Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Chylomicron Retention Disease. Core disease mechanisms, molecular and cell...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Unraveling Chylomicron Retention Disease Enhances Insight into SAR1B GTPase Functions and Mechanisms of Actions, While Shedding Light of Intracellular Chylomicron Trafficking

• Authors: Emile Levy, C. Fallet-Bianco, Nickolas Auclair, Natalie Patey, V. Marcil et al.
• Year: 2024
• Venue: Biomedicines
• URL: https://www.semanticscholar.org/paper/82b6c2cae3986e94f2569f19529aca4e3354780b
• DOI: 10.3390/biomedicines12071548
• PMID: 39062121
• PMCID: 11274388
• Citations: 1
• Summary: This comprehensive review provides an in-depth and contemporary analysis of CRD, offering a meticulous examination of the CRD current landscape by synthesizing the latest research findings and advancements in the field.
• Evidence snippets:
• Snippet 1 (score: 0.469) > Over the past three decades, significant efforts have been focused on unraveling congenital intestinal disorders that disrupt the absorption of dietary lipids and fat-soluble vitamins. The primary goal has been to gain deeper insights into intra-enterocyte sites, molecular steps, and crucial proteins/regulatory pathways involved, while simultaneously identifying novel therapeutic targets and diagnostic tools. This research not only delves into specific and rare malabsorptive conditions, such as chylomicron retention disease (CRD), but also contributes to our understanding of normal physiology through the utilization of cutting-edge cellular and animal models alongside advanced research methodologies. This review elucidates how modern techniques have facilitated the decoding of CRD gene defects, the identification of dysfunctional cellular processes, disease regulatory mechanisms, and the essential role of coat protein complex II-coated vesicles and cargo receptors in chylomicron trafficking and endoplasmic reticulum (ER) exit sites. Moreover, experimental approaches have shed light on the multifaceted functions of SAR1B GTPase, wherein loss-of-function mutations not only predispose individuals to CRD but also exacerbate oxidative stress, inflammation, and ER stress, potentially contributing to clinical complications associated with CRD. In addition to dissecting the primary disease pathology, genetically modified animal models have emerged as invaluable assets in exploring various ancillary aspects, including responses to environmental challenges such as dietary alterations, gender-specific disparities in disease onset and progression, and embryonic lethality or developmental abnormalities. In summary, this comprehensive review provides an in-depth and contemporary analysis of CRD, offering a meticulous examination of the CRD current landscape by synthesizing the latest research findings and advancements in the field.

[2] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

• Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
• Year: 2025
• Venue: Journal of Veterinary Internal Medicine
• URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
• DOI: 10.1111/jvim.70139
• PMID: 40492724
• PMCID: 12150350
• Citations: 2
• Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
• Evidence snippets:
• Snippet 1 (score: 0.436) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[3] From Congenital Disorders of Fat Malabsorption to Understanding Intra-Enterocyte Mechanisms Behind Chylomicron Assembly and Secretion

• Authors: E. Levy, J. Beaulieu, S. Spahis
• Year: 2021
• Venue: Frontiers in Physiology
• URL: https://www.semanticscholar.org/paper/d6851fd6233246c17b0c83e3e85ba7fc24456295
• DOI: 10.3389/fphys.2021.629222
• PMID: 33584351
• PMCID: 7873531
• Citations: 11
• Summary: The ultimate goal of this approach is that “experiments of nature” and in vivo model strategy collectively allow gaining novel mechanistic insight and filling the gap between the underlying genetic defect and the apparent clinical phenotype.
• Evidence snippets:
• Snippet 1 (score: 0.433) > During the last two decades, a large body of information on the events responsible for intestinal fat digestion and absorption has been accumulated. In particular, many groups have extensively focused on the absorptive phase in order to highlight the critical “players” and the main mechanisms orchestrating the assembly and secretion of chylomicrons (CM) as essential vehicles of alimentary lipids. The major aim of this article is to review understanding derived from basic science and clinical conditions associated with impaired packaging and export of CM. We have particularly insisted on inborn metabolic pathways in humans as well as on genetically modified animal models (recapitulating pathological features). The ultimate goal of this approach is that “experiments of nature” and in vivo model strategy collectively allow gaining novel mechanistic insight and filling the gap between the underlying genetic defect and the apparent clinical phenotype. Thus, uncovering the cause of disease contributes not only to understanding normal physiologic pathway, but also to capturing disorder onset, progression, treatment and prognosis.

[4] From molecular signatures to predictive biomarkers: modeling disease pathophysiology and drug mechanism of action

• Authors: A. Heinzel, P. Perco, G. Mayer, R. Oberbauer, A. Lukas et al.
• Year: 2014
• Venue: Frontiers in Cell and Developmental Biology
• URL: https://www.semanticscholar.org/paper/36d6c03a528c1358c0ae5b667cca5ce73b2fbee5
• DOI: 10.3389/fcell.2014.00037
• PMID: 25364744
• PMCID: 4207010
• Citations: 27
• Summary: This work exemplifies a computational workflow for expanding from statistics-based association analysis toward deriving molecular pathway and process models for characterizing phenotypes and drug mechanism of action, in turn providing precision medicine hypotheses utilizing predictive biomarkers.
• Evidence snippets:
• Snippet 1 (score: 0.417) > Omics profiling significantly expanded the molecular landscape describing clinical phenotypes. Association analysis resulted in first diagnostic and prognostic biomarker signatures entering clinical utility. However, utilizing Omics for deepening our understanding of disease pathophysiology, and further including specific interference with drug mechanism of action on a molecular process level still sees limited added value in the clinical setting. We exemplify a computational workflow for expanding from statistics-based association analysis toward deriving molecular pathway and process models for characterizing phenotypes and drug mechanism of action. Interference analysis on the molecular model level allows identification of predictive biomarker candidates for testing drug response. We discuss this strategy on diabetic nephropathy (DN), a complex clinical phenotype triggered by diabetes and presenting with renal as well as cardiovascular endpoints. A molecular pathway map indicates involvement of multiple molecular mechanisms, and selected biomarker candidates reported as associated with disease progression are identified for specific molecular processes. Selective interference of drug mechanism of action and disease-associated processes is identified for drug classes in clinical use, in turn providing precision medicine hypotheses utilizing predictive biomarkers.

[5] Apolipoprotein B48 Knockout Ameliorates High-Fat-Diet-Induced Metabolic Impairment in Mice

• Authors: Yale Tang, Chao Wang, Luxuan Li, Xiaoyu Wang, Linquan Yang et al.
• Year: 2025
• Venue: Biomolecules
• URL: https://www.semanticscholar.org/paper/db7e0cd6dbd61154f65d83f7b12d155909495d79
• DOI: 10.3390/biom15101454
• PMID: 41154683
• PMCID: 12564635
• Summary: Reduced expression of ApoB48 can ameliorate lipid metabolism disorders induced by an HFD, which may be related to the CerS6/PP2A/AKT pathway, which might represent a new approach for exploring methods to treat hyperlipidaemia.
• Evidence snippets:
• Snippet 1 (score: 0.404) > Hyperlipidaemia has become increasingly common due to lifestyle changes, with M = more than 25% of the population in Europe and the United States being affected [1,2]. In 2020, the prevalence of dyslipidaemia among young adults (aged 18-45 years) in the southeastern coastal region of China was 22.9% [3]. Hyperlipidaemia is a pathological condition characterised by lipid metabolism disorders caused by genetic susceptibility, dietary factors, environmental triggers, and metabolic disorders [4][5][6], which can lead to various harmful effects. Cohort studies have confirmed the correlation between hypertriglyceridaemia and atherosclerotic cardiovascular disease (ASCVD) [7]. Researchers predict that between 2010 and 2030, the number of cardiovascular events caused by hyperlipidaemia in China will increase to over 9 million [8]. Additionally, this condition can cause various metabolic disorders, such as acute and chronic pancreatitis, hyperglycaemia, and hepatic steatosis [9,10]. Therefore, the risks associated with metabolic complications pose a significant challenge to the prevention and treatment of hyperlipidaemia. Hence, exploring the underlying mechanisms is crucial. However, people spend most of their time in a postprandial state, and in clinical practice, and only fasting blood lipids are usually tested, meaning that postprandial hyperlipidaemia is often overlooked. > Furthermore, lipoproteins are closely associated with postprandial hyperlipidaemia and various metabolic disorders. Apolipoprotein B48 (ApoB48), a subtype of the lipoprotein B family, is a core apolipoprotein involved in exogenous lipid transport, that is, an intestinal lipoprotein. After food intake, dietary lipids are absorbed by small intestinal epithelial cells and subsequently assembled into chylomicrons in association with ApoB48. These chylomicrons transport lipids to peripheral tissues, especially adipose tissue, upon entering the systemic circulation. Abnormal function is directly related to chylomicron (CM) metabolic disorders and hypertriglyceridaemia.

[6] Differentially expressed serum proteins from obese Wistar rats as a risk factor for obesity-induced diseases

• Authors: K. Gabuza, N. Sibuyi, M. Mobo, A. Madiehe
• Year: 2020
• Venue: Scientific Reports
• URL: https://www.semanticscholar.org/paper/899246fb2d0d3e1d858b292c904d5ff16850fe79
• DOI: 10.1038/s41598-020-69198-2
• PMID: 32709962
• PMCID: 7381623
• Citations: 6
• Summary: Variation in the expression of serum proteins during acute and chronic exposure to high fat diet is shown, indicating that these proteins might interactively play a crucial role in development of obesity-induced diseases.
• Evidence snippets:
• Snippet 1 (score: 0.398) > Sodium dodecyl sulfate polyacrylamide gel electrophoresis T2D Type 2 diabetes TCA Trichloroacetic acid > Obesity, defined by a body mass index of ≥ 30 kg/m 2 , is a global epidemic affecting both developed and developing countries 1 . Despite the major progress made in regulating energy balance and understanding the molecular mechanisms leading to the development of obesity in both human and animal studies, no safe or effective treatment has yet been found 1 . Obesity is a chronic disease that is clinically managed by lifestyle modification, pharmacotherapy, and surgery. Failure to maintain a healthy body weight has been associated with development of chronic diseases such as cardiovascular diseases, type 2 diabetes (T2D) and some forms of cancer [2][3][4] . These diseases pose a major health threat as they are considered the top ten leading causes of death worldwide 5 . Therefore, identification of alternative approaches that can unravel the biochemical and physiological processes that occur during development of obesity and progression to chronic diseases are urgently needed. These might give insights on obesity and obesity-induced diseases, uncover ways to prevent their development in susceptible individuals, and improve on the current treatment strategies. Serum plays a major role in diagnosis and monitoring of many diseases through immunological assays. Serum contains many proteins originating from various tissues and cells within the body 6 , and serve as an attractive source for biomarker discovery as it can reflect the molecular changes taking place during the development of obesity and progression to chronic diseases of lifestyle 7 . These proteins can be used as potential biomarkers or targets for the targeted treatment of obesity, diagnosis and/or identification of individuals at risk of developing obesity-induced diseases. Obesity is a multifaceted disease, as a result a single biomarker cannot entirely describe all the pathways affected. Several adipokines, cytokines, metabolites, and microRNAs are implicated in obesityinduced diseases, some are dysregulated in more than one disease while some show potential as disease-specific biomarkers. Their expression levels can identify individuals with or at risk of developing obesity-related diseases such as inflammatory diseases 8 , diabetes 9 , CVDs 10 and metabolically unhealthy obese people 11 .

[7] Frontiers in metabolic physiology grand challenges

• Authors: J. Imig
• Year: 2022
• Venue: Frontiers in Physiology
• URL: https://www.semanticscholar.org/paper/19e2780d459288513f034516e0a7d5fa4e12298f
• DOI: 10.3389/fphys.2022.879617
• PMID: 36035475
• PMCID: 9399398
• Citations: 2
• Summary: In this chapter seven subsequent studies of the determinants of infectious disease in eight operation rooms were studied.
• Evidence snippets:
• Snippet 1 (score: 0.397) > Research in this area will identify novel therapeutic targets for diabetic complications at the levels of transcription and translation, protein expression and activity, and cell and organ levels. Major challenges in diabetes include defining molecular mechanisms and pathways implicated in insulin metabolism, evaluating transcriptomics of high glucose on different cell types, defining the contribution of the innate immune response and NLRP3 inflammasome, understanding metabolic mechanisms that drive beta cell dysfunction, and defining metabolic processes in key insulin-target tissues. > NAFLD is a rapidly growing public health concern that occurs in 25% of the world population and is driven in large part by the obesity and type 2 diabetes epidemic (Caussy et al., 2021;Targher et al., 2021). Intriguingly, NAFLD can be as high as 75% in diabetic patients (Caussy et al., 2021;Targher et al., 2021). Non-alcoholic steatosis (NASH) is a type of NAFLD that is associated with inflammation and hepatocyte lipotoxicity which leads to liver fibrosis and cancer (Caussy et al., 2021;Targher et al., 2021). NASH is expected to become the leading cause for liver transplantation in the next decade (Nephew and Serper, 2021). Mechanisms that contribute to NAFLD and progression to NASH include regulation of de novo lipogenesis by acetyl-CoA carboxylase, regulation of bile acid signaling by farnesoid X receptor (FXR), or oxidative stress induced fibrogenesis and inflammation by apoptosis signal-regulating kinase 1 (ASK1) (Attia et al., 2021;Koo and Han, 2021). Although often associated with obesity and diabetes, understanding pathophysiological mechanisms at the cellular hepatocyte and organ liver levels that result in NAFLD and progression to NASH will be key to developing therapeutics. > Major challenges to the epidemic of metabolic diseases are the focus of several publications in Frontiers in Metabolic Physiology. Studies in mice with type 2 diabetes have revealed metabolites involved in diabetic kidney disease.

[8] Unmasking the enigma of lipid metabolism in metabolic dysfunction-associated steatotic liver disease: from mechanism to the clinic

• Authors: G.-C. Rao, Xi Peng, Xinqiong Li, Kang An, He He et al.
• Year: 2023
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/d2b35f7a86b14e6dc3383a31166a9ba255454237
• DOI: 10.3389/fmed.2023.1294267
• PMID: 38089874
• PMCID: 10711211
• Citations: 76
• Influential citations: 3
• Summary: The existing literature on the key process of lipid metabolism in MASLD is reviewed to understand the latest progress in this molecular mechanism, and de novo lipogenesis and the roles of its two main transcription factors and other key metabolic enzymes are highlighted.
• Evidence snippets:
• Snippet 1 (score: 0.396) > Over the last few decades, significant advancements have been made in comprehending the pathogenesis of MASLD. Excessive energy substrates, especially carbohydrates, cause DNL in the liver, while fat in the diet and adipose tissue with metabolic disorders provide excessive FFAs. Although the initial storage of liver triglycerides may play a buffering role, the production of toxic lipid metabolites is the main feature of progressive MASLD, which involves the production of cell pressure, mitochondrial dysfunction, the increase of reactive oxygen species, and the development of endoplasmic reticulum pressure (Figure 2). Reducing liver lipid deposition by targeting different pathways, especially key molecules, is of great clinical value to help identify key metabolic weaknesses that can be targeted to attenuate hepatic damage, inflammation, and fibrosis. This review systematically introduces the causes of liver lipid metabolism imbalance and the drug development and research progress of key molecules, aiming at a deeper understanding of the role of lipid metabolism in MASLD and providing ideas for clinical drug development from the molecular mechanism. > As we delve deeper into our research, it is crucial to consider the impact of ethnic and individual variances. By integrating genetic and metabolic factors, a more comprehensive understanding of the pathogenesis of MASLD can be achieved, and individualized therapeutic strategies can be developed. This may include explorations in genomic studies, metabolomic analysis, and drug development to accelerate therapeutic advances in MASLD. The application of this holistic approach is expected to provide more effective treatment options for patients with MASLD and improve the feasibility and success of treatment. > Additionally, due to the intricate nature of the pathophysiology involved in MASLD, it is possible that a solitary medication may not suffice to reverse the disease, necessitating the use of a combination therapy. The combination therapy of two or more drugs may improve the curative effect through complementation or synergy and improve tolerance by using a lower dose of candidate drugs. However, it is still a challenge to determine the ideal combination of drugs. The ideal combination therapy will aim at multiple steps of the pathogenesis, from energy balance to fibrosis. In addition to liver-oriented therapy, it should also include drugs with significant metabolic effects (such as drugs for treating type 2 diabetes).

[9] Gut Microbiota as a Systemic Regulator: Immunological and Neurological Implications Beyond Digestive Disease

• Authors: María Paulina, P. Morales, Alejandra Isabel Carla, Farina Guzman, G. Amaya et al.
• Year: 2026
• Venue: International Science Journal
• URL: https://www.semanticscholar.org/paper/ffce27bfcfa333f0af707d08958d04464a6c3cf8
• DOI: 10.64784/218
• Summary: Key mechanisms identified included increased intestinal permeability, chronic low-grade inflammation, abnormal immune activation, altered short-chain fatty acid production, and neuroimmune dysregulation mediated through the gut–brain axis, which demonstrated promising therapeutic potential in restoring microbial balance and reducing inflammatory activity.
• Evidence snippets:
• Snippet 1 (score: 0.394) > To identify the principal microbial populations, metabolites, and physiological mechanisms involved in the gut-brain axis and gut-immune axis based on current scientific evidence. 2. To explain how intestinal dysbiosis contributes to systemic inflammation, immune dysregulation, metabolic dysfunction, and neurological alterations associated with chronic disease progression. 3. To relate microbiota-derived mechanisms with the pathophysiology of systemic diseases including obesity, diabetes mellitus, cardiovascular disorders, autoimmune diseases, and neurodegenerative conditions. 4. To compare the immunological and neurological pathways through which gut microbiota influences systemic homeostasis and disease development across different organ systems. 5. To critically assess the current evidence regarding microbiota-based therapeutic interventions such as probiotics, prebiotics, dietary modulation, and fecal microbiota transplantation in clinical practice. 6. To propose integrative perspectives regarding the future role of microbiome-centered approaches in preventive medicine, personalized treatment, and translational biomedical research

[10] Mitochondrial transplantation as a promising therapy for mitochondrial diseases

• Authors: Tian-Guang Zhang, Chaoyu Miao
• Year: 2022
• Venue: Acta Pharmaceutica Sinica. B
• URL: https://www.semanticscholar.org/paper/72802097939b0bffc319c93d05128d7e3160e0eb
• DOI: 10.1016/j.apsb.2022.10.008
• PMID: 36970208
• PMCID: 10031255
• Citations: 108
• Influential citations: 2
• Summary: Different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application are presented.
• Evidence snippets:
• Snippet 1 (score: 0.391) > Mitochondria, the vital organelles of eukaryotic cells, are integrators of various cellular metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, urea cycle, Krebs cycle, ketogenesis and gluconeogenesis 1 . Mitochondria are also important in many other essential cellular processes such as calcium homeostasis, lipid metabolism, amino acid metabolism, biosynthesis of heme, and thermogenesis 2 . However, they also have important roles in many pathways which can cause both apoptosis and necrosis 3 . Therefore, the importance of the mitochondrion in the maintenance of cellular homeostasis is well established, meanwhile a large amount of evidence shows that mitochondrial dysfunction is deleterious 4 . > Due to the essential function of mitochondria in the human body, mitochondrial dysfunction causes a great variety of mitochondrial diseases, which can affect almost all the organs in the body and present at any age 4,5 . Mitochondrial diseases are a group of metabolic disorders characterized by energy metabolism dysfunction. The pathophysiology is further complicated by the involvement of genetic mutations in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) which encode mitochondrial proteins. This means that mitochondrial diseases may result from inheritance for nDNA mutations and maternal inheritance for mtDNA mutations. The estimated minimum prevalence of mitochondrial diseases is 1 in 5000, whereas it could be higher 6 . > As advances in molecular and biochemical methodologies led to a better understanding of the mechanisms of mitochondrial disorders for various diseases, mitochondria have become a major target for research institutions and pharma companies. Pharmacological approaches include dietary supplements such as agents increasing respiratory chain function (coenzyme Q10 and riboflavin), agents inducing mitochondrial biogenesis (AICAR and bezafibrate), antioxidants (vitamin C and vitamin E), mitochondrial substrates (L-carnitine) and so on 7,8 . However, these agents fail to significantly alleviate disease symptoms or effectively slow disease progressions, there has therefore been no satisfactory therapeutic strategy available for mitochondrial diseases so far 9 . In addition, all new drugs under clinical trials for treatment of mitochondrial diseases are unable to cure these diseases permanently 9 .

[11] Drug discovery for psychiatric disorders using high-content single-cell screening of signaling network responses ex vivo

• Authors: Santiago G. Lago, Jakub Tomasik, Geertje F. van Rees, Hannah Steeb, D. Cox et al.
• Year: 2019
• Venue: Science Advances
• URL: https://www.semanticscholar.org/paper/8c5705beab72c173a2527e5d8db99aac5533ca2b
• DOI: 10.1126/sciadv.aau9093
• PMID: 31086815
• PMCID: 6506238
• Citations: 28
• Influential citations: 1
• Summary: A novel approach to neuropsychiatric drug discovery based on high-content characterization of druggable signaling network responses at the single-cell level in patient-derived lymphocytes ex vivo, which has the potential to discern new drug targets and accelerate drug discovery and personalized medicine for Neuropsychiatric conditions.
• Evidence snippets:
• Snippet 1 (score: 0.390) > Subsets of protein alterations common to both cell lineages have been associated with disease status, symptom severity, and therapeutic efficacy (17)(18)(19). Furthermore, recent GWAS data suggest the enrichment of single-nucleotide polymorphisms (SNPs) associated with neuropsychiatric (SCZ) risk loci within PBMC subtype-specific gene expression enhancers (7) and the coexpression of neuropsychiatric genetic risk phenotypes in both peripheral and CNS tissues (20,21). Although the functional correspondence between shared signaling motifs in PBMCs and CNS cells remains to be fully explored, it is possible that subsets of pathways, or even individual protein-protein interactions, which do overlap, are clinically relevant and can be practically exploited for drug discovery. Moreover, evidence that peripheral alterations can induce functional changes in the CNS with corresponding behavioral symptomatology [e.g., psychotic symptoms linked to gut microbiome alterations (22) or depressive-like symptoms following proinflammatory cytokine release during microbial infection (23)] suggests that peripheral cellular models may not solely be confined to surrogate identification of CNS targets but may also represent underlying pathophysiological mechanisms. > Exploration of neuropsychiatric patient PBMCs, with regard to functional alterations that reflect the disease state, could have important implications for overcoming current obstacles in neuropsychiatric drug discovery. First, the use of primary patient cells in the early stages of the drug discovery pipeline is associated with a higher success rate for putative targets and compounds (24). Second, the use of functional testing in live cells enables the elucidation of relevant disease-specific alterations in cell signaling networks, which are not observable simply by quantification of protein levels in their basal state, including homeostatic and regulatory mechanisms (13). Third, the focus on cellular responses provides the opportunity to summarize complex genetic risk factors with heterogeneous manifestations as integrated phenotypes, which are more amenable to drug screening and clinical treatment response prediction (25).

[12] Induction of Body Weight Loss through RNAi-Knockdown of APOBEC1 Gene Expression in Transgenic Rabbits

• Authors: G. Jolivet, S. Braud, B. da-Silva, B. Passet, Erwana Harscoët et al.
• Year: 2014
• Venue: PLoS ONE
• URL: https://www.semanticscholar.org/paper/355ea28b6f1283f281b3835a57785163f684d078
• DOI: 10.1371/journal.pone.0106655
• PMID: 25216115
• PMCID: 4162549
• Citations: 16
• Summary: A moderate reduction of the APOBEC1 dependent editing induces a lean phenotype at least in the rabbit species, suggesting that the AP OBEC1 gene might be a novel target for obesity treatment.
• Evidence snippets:
• Snippet 1 (score: 0.390) > A great number of genes are devoted to the storage of energy, and it is reasonable to propose that evolution has selected organisms able to survive in scarce conditions thanks to efficient mechanisms of energy storage. Limiting energy uptake and storage is probably a valuable strategy to fight against obesity. Thus, our approach consisted of looking for critical genes in people with lean phenotype. If a monogenic slimness disease resulting from a deficiency of fat absorption can be found, the implicated gene likely plays a critical role in the disease and is a potential target for new anti-obesity drugs. When this gene is not compensated by other mechanisms, it is therefore a powerful target for obesity treatment. > Three human genetic diseases have been described with very similar lean phenotypes: abetalipoproteinemia, hypobetalipoproteinemia, and chylomicron retention disease also known as Anderson's disease [19]. The genes involved in the first two diseases, abetalipoproteinemia and hypobetalipoproteinemia, have now been identified, but it is not yet the case in the Anderson's disease [20,21]. All three diseases are characterized by a severe reduction or total absence of APOB48 protein in intestinal cells and plasma and of chylomicrons production. This led us to investigate further the possibility of fighting against obesity through regulating APOB48 production. APOB48 resulting exclusively from the translation of the APOBEC1 dependent edited APOB mRNA, we decided to target the expression of the APOBEC1 gene. The phenotype of mice harboring a complete invalidation of the APOBEC1 gene has been already reported by a series of laboratories [22][23][24][25]. As expected, the editing of the APOB mRNA was suppressed, and no APOB48 was produced in these mice. It was observed that intestinal fat absorption was less efficient in APOBEC1 2/2 mice containing only APOB100 than in wild type mice but it was not totally abolished. Probably, APOB100 could replace to some extent APOB48 in chylomicron formation and finally the plasma lipoprotein cholesterol and triglycerides profiles were not different in knock out and wild type mice [7] [8].

[13] Identification of Key Biomarkers Related to Lipid Metabolism in Acute Pancreatitis and Their Regulatory Mechanisms Based on Bioinformatics and Machine Learning

• Authors: Liang Zhang, Yujie Jiang, Taojun Jin, Mingxian Zheng, Yixuan Yap et al.
• Year: 2025
• Venue: Biomedicines
• URL: https://www.semanticscholar.org/paper/e7ce2244e2bc25df76718a7b46e860a9c0478c01
• DOI: 10.3390/biomedicines13092132
• PMID: 41007695
• PMCID: 12467098
• Citations: 4
• Summary: Findings are crucial for a deeper understanding of lipid metabolism pathways in AP and for the early implementation of preventive clinical measures, such as the control of blood lipid levels.
• Evidence snippets:
• Snippet 1 (score: 0.389) > FFAs have activated inflammatory cytokines, including tumor necrosis factor (TNF)-α, Interleukin (IL)-6, IL-1β, and monocyte chemoattractant protein (MCP)-1, which exacerbate the inflammatory cascade in AP [12,13]. These findings suggest that lipid metabolism disorders are closely linked to the regulation of the local immune micro-environment of the pancreas. Abnormal expression of specific lipid metabolism-related genes may play a crucial role in AP progression. Notably, ACSL4, a gene involved in cell membrane lipid synthesis, has been shown to be central to AP pathology and may serve as a potential therapeutic target [14]. However, the molecular mechanisms by which lipid metabolism abnormalities regulate AP development remain unclear. A systematic analysis of the expression patterns of relevant genes and their regulatory mechanisms could enhance our understanding of AP pathogenesis and inform personalized treatment strategies. > Advancements in high-throughput sequencing and computational biology have made machine learning and bioinformatics essential tools for exploring disease diagnosis, treatment, and underlying pathological mechanisms. In this study, we conducted a systematic analysis of AP-related lipid metabolism core genes and their regulatory mechanisms by integrating gene expression data, gene enrichment analysis, machine learning, protein interaction networks, and metabolic pathway analysis [15][16][17][18]. We then experimentally validated the candidate genes using an AP mouse model to ensure the reliability and clinical translational value of the identified biomarkers. > This study aims to identify key lipid metabolism-related genes involved in the pathogenesis of acute pancreatitis and elucidate their core regulatory mechanisms through integrative bioinformatics, machine learning, and animal experiments.

[14] Altered vitamin E status in Niemann-Pick type C disease

• Authors: L. Ulatowski, Robert S. Parker, Cristin D. Davidson, N. Yanjanin, Thomas Kelley et al.
• Year: 2011
• Venue: Journal of Lipid Research
• URL: https://www.semanticscholar.org/paper/8cc5bfbaf50d3233757bbee6bbe7df8347ab4128
• DOI: 10.1194/jlr.M015560
• PMID: 21550990
• Citations: 44
• Influential citations: 2
• Summary: Observations indicate that functionality of NPC1/2 proteins is necessary for proper bioavailability of vitamin E and that the NPC pathology might involve tissue-specific perturbations ofitamin E status.
• Evidence snippets:
• Snippet 1 (score: 0.384) > Niemann-Pick type C disease is a debilitating, fatal disorder in which intracellular lipid transport is impaired due to loss-of-function mutations in the NPC1 or NPC2 protein. The main biochemical phenotype associated with NPC disease is accumulation of unesterifi ed cholesterol and other lipids in a vesicular compartment of an endosomal/lysosomal origin. A number of metabolic scenarios can be envisioned to be at the root of NPC pathology. First, the extensive localized accumulation of lipids may be toxic, thereby compromising cell function and viability. Second, since the affected lipids are "sequestered" away from their proper sites of action, the affected cell may experience a catastrophic defi ciency of these metabolites. Lastly, physical disruption of the endocytic compartment may deprive the cell of other molecules that rely on this pathway for cellular transport. Despite intense research efforts in the past 50 years, many questions regarding the etiology of NPC disease remain unanswered. Thus, it is still not known which of scenarios described above is of highest signifi cance during disease progression. Similarly, it has not been conclusively determined which of the lipids sequestered in NPC lysosomes is the primary culprit re-accumulate under NPC1 or NPC2 loss-of-function ( 21,67,68 ).

[15] 3-Hydroxystearic acid promotes cholesterol efflux and attenuates atherosclerosis via the ALKBH5/PAX-8/ABCA1 pathway

• Authors: Qin-Yi Zhou, Wang Liu, Zhenwang Zhao, Duo Gong, Xiaofeng Ma et al.
• Year: 2026
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/983d2564a739e449bd1275eeca318066e55721f4
• DOI: 10.3389/fimmu.2026.1750021
• PMID: 41694370
• PMCID: 12902941
• Summary: The results demonstrated that C18-3OH promoted cholesterol efflux in foam cells and alleviated lipid accumulation by upregulating ABCA1 expression, and clarifies the impact and mechanisms of gut microbiota-derived C18-3OH on atherosclerosis progression.
• Evidence snippets:
• Snippet 1 (score: 0.380) > Gut microbiota-derived bioactive metabolites modulate host physiological functions through genetic and epigenetic mechanisms, directly or indirectly influencing the development of cardiovascular diseases such as coronary artery disease, heart failure, hypertension, and obesity (36). The relationship between gut microbial metabolites and lipid metabolism has received increasing attention (37). Fatty acid metabolites from gut microbiota represent a novel class of mediators in cardiovascular pathophysiology. Fatty acids are categorized into three types: shortchain fatty acids (<6 carbons), medium-chain fatty acids (6-12 carbons), and long-chain fatty acids (>12 carbons). Short-chain fatty acids exert significant regulatory effects on lipid metabolism and atherosclerosis by modulating macrophage inflammation, cholesterol metabolism, and endothelial function (38). However, the roles and mechanisms of long-chain fatty acids in lipid metabolism and atherosclerosis remain incompletely characterized. > Foam cell accumulation and subsequent plaque formation constitute a critical pathological basis for atherosclerosis. Maintenance of cellular cholesterol homeostasis is essential for normal cellular function, as cholesterol accumulation plays a key role in the pathogenesis of foam cell. Cholesterol efflux serves as a primary pathway for peripheral tissues to eliminate excess cholesterol from foam cells. ABCA1, the most pivotal transporter mediating reverse cholesterol transport (RCT) in atherosclerosis, plays a central role in this process (39, 40). Microbial metabolites are increasingly recognized as regulators of macrophage cholesterol metabolism. For instance, the tryptophan metabolite indole-3propionic acid (IPA) promotes cholesterol efflux via ABCA1 upregulation, thereby attenuating coronary artery disease progression; hence, IPA is negatively correlated with the risk of atherosclerosis (41). Similarly, the gut microbiota-derived butyrate ameliorates atherosclerosis in apoE -/-mice through ABCA1mediated cholesterol efflux (42).

[16] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

• Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
• Year: 2025
• Venue: Pathophysiology
• URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
• DOI: 10.3390/pathophysiology32010009
• PMID: 39982365
• PMCID: 12077258
• Citations: 43
• Influential citations: 1
• Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
• Evidence snippets:
• Snippet 1 (score: 0.376) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[17] Toxicity and mechanistic analysis of di(2-ethylhexyl)phthalate in renal cell carcinoma progression: a systematic study with network toxicology and molecular docking strategies

• Authors: Biao Ran, Xinyi Wang, Bohan Liu, Junjiang Ye, Liangren Liu et al.
• Year: 2025
• Venue: Discover Oncology
• URL: https://www.semanticscholar.org/paper/66397aea42392baaaa9cf4e6e031b21c70d46c48
• DOI: 10.1007/s12672-025-03543-7
• PMID: 41071403
• PMCID: 12514089
• Citations: 2
• Summary: The results suggest that DEHP exposure may promote the development of RCC by regulating apoptosis and proliferation through pathways such as neuroactive ligand–receptor interactions, pathways related to cancer, and apoptosis.
• Evidence snippets:
• Snippet 1 (score: 0.376) > Additional relevant functions include proteoglycan binding, collagen binding, fibronectin binding, and cysteine-type endopeptidase activity, indicating diverse regulatory roles of these genes. Overall, these GO analyses (BP, CC, and MF) demonstrated that these genes are integral to a variety of biological processes, cellular structures, and molecular functions, contributing to essential cellular defense mechanisms, structural stability, and enzymatic regulation. > According to the KEGG pathway enrichment analysis shown in Fig. 5, these genes are significantly enriched in pathways such as neuroactive ligand-receptor interaction, the calcium signaling pathway, the TNF signaling pathway, the cAMP signaling pathway, and apoptosis, underscoring their critical roles in cellular communication, Fig. 3 The PPI network of core targets inflammation, and disease mechanisms. Additional significant pathways included pathways associated with cancer, pathways associated with neurodegeneration, diabetic cardiomyopathy, and lipid and atherosclerosis, highlighting their involvement in diverse disease processes. Figure 5A (bubble plot) shows the top 20 enriched KEGG pathways ranked by FDR values, where bubble size represents the number of enriched genes, and color intensity indicates statistical significance. These pathways suggest that these genes play roles in cellular functions and disease progression, such as DEHP-induced renal cell carcinoma. Figure 5B (bar plot) categorizes these pathways by the number of genes involved, with neuroactive ligand-receptor interactions having the highest gene count, followed by pathways in cancer, apoptosis, and the TNF signaling pathway. The pathways are grouped into categories such as Environmental Information Processing, Cellular Processes, and Human Diseases, which have broad gene distributions across biological systems. Together, Fig. 5A, B emphasize the significant involvement of these genes in cellular signaling, inflammation, and various disease mechanisms, highlighting their relevance to disease development and cellular regulation.

[18] Autophagy Dysregulation in Diabetic Kidney Disease: From Pathophysiology to Pharmacological Interventions

• Authors: Claudio D. Gonzalez, María Paula Carro Negueruela, Catalina Nicora Santamarina, R. Resnik, M. Vaccaro
• Year: 2021
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/7947636a7b11fdbf5fe9717b179f065548444576
• DOI: 10.3390/cells10092497
• PMID: 34572148
• PMCID: 8469825
• Citations: 50
• Influential citations: 1
• Summary: The relationship between autophagy and Diabetic kidney disease and the potential value of Autophagy modulation as a target for pharmacological intervention are discussed.
• Evidence snippets:
• Snippet 1 (score: 0.374) > Diabetic kidney disease (DKD) is a frequent, potentially devastating complication of diabetes mellitus. Several factors are involved in its pathophysiology. At a cellular level, diabetic kidney disease is associated with many structural and functional alterations. Autophagy is a cellular mechanism that transports intracytoplasmic components to lysosomes to preserve cellular function and homeostasis. Autophagy integrity is essential for cell homeostasis, its alteration can drive to cell damage or death. Diabetic kidney disease is associated with profound autophagy dysregulation. Autophagy rate and flux alterations were described in several models of diabetic kidney disease. Some of them are closely linked with disease progression and severity. Some antidiabetic agents have shown significant effects on autophagy. A few of them have also demonstrated to modify disease progression and improved outcomes in affected patients. Other drugs also target autophagy and are being explored for clinical use in patients with diabetic kidney disease. The modulation of autophagy could be relevant for the pharmacological treatment and prevention of this disease in the future. Therefore, this is an evolving area that requires further experimental and clinical research. Here we discuss the relationship between autophagy and Diabetic kidney disease and the potential value of autophagy modulation as a target for pharmacological intervention.

[19] Hypoxia-associated genes and metabolic abnormalities in peripheral blood mononuclear cells of type 1 diabetes mellitus patients

• Authors: Wenxue Ma, Xue-ying Wang, Yuan Zuo
• Year: 2025
• Venue: Hereditas
• URL: https://www.semanticscholar.org/paper/daa85eddc3e8ad7e335d87d5de402ef2337b43ea
• DOI: 10.1186/s41065-025-00537-x
• PMID: 40836269
• PMCID: 12369233
• Summary: These findings not only identify specific hub genes as key mediators connecting signaling pathways, biological processes, and metabolic changes but also provide novel insights into the pathophysiology of T1DM.
• Evidence snippets:
• Snippet 1 (score: 0.374) > Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disorder characterized by the destruction of pancreatic β-cells, which leads to insulin deficiency and hyperglycemia [1]. T1DM affects millions of individuals worldwide, imposing significant health and economic burdens due to its associated complications, such as neuropathy, retinopathy, and cardiovascular diseases [2]. While current management strategies mainly focus on insulin therapy and lifestyle modifications, these approaches fail to address the underlying pathological molecular mechanisms or prevent disease progression [3]. While several studies have investigated the genetic and environmental factors contributing to T1DM, the identification of key regulatory genes and their functional roles in disease pathogenesis remains limited [4]. Furthermore, the integration of gene expression data with pathway and metabolite analyses to reveal the complex interplay between molecular networks and clinical outcomes has not been extensively investigated [5]. Addressing these gaps is critical for developing targeted therapies and improving patient outcomes, underscoring the necessity of this study [6]. > T1DM is characterized by dysregulated immune responses and metabolic disturbances, yet the underlying molecular mechanisms are not completely understood [7]. Previous studies have identified altered gene expression and disrupted signaling pathways in T1DM, including TGF-beta and MAPK signaling, as well as retinol metabolism, all of which are implicated in immune modulation and metabolic regulation [8][9][10]. Additionally, biological processes, such as neutrophil activation, epithelial-mesenchymal transition (EMT), and hypoxia, have been associated with T1DM pathophysiology [11][12][13]. However, the interplay between these pathways, key regulatory genes, and metabolic changes remains underexplored. This study addresses this gap by integrating differential gene expression analysis, functional enrichment, protein-protein interaction (PPI) network construction, and correlation analyses to identify specific hub genes (FOS, JUNB, and NR4A2) that connect signaling pathways, biological processes, and metabolite dysregulation.

[20] Metabolomic Profiling for Identification of Novel Biomarkers and Mechanisms Related to Common Cardiovascular Diseases: Form and Function

• Authors: Svati H. Shah, W. Kraus, C. Newgard
• Year: 2012
• Venue: Circulation
• URL: https://www.semanticscholar.org/paper/54a51dd998a16a06162956d38c9a13501fadeeef
• DOI: 10.1161/CIRCULATIONAHA.111.060368
• PMID: 22927473
• PMCID: 4374548
• Citations: 358
• Influential citations: 8
• Summary: Comprehensive metabolic profiling, or “metabolomics” is increasingly being applied to CVD, leading to recent discoveries with both form and function implications, and recent progress in this rapidly expanding area is reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.374) > The hierarchy of molecular control of biological systems passes from gene through gene modification (epigenetics) to gene expression (transcriptomics) to protein expression (proteomics) to metabolites/metabolic pathways (metabolomics) to clinical phenotype or outcome (Figure 3, top). In this scheme, metabolism sits closest in proximity to clinical phenotype and is therefore a strong candidate for identifying causative molecular mechanisms for disease. However, in identifying genes responsible for the metabolic intermediates that affect outcome, it is clear that the biological complexity of the system increases as one passes from gene to outcome, 17 thus making the task of identifying the specific pathways involved in genetic cause or mediation of disease quite daunting-conceptually, experimentally, and statistically. The experimental challenge is illustrated by the fact that the 9p21 genetic locus undoubtedly contains the strongest and most consistent genetic marker of CVD risk identified so far, 50 yet 5 years after its discovery, the biological mechanism or pathway by which this genetic variant mediates disease is still a mystery. > The statistical challenge is illustrated by our own recent work and similar studies being performed by others (Figure 3, bottom). In our CATHGEN cohort, we have genome-wide association study data containing 10 6 single-nucleotide polymorphisms on 3500 individuals, whole-genome transcript data with 2ϫ10 4 gene tags on 1500 of the same individuals, data for Ͼ70 metabolites on 3500 individuals, and at least 10 outcomes or phenotypes on close to 10 000 individuals. Our work to date reveals strong associations of specific genetic loci with the cluster of small-to medium-chain dicarboxylated acylcarnitines found in the same population to be prognostic for incident cardiovascular events. The potential functional relationships between these genetic loci and variation in the dicarboxylated acylcarnitines are currently being investigated. The statistical complexity and the risk for false discovery (the multiple-comparisons problem) are daunting, exceeding 10 13 comparisons in each individual in the study population. Thus, in moving forward, we propose to adopt both the classic and retrograde approaches summarized in Figure 3. In the classic genetic variant mapped to outcome approach, used in the majority of genome-wide association studies published to date, the risk is that although

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