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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)

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

PROVIDER: PRJNA998739 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25419566_1.fastq.gz	Fastqsanger.gz
	SRR25419566_2.fastq.gz	Fastqsanger.gz
	SRR25419567_1.fastq.gz	Fastqsanger.gz
	SRR25419567_2.fastq.gz	Fastqsanger.gz
	SRR25419568_1.fastq.gz	Fastqsanger.gz

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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

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) [MouseMethylation]

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2026-01-16 | E-MTAB-15610 | biostudies-arrayexpress

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

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Allantoin promotes MASLD progression

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Project description:Hepatosteatosis, a common liver condition, involves excessive lipid accumulation and can lead to severe complications. Its molecular mechanisms are poorly understood, highlighting the need for therapies. The molecular mechanisms are poorly understood, emphasizing the need for effective therapies. In this study, we identified hyodeoxycholic acid (HDCA) as a potent anti-steatotic agent capable of preventing diet-induced fatty liver. Mechanistically, HDCA treatment enhanced the hepatic expression of numerous PPARα target genes while also promoting the secretion of the gut hormone GLP-1. The significance of PPARα signalling was emphasised by the fact that the anti-steatotic effects of HDCA were completely abolished in PPARα-knockout mice. Our findings further reveal a novel mechanism involving invariant natural killer T (iNKT) cells. HDCA treatment increased both the number and proliferation of iNKT cells in vivo, a phenomenon recapitulated in vitro using a GLP-1 agonist. This indicates that the anti-steatotic action of HDCA requires the coordinated activity of PPARα signalling and iNKT cells. These insights offer a promising avenue for developing targeted therapies for MASLD.

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