cell_types:
  - preferred_term: iPSC-derived white adipocyte (iADIPO)
    term:
      id: CL:0000448
      label: white adipocyte
  - preferred_term: iPSC-derived hepatocyte (iHEP)
    term:
      id: CL:0000182
      label: hepatocyte
  conditions:
  - heterochronic human serum exposure
  - tissue aging and candidate rejuvenation
  cell_source: >-
    Human induced pluripotent stem cell-derived adipocytes and hepatocytes perfused
    with young or aged human serum
  culture_system: >-
    Interconnected adipose tissue-liver microphysiological chip under heterochronic
    serum perfusion
  publication: PMID:41882175
  modeled_mechanisms:
  - target: Cardiometabolic Dysfunction and Adipose Insulin Resistance
    relationship: MEASURES
    fidelity: UNKNOWN
    description: >-
      Reads out how the state of the adipose compartment propagates to the liver
      compartment under an aging stimulus, on the same axis this trigger node
      describes. Curated as measuring, not recapitulating, because the manipulated
      variable is serum age rather than cardiometabolic dysfunction.
    limitations: >-
      No steatosis, insulin-resistance or histologic endpoint for MASLD is reported,
      so this model supports the existence and directionality of the fat-to-liver
      limb rather than any MASLD-specific claim. Fidelity is left UNKNOWN
      deliberately: the correspondence between four days of heterochronic serum and
      decades of human aging is the model's own open question. A curator should not
      promote this link without a MASLD-relevant readout.
    readouts:
    - name: Aging hallmarks in the adipose-liver chip under heterochronic serum
      target: Cardiometabolic Dysfunction and Adipose Insulin Resistance
      direction: ALTERED
      interpretation: >-
        Establishes that the chip registers a systemic humoral input as coordinated
        change across both tissues, which is the property that would let it carry a
        cardiometabolic exposure in future work.
      evidence:
      - reference: PMID:41882175
        reference_title: Human microphysiological systems of aging recreate the in vivo
          process expediting evaluation of anti-geronic strategies.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          The microphysiological chip recapitulates, in 4 days, aging-associated
          hallmarks that occur after decades of aging in people, including gerontic
          shifts in gene expression and oxidative DNA damage.
        explanation: >-
          States what the model reproduces and on what timescale, which is the basis
          for the readout and for the fidelity caveat recorded on this link.
    evidence:
    - reference: PMID:41882175
      reference_title: Human microphysiological systems of aging recreate the in vivo
        process expediting evaluation of anti-geronic strategies.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We uncover unknown signalling networks in human aging, knock-on effects of
        aging in fat on liver, sexual polymorphisms of aging and tissue memory of
        age
      explanation: >-
        The fat-to-liver propagation claim, which is the only reason this aging model
        is linked to a MASLD node at all.
discussions:
- discussion_id: kgap_masld_osa_cpap_hepatic_benefit
  prompt: >-
    If chronic intermittent hypoxia is a genuine driver of MASLD progression, why
    does correcting it with CPAP not improve the liver — and is the hypoxic
    exposure therefore a causal driver, a marker of adiposity, or a driver whose
    damage is not reversible on trial timescales?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Obstructive Sleep Apnea-Associated Chronic Intermittent Hypoxia
  - pathophysiology#Hypoxia-Driven Hepatic Lipogenesis and Oxidative Stress
  rationale: >-
    The observational and mechanistic arms of this hypothesis point one way and
    the interventional arm points the other, and the disagreement is the gap.
    Observationally, hypoxia metrics track hepatic severity after adjustment for
    obesity in biopsy-based cohorts; mechanistically, controlled murine
    intermittent hypoxia raises hepatic SREBP-1/SCD-1 and liver triglyceride, and
    the triglyceride response is HIF-1-dependent. Yet randomized trials of CPAP
    monotherapy show no change in steatosis, fibrosis or aminotransferases, and a
    2026 scoping review of 74 studies reports that what hepatic improvement does
    occur in CPAP trials tracks weight change rather than correction of
    sleep-disordered breathing. At least four readings remain open and the
    curated evidence does not discriminate between them: the association is
    residual confounding by adiposity that adjustment did not remove; CPAP
    adherence in the trials was too low or the follow-up too short to register a
    histological change; hypoxia contributes to establishing steatosis but not to
    sustaining it once the metabolic state exists; or the hepatic lesion is real
    but not reversible without concurrent weight loss. Until one of these is
    settled, CPAP must not be curated as a MASLD treatment, and the hypoxia arm
    must not be promoted out of EMERGING.
  evidence:
  - reference: PMID:29151428
    reference_title: 'Continuous Positive Airway Pressure in Patients With Obstructive
      Sleep Apnea and Non-Alcoholic Steatohepatitis: A Systematic Review and Meta-Analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After CPAP treatment, no changes in liver steatosis, liver fibrosis, and
      aminotransferase levels (alanine aminotransferase and aspartate
      aminotransferase) were found.
    explanation: >-
      Five randomized controlled trials pooled; the null interventional result
      that creates the gap. The authors grade the evidence low to very low, which
      is itself part of why the question stays open rather than being answered
      negatively.
  - reference: PPR:PPR1293874
    reference_title: 'The Association and Treatment of Metabolic
      Dysfunction-Associated Steatotic Liver Disease in Obstructive Sleep Apnoea:
      A Scoping Review'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      RCTs demonstrated limited hepatic benefit from CPAP monotherapy, with
      improvements more closely related to weight change than correction of OSA
      alone.
    explanation: >-
      A 74-study scoping review that states the weight-versus-airway attribution
      explicitly. Cited as a non-peer-reviewed preprint and deliberately not the
      sole support for any claim here — the same null result is carried by the
      peer-reviewed randomized-trial meta-analysis above.
  proposed_experiments:
  - experiment_id: exp_masld_cpap_adherence_stratified_pdff
    name: Adherence-stratified CPAP trial with MRI-PDFF and hypoxic-burden endpoints
    description: >-
      Randomize CPAP-naive patients with biopsy- or MRI-confirmed MASLD and
      moderate-to-severe OSA to CPAP versus sham, with telemonitored objective
      adherence, weight held as a prespecified covariate rather than an outcome,
      and MRI proton density fat fraction plus liver stiffness at 12 months. Test
      whether a hepatic effect emerges above an adherence threshold and above a
      hypoxic-burden threshold, both of which prior trials averaged below.
    experiment_type:
      preferred_term: adherence-stratified randomized sham-controlled trial
    decision_criterion: >-
      A dose-response between nightly CPAP hours (or reduction in time below 90%
      saturation) and fall in MRI-PDFF, independent of weight change, supports the
      hypoxia arm as causal and reversible; a flat response across the adherence
      range with weight change explaining the variance supports adiposity as the
      operative variable.
    would_support:
    - pathophysiology#Obstructive Sleep Apnea-Associated Chronic Intermittent Hypoxia
    would_refute:
    - pathophysiology#Hypoxia-Driven Hepatic Lipogenesis and Oxidative Stress
  - experiment_id: exp_masld_ih_weight_clamped_rodent
    name: Weight-clamped intermittent hypoxia exposure in diet-induced steatohepatitis
    description: >-
      Expose mice with established diet-induced steatohepatitis to intermittent
      hypoxia versus normoxia under pair-feeding so body weight and adiposity are
      matched between arms, then measure hepatic SREBP-1/SCD-1, 4-hydroxynonenal
      adducts, NAFLD activity score and fibrosis stage, with a
      hepatocyte-specific Hif1a deletion arm. This separates the hypoxic signal
      from the adiposity it is confounded with in every human cohort, and tests
      whether the effect exists on an already-steatotic background rather than
      only in the lean state where it was first shown.
    experiment_type:
      preferred_term: pair-fed intermittent-hypoxia exposure with conditional knockout
    decision_criterion: >-
      Higher activity score or fibrosis stage in the hypoxia arm at matched body
      weight, abolished by hepatocyte Hif1a deletion, establishes a
      weight-independent hepatic effect of intermittent hypoxia; no difference at
      matched weight argues the human association is adiposity-mediated.
    would_support:
    - pathophysiology#Hypoxia-Driven Hepatic Lipogenesis and Oxidative Stress
- discussion_id: hmm_masld_hepatic_fatp_uptake_human_translation
  prompt: >-
    Is transporter-mediated hepatic fatty acid uptake rate-limiting in human MASLD,
    or is the reversal of steatosis on FATP5/FATP2 knockdown a property of the
    diet-induced mouse — and why has the one human system that can measure hepatic
    fatty acid uptake never been used to perturb the transporters?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Transporter-Mediated Hepatic Fatty Acid Uptake
  - mechanistic_hypotheses#hepatic_fatty_acid_uptake_masld
  rationale: >-
    This is a model-fidelity question rather than an absence of evidence, which is
    why it is curated as HUMAN_MODEL_MISMATCH and not as a knowledge gap. The rodent
    evidence is strong and internally replicated: hepatocyte long-chain fatty acid
    entry is protein-mediated, silencing FATP5 reverses established diet-induced
    fatty liver and improves glucose homeostasis, and liver-specific FATP2 knockdown
    reproduces the steatosis result through a different gene while high-fat feeding
    continues. What is missing is not another mouse.
    Three things bound the translation. First, the FATP5 knockdown reduced
    whole-animal caloric uptake as well as hepatic fatty acid uptake, so the
    published protection is not cleanly attributable to the hepatic step — the
    confound is in the source paper's own summary sentence. Second, no human genetic
    evidence links SLC27A5 or SLC27A2 variation to MASLD in this entry, in contrast
    to the PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 signals that anchor the other
    hepatocyte-intrinsic arms, and no FATP-directed agent has entered human testing.
    Third — and this is what makes the mismatch actionable rather than merely
    noted — the human iPSC adipose-liver microphysiological system curated in this
    entry already measures hepatocyte fatty acid uptake as a primary endpoint and
    already shows that uptake rises when the connected adipose compartment is
    inflamed. It has the readout. It has never been reported with the transporters
    knocked down, so the human system that could adjudicate the hypothesis has been
    used to observe the flux and not to test what gates it.
    A curator should not resolve this by promoting the uptake hypothesis on the
    strength of additional rodent replication, and should not retire it on the
    absence of human data: the discriminating experiment has not been done.
  evidence:
  - reference: PMID:18524776
    reference_title: Silencing of hepatic fatty acid transporter protein 5 in vivo
      reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      resulting in a marked reduction of hepatic dietary fatty acid uptake, reduced
      caloric uptake, and concomitant protection from diet-induced non-alcoholic
      fatty liver disease.
    explanation: >-
      The murine result and its confound in one sentence: hepatic uptake and
      whole-animal caloric uptake both fall, so the model cannot attribute the
      protection to the hepatic transport step alone.
  - reference: PMID:39266553
    reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
      resistance in a human iPSC-based microphysiological system.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consequently, the iHEP-MPS showed increased fatty acid uptake and lipid
      accumulation under inflamed iADIPO-MPS conditions
    explanation: >-
      Establishes that the human non-animal system has the hepatocyte fatty acid
      uptake readout this question needs, which is what makes the missing
      transporter perturbation a specific and reachable experiment rather than an
      open-ended wish for human data.
  - reference: PMID:39266553
    reference_title: Adipocyte inflammation is the primary driver of hepatic insulin
      resistance in a human iPSC-based microphysiological system.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Whether WAT expansion or its inflammation is the main trigger in WAT-driven
      MASLD and hepatic insulin resistance (HIR) has been difficult to address in
      animal models because lipid accumulation and lipotoxic events often go hand in
      hand with inflammation of WAT and liver
    explanation: >-
      The authors state the general form of this mismatch for a neighbouring
      question — that variables which can be separated in a microphysiological
      system are confounded in animal models — which is the same structural argument
      that applies to the caloric-uptake confound in the FATP5 experiment.
  proposed_experiments:
  - experiment_id: exp_masld_fatp_knockdown_in_human_adipose_liver_mps
    name: FATP5 and FATP2 knockdown in the human iPSC adipose-liver microphysiological
      system under adipose inflammation
    description: >-
      Take the isogenic iPSC adipose-liver chip in its inflamed configuration, in
      which hepatocyte fatty acid uptake and lipid accumulation are already elevated,
      and silence SLC27A5 and SLC27A2 in the hepatocyte compartment singly and
      together, with a non-targeting control. Measure hepatocyte fatty acid uptake
      and lipid content as the primary endpoints, and hepatic glucose production
      under insulin as the secondary endpoint. The design is what the whole-animal
      experiments cannot supply: the adipose fatty acid supply is fixed by the chip
      rather than varying with the animal's feeding behaviour, so a fall in
      hepatocyte lipid can be attributed to the transport step and not to reduced
      caloric intake. Running the knockdown after inflammation is established tests
      reversal rather than prevention, matching the design of the murine knockdown.
    experiment_type:
      preferred_term: transporter knockdown in a human multi-tissue microphysiological
        system
    perturbations:
    - name: Hepatocyte-compartment SLC27A5 and SLC27A2 silencing
      target: pathophysiology#Transporter-Mediated Hepatic Fatty Acid Uptake
      description: >-
        RNA-interference or CRISPR-interference knockdown of each transporter alone
        and in combination in the iPSC-derived hepatocyte compartment only, leaving
        the adipocyte and macrophage compartments unmodified.
      genes:
      - preferred_term: SLC27A5
        term:
          id: hgnc:10999
          label: SLC27A5
      - preferred_term: SLC27A2
        term:
          id: hgnc:10996
          label: SLC27A2
    readouts:
    - name: Hepatocyte fatty acid uptake after transporter knockdown
      target: pathophysiology#Transporter-Mediated Hepatic Fatty Acid Uptake
      direction: DECREASED
      biological_processes:
      - preferred_term: long-chain fatty acid import into hepatocytes
        term:
          id: GO:0044539
          label: long-chain fatty acid import into cell
      interpretation: >-
        On-target confirmation. If uptake does not fall, the human hepatocyte does
        not depend on these transporters in the way the mouse liver does, and that is
        itself the answer.
    - name: Hepatocyte lipid content at fixed adipose fatty acid supply
      target: pathophysiology#Hepatocyte Lipid Overload
      direction: DECREASED
      biological_processes:
      - preferred_term: lipid storage
        term:
          id: GO:0019915
          label: lipid storage
      interpretation: >-
        The discriminating measurement. Because substrate delivery is held constant
        by the chip, a fall here isolates the contribution of the transport step in
        a way the murine caloric-uptake confound prevents.
    controls:
    - name: Non-targeting knockdown construct
      description: >-
        Scrambled or non-targeting construct delivered to the hepatocyte
        compartment on the same schedule, controlling for the delivery vehicle and
        the knockdown procedure rather than for the transporters.
    - name: Uninflamed (M0 macrophage) chip
      description: >-
        The same chip with non-activated macrophages, in which hepatocyte fatty
        acid uptake is not elevated. Sets the floor against which a knockdown
        effect in the inflamed arm is measured.
    - name: Knockdown before versus after adipose inflammation
      description: >-
        Two timing arms, so prevention of hepatocyte lipid accumulation is
        separated from reversal of accumulation that has already occurred — the
        distinction that made the murine FATP5 knockdown result stronger than a
        prevention-only design.
    decision_criterion: >-
      A fall in hepatocyte lipid content on transporter knockdown, at unchanged
      adipose fatty acid release and unchanged media fatty acid concentration,
      supports the uptake step as rate-limiting in human hepatocytes and would move
      the hypothesis toward canonical. Confirmed on-target knockdown with no change
      in hepatocyte lipid content refutes the rate-limiting claim for human cells and
      reassigns the murine result to a whole-animal energy-balance effect.
    would_support:
    - pathophysiology#Transporter-Mediated Hepatic Fatty Acid Uptake
    - mechanistic_hypotheses#hepatic_fatty_acid_uptake_masld
    would_refute:
    - mechanistic_hypotheses#hepatic_fatty_acid_uptake_masld
    supporting_outcome:
    - >-
      Hepatocyte fatty acid uptake and lipid content both fall on knockdown while
      adipose fatty acid release and circulating fatty acid levels are unchanged,
      with the combined SLC27A5/SLC27A2 knockdown exceeding either alone.
    - >-
      The fall in hepatocyte lipid content is present in the arm where knockdown
      follows established inflammation, showing reversal rather than prevention
      only.
    refuting_outcome:
    - >-
      Transporter transcript and protein fall as intended but hepatocyte fatty acid
      uptake and lipid content are unchanged, indicating that human hepatocyte fatty
      acid entry in this system is not gated by these transporters.
    - >-
      Hepatocyte lipid content falls only alongside a fall in circulating fatty
      acid availability in the chip, which would place the effect on supply rather
      than on the hepatocyte transport step.
notes: >-
  Naming follows the 2023 multisociety Delphi consensus: MASLD replaces NAFLD and
  MASH replaces NASH, with steatotic liver disease as the overarching term.
  Because MetALD (metabolic dysfunction plus greater alcohol intake) is defined by
  that consensus as a category outside pure MASLD, it is deliberately not modeled
  here as a subtype; the alcohol arm lives in the Alcohol-Associated Liver Disease
  entry. Most cited evidence predates the nomenclature change and therefore uses
  NAFLD/NASH terminology and the exclusion-based case definition; snippets are
  quoted verbatim in the original terminology. The mitophagy node is deliberately
  marked as an emerging amplifier: the causal experiments are in cultured
  hepatocytes and rodent models, and no human trial has yet shown that restoring
  mitophagy changes MASLD outcomes. Fibrosis stage, not steatohepatitis activity,
  is the outcome-determining lesion, which is why the fibrosis node carries the
  prognostic evidence. Prevalence figures are imaging-based NAFLD estimates and
  approximate rather than exactly measure MASLD. The histopathology section models
  the three NAFLD activity score components plus fibrosis staging; hepatocellular
  ballooning is left without a bound ontology term because NCIT codes only the
  grading assessment (NCIT:C181484), not the morphologic finding, and no HP term
  under Abnormal cell morphology covers it either. The obstructive sleep apnea
  arm is curated with three deliberate omissions a later curator should not
  silently reverse. CPAP is not curated as a treatment: the pooled randomized
  evidence is null for steatosis, fibrosis and aminotransferases, so a
  target_mechanisms edge into the hypoxia node would assert an efficacy the
  evidence refuses. Sleep fragmentation is not modeled as a separate MASLD node
  even though it is a real consequence of apnea, because the studies that
  separate the two components attribute the hepatic signal to the hypoxic one;
  the fragmentation arm belongs to Obstructive_Sleep_Apnea, whose own
  kgap_osa_multiorgan_fibrosis discussion already names the liver. And no
  comorbidity entry is created for the pair: the interventional evidence is
  null and both the steatosis and the fibrosis limbs are contested, so a com_
  entry would have to assert
  a shared-mechanism direction the sources do not yet license — revisit if a
  weight-independent effect is demonstrated.
  The hepatic fatty acid uptake arm is deliberately a separate pathophysiology
  node rather than content folded into Hepatocyte Lipid Overload, because it is
  the step the two rodent reversal experiments act on and it is where the
  human-model mismatch sits; it carries an EMERGING hypothesis and must not be
  promoted on further rodent replication alone. Its biological process is marked
  INCREASED to describe flux in the high-fat state, not transporter upregulation,
  which the curated evidence does not show — a later curator adding a human
  SLC27A5/SLC27A2 expression result should say which of the two it establishes.
  The New Approach Methodology entries are curated in `experimental_models`
  because they are non-animal human systems; the four are one platform lineage
  (Stahl laboratory, UC Berkeley/UCSF), which is why the platform-qualification
  chip is included even though it is not a disease model — it is what establishes
  that the derived models are insulin-sensitive at baseline and can therefore
  report a loss of insulin sensitivity. The aging chip is linked as MEASURES with
  fidelity UNKNOWN and no MASLD endpoint, and should not be promoted without one.
  Semaglutide's adipose-compartment mechanism is curated as INDIRECT evidence on
  the existing cardiometabolic target_mechanisms edge rather than as a new node:
  the compartment-selective chip result explains where the approved drug acts, but
  the efficacy claim still rests on the phase 3 trial.
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  findings: []

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