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Loss of PPARα function promotes epigenetic dysregulation of lipid homeostasis driving ferroptosis and pyroptosis lipotoxicity in Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) [MouseMethylation]

ABSTRACT: Loss of PPARα function promotes epigenetic dysregulation of lipid homeostasis driving ferroptosis and pyroptosis lipotoxicity in Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) [MouseMethylation]

PROVIDER: PRJNA998166 | ENA |

REPOSITORIES: ENA

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Loss of PPARα function promotes epigenetic dysregulation of lipid homeostasis driving ferroptosis and pyroptosis lipotoxicity in Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) [MouseMethylation]

Project description:Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is a growing epidemic with an estimated prevalence of 20‑30% in Europe and the most common cause of chronic liver disease worldwide. The onset and progression of MASLD are orchestrated by an interplay of the metabolic environment with genetic and epigenetic factors. Emerging evidence suggests altered DNA methylation pattern as a major determinant of MASLD pathogenesis coinciding with progressive DNA hypermethylation and gene silencing of the liver‑specific nuclear receptor PPARα, a key regulator of lipid metabolism. To investigate how PPARα loss of function contributes to epigenetic dysregulation in MASLD pathology, we studied DNA methylation changes in liver biopsies of WT and hepatocyte‑specific PPARα KO mice, following a 6‑week CDAHFD (choline-deficient, L-amino acid-defined, high-fat diet) or chow diet. Interestingly, genetic loss of PPARα function in hepatocyte‑specific KO mice could be phenocopied by a 6-week CDAHFD diet in WT mice which promotes epigenetic silencing of PPARα function via DNA hypermethylation, similar to MASLD pathology. Remarkably, genetic and lipid diet‑induced loss of PPARα function triggers compensatory activation of multiple lipid sensing transcription factors and epigenetic writer-eraser-reader proteins, which promotes the epigenetic transition from lipid metabolic stress towards ferroptosis and pyroptosis lipid hepatoxicity pathways associated with advanced MASLD. In conclusion, we show that PPARα function is essential to support lipid homeostasis and to suppress the epigenetic progression of ferroptosis‑pyroptosis lipid damage associated pathways towards MASLD fibrosis.

2024-03-01 | GSE238173 | GEO

Project description:Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) is a growing epidemic with an estimated prevalence of 20‑30% in Europe and the most common cause of chronic liver disease worldwide. The onset and progression of MASLD are orchestrated by an interplay of the metabolic environment with genetic and epigenetic factors. Emerging evidence suggests altered DNA methylation pattern as a major determinant of MASLD pathogenesis coinciding with progressive DNA hypermethylation and gene silencing of the liver‑specific nuclear receptor PPARα, a key regulator of lipid metabolism. To investigate how PPARα loss of function contributes to epigenetic dysregulation in MASLD pathology, we studied transcriptome profile changes that could induce changes in DNA methylation in liver biopsies of WT and hepatocyte‑specific PPARα KO mice, following a 6‑week CDAHFD (choline-deficient, L-amino acid-defined, high-fat diet) or chow diet. Interestingly, genetic loss of PPARα function in hepatocyte‑specific KO mice could be phenocopied by a 6-week CDAHFD diet in WT mice which promotes epigenetic silencing of PPARα function via DNA hypermethylation, similar to MASLD pathology. Remarkably, genetic and lipid diet‑induced loss of PPARα function triggers compensatory transcription of multiple lipid sensing transcription factors and epigenetic writer-eraser-reader proteins, which promotes the epigenetic transition from lipid metabolic stress towards ferroptosis and pyroptosis lipid hepatoxicity pathways associated with advanced MASLD. In conclusion, we show that PPARα function is essential to support lipid homeostasis and to suppress the epigenetic progression of ferroptosis‑pyroptosis lipid damage associated pathways towards MASLD fibrosis.

2024-03-01 | GSE238201 | GEO

Loss of PPARα function promotes epigenetic dysregulation of lipid homeostasis driving ferroptosis and pyroptosis lipotoxicity in Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD)

Project description:Loss of PPARα function promotes epigenetic dysregulation of lipid homeostasis driving ferroptosis and pyroptosis lipotoxicity in Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD)

| PRJNA998739 | ENA

| PRJNA998364 | ENA

Loss of PPARα function promotes epigenetic dysregulation of lipid homeostasis driving ferroptosis and pyroptosis lipotoxicity in metabolic dysfunction associated Steatotic liver disease (MASLD).

Project description: Not available

| S-EPMC11285560 | biostudies-literature

Allantoin promotes MASLD progression

Project description:Uric acid has garnered increasing attention for its association with metabolic dysfunction-associated steatotic liver disease (MASLD) in recent cross-sectional studies, although detailed understanding of its involvement remains limited. This study confirms a strong association between urate levels and elevated risk of both MASLD and type 2 diabetes (T2D) through a large-scale observational analysis of UK Biobank data. However, Mendelian randomization (MR) analysis involving over 2 million samples identified only causal effects of urate on serum triglyceride levels and the risk of T2D. Additionally, a targeted metabolomics study involving elderly Chinese participants revealed that, rather than UA, allantoin—a byproduct of UA oxidation—was significantly elevated in individuals with dyslipidemia or T2D. Notably, a significant negative correlation was found between serum allantoin level and fasting glucose, as well as serum triglyceride and cholesterol levels. Animal studies demonstrated that allantoin exacerbates hepatic lipid accumulation and glucose intolerance in mice fed a high-fat diet, which was accompanied by increased hepatic lipid biogenesis and reduced bile acid production. Interestingly, our findings indicate that allantoin exhibits a strong binding affinity for PPARα, suggesting that it may act as an inhibitor of PPARα, thereby promoting the progression of MASLD. These results underscore the critical role of allantoin, rather than UA, in the development of MASLD, offering valuable insights for the prediction and management of hepatic metabolic disorders.

2025-06-04 | GSE283505 | GEO

Loss of PPARα function promotes epigenetic dysregulation of lipid homeostasis driving ferroptosis and pyroptosis lipotoxicity in Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD)

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-03-01 | GSE239279 | GEO

Effects of D4-MASLD and D5-MASLD Diets on Rats: Pathway Alterations Similar to Human MASLD

Project description:Animal models are essential to understand the mechanisms underlying the onset and progression of metabolic associated steatotic liver disease (MASLD), a rapidly growing form of chronic liver disease driven largely by the global rise in metabolic syndrome. However, existing animal models for MASLD often fail to accurately reproduce advanced human liver disease, and have varying degrees of clinical relevance. To address this, we have undertaken efforts to create a dietary translational model of MASLD in rats that closely replicates the full MASLD phenotype observed in humans, including advanced fibrosis, portal hypertension, and metabolic syndrome. Three MASLD rat models were developed by sequentially combining a high-fat glucose-fructose diet (HFGFD) with additional factors: lipopolysaccharide, increased cholesterol (Chol), and cholic acid (CA) at different concentrations. Of these, two diets—D4-MASLD (HFGFD + 2% Chol) and D5-MASLD (HFGFD + 2% Chol + 0.1% CA)—effectively replicated MASLD characteristics. Transcriptomic analysis revealed that while both diets significantly altered gene expression compared to controls, D5-MASLD had a greater impact on the activation of inflammation and immune response pathways. The inclusion of CA in D5-MASLD exacerbated pathways related to microbiota changes, intestinal barrier dysfunction, and bacterial translocation. Additionally, comparison of the transcriptomic profiles of these diet-induced rat models with data from MASLD/MASH patients further validated the relevance of these models, establishing a robust platform for studying MASLD pathogenesis and evaluating potential therapeutic interventions.

2026-04-20 | GSE282001 | GEO

Deep proteome profiling of metabolic dysfunction-associated steatotic liver disease

Project description:Analyze human biopsies for the investigation of metabolic dysfunction-associated steatotic liver disease (MASLD). We also analyzed plasma samples for biomarker discovery. And analyzed the role of the impact of the adipose tissue on plasma proteins in relation to MASLD

2025-03-05 | PXD051911 | Pride

Effect of hepatocytic RKIP depletion on HFD-induced MASLD

Project description:High-fat diet (HFD) is a risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), yet the molecular pathways that connect dietary fats to liver dysfunction remain unclear. Hepatocyte-specific RKIP depletion in male mice exacerbates ER stress, resulting in lipid droplets accumulation and MASLD progression.

2025-09-03 | GSE300123 | GEO

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