This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "hepatic_steatosis_lipotoxicity#Lipotoxic Stress and Organelle Dysfunction"). The fibrosis arm of this module connects conceptually to the fibrotic_response module: a conforming hepatic disorder node may declare conformance both to this module's "Hepatic Stellate Cell Activation and Fibrosis" node and to "fibrotic_response#Mesenchymal Cell Activation". Key organ-specific cell types are fixed (liver): hepatocyte (CL:0000182), Kupffer cell/macrophage (CL:0000091/CL:0000235), and hepatic stellate cell (CL:0000632). Conforming disorder nodes substitute the disorder-specific initiating insult (overnutrition/insulin resistance in MASLD, ethanol metabolism in alcohol-associated disease, PNPLA3/TM6SF2 retention defects in genetic forms) while preserving the conserved chain.
Hepatocyte Lipid Overload
trigger
Hepatocyte intracellular lipid accumulates when the inflow of free fatty acids (from adipose lipolysis and dietary fat) plus de novo lipogenesis exceeds the capacity for fatty acid oxidation and very-low-density lipoprotein export. The resulting triglyceride accumulation in lipid droplets defines steatosis. This initiating imbalance is shared across metabolic, alcoholic, and genetic forms of steatotic liver disease.
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Lipotoxic Stress and Organelle Dysfunction
Show evidence (2 references)
"Most commonly, it occurs when there is an imbalance between the delivery or synthesis of fatty acids in the liver and their disposal through oxidative pathways or secretion into the blood as a component of triacylglycerols in very low density lipoprotein."
Defines hepatic steatosis as the imbalance between fatty acid delivery/synthesis and disposal, establishing the lipid-overload trigger state. Evidence source is OTHER because this is a comprehensive physiology review.
"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."
Directly attributes hepatocyte triglyceride accumulation to increased free fatty acid inflow and de novo lipogenesis. Evidence source is OTHER because this is a review synthesizing human and model organism data.
Lipotoxic Stress and Organelle Dysfunction
amplifier
Beyond inert triglyceride storage, the accumulation of toxic non-triglyceride lipid species (e.g., diacylglycerols, ceramides, free fatty acid metabolites) drives lipotoxicity. These metabolites induce endoplasmic reticulum stress, mitochondrial dysfunction, and accumulation of reactive oxygen species, sensitizing the hepatocyte to injury. This is the amplification step that converts simple steatosis toward steatohepatitis.
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Hepatocyte Injury and Inflammatory Activation
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"Emerging data now point to nontriglyceride lipotoxicity and complex mechanisms of hepatocyte injury and apoptosis as the major contributors to the disease phenotype currently recognized as NASH."
Establishes non-triglyceride lipotoxic metabolites, rather than triglyceride storage itself, as the major driver of hepatocyte injury. Evidence source is OTHER because this is a mechanistic review.
"Secondly, when adaptive mechanisms for stress tolerance are overwhelmed, lipotoxicity and chronic inflammation trigger major hepatic damages, mainly via oxidative and inflammatory stress, lipid peroxidation and cell death."
Links lipotoxicity to oxidative stress and downstream hepatic damage when adaptive responses are overwhelmed. Evidence source is OTHER because this is a review synthesizing OMICS and mechanistic data.
Hepatocyte Injury and Inflammatory Activation
central effector
Lipotoxic hepatocytes undergo apoptosis and other forms of regulated cell death, releasing damage signals that activate Kupffer cells and recruited macrophages. The resulting inflammatory response, with inflammasome activation and pro-inflammatory cytokine release, defines the transition from bland steatosis to steatohepatitis and is the central effector step of progressive liver injury.
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Hepatic Stellate Cell Activation and Fibrosis
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"Hepatocyte cell death and liver inflammation have been well recognized as central characteristics of nonalcoholic steatohepatitis (NASH), however, the underlying molecular basis remains elusive."
Establishes hepatocyte cell death and liver inflammation as the central characteristics of steatohepatitis. The study uses high-fat-diet mouse models with Kupffer-cell and macrophage experiments, so evidence source is MODEL_ORGANISM.
"Furthermore, hepatocyte lipoapoptosis is a critical feature of NASH."
Identifies hepatocyte lipoapoptosis as a critical feature of steatohepatitis, supporting hepatocyte death as a central effector. Evidence source is OTHER because this is a review.
Hepatic Stellate Cell Activation and Fibrosis
effector
Sustained hepatocyte injury and macrophage-driven inflammation activate hepatic stellate cells, which transdifferentiate into myofibroblast-like cells that deposit excessive extracellular matrix. This is the fibrotic effector arm of steatotic liver disease and connects conceptually to the conserved fibrotic_response module, with hepatic stellate cells serving as the organ-specific mesenchymal precursor.
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Hepatic Steatosis Progressing to Steatohepatitis and Fibrosis
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"Here we provide an in-depth discussion of the underlying pathogenetic mechanisms that lead to progressive liver injury, including the metabolic origins of NAFLD, the effect of NAFLD on hepatic glucose and lipid metabolism, bile acid toxicity, macrophage dysfunction, and hepatic stellate cell..."
Landmark review identifying hepatic stellate cell activation, alongside macrophage dysfunction, as a pathogenetic mechanism driving fibrosis progression in NASH. Evidence source is OTHER because this is a review synthesizing multiple study types.
Hepatic Steatosis Progressing to Steatohepatitis and Fibrosis
consequence
The convergent outcome is the hepatic steatosis phenotype (fatty liver disease) and its progression: bland steatosis can advance to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. This final node represents the disease-like phenotype of hepatic steatosis and its progressive sequelae shared across metabolic, alcoholic, and genetic forms of steatotic liver disease.
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"Its more advanced subtype, nonalcoholic steatohepatitis (NASH), connotes progressive liver injury that can lead to cirrhosis and hepatocellular carcinoma."
Directly states that the advanced steatohepatitis subtype produces progressive liver injury culminating in cirrhosis and hepatocellular carcinoma, the defining consequence of this module. Evidence source is OTHER because this is a review.
"As a consequence, all these processes concur to favor steatohepatitis, fibrosis and cancer."
Summarizes that the lipid-overload and lipotoxicity processes together converge on steatohepatitis, fibrosis, and cancer. Evidence source is OTHER because this is a review.