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Mitochondrial GpC and CpG DNA hypermethylation cause metabolic stress induced mitophagy and cholestophagy

ABSTRACT: Metabolic dysfunction associated steatotic liver disease (MASLD) is characterized by a constant accumulation of lipids in the liver. This lipotoxicity in the liver is associated with dysregulation of the first step in lipid catabolism called beta oxidation in the mitochondrial matrix, eventually leading to mitochondrial dysfunction. To evaluate possible involvement of mitochondrial DNA methylation in this lipid metabolic dysfunction we investigated the functional metabolic effects of mitochondrial overexpression of CpG (MSssI) and GpC (MCviPI) DNA methyltransferases in relation to gene expression and (mito)epigenetic signatures. Overall, the results show that mitochondrial GpC and to a lesser extent CpG methylation increase bile acid metabolic gene expression, inducing cholestasis by mito-nuclear epigenetic reprogramming. Moreover, increased expression of metabolic nuclear receptors in both MSssI and MCviPI cells promote mitochondrial swelling and induce basal overactivation of mitochondrial respiration which favours lipid accumulation and metabolic-stress induced mitophagy and autophagy stress responses. Altogether GpC and CpG mitochondrial induce a metabolic challenging environment that is similar to mitochondrial dysfunction in the progression of MASLD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240988 | GEO | 2023/12/08

REPOSITORIES: GEO

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Mitochondrial GpC and CpG DNA hypermethylation cause metabolic stress induced mitophagy and cholestophagy [RNA-seq]

Project description:Metabolic dysfunction associated steatotic liver disease (MASLD) is characterized by a constant accumulation of lipids in the liver. This lipotoxicity in the liver is associated with dysregulation of the first step in lipid catabolism called beta oxidation in the mitochondrial matrix, eventually leading to mitochondrial dysfunction. To evaluate possible involvement of mitochondrial DNA methylation in this lipid metabolic dysfunction we investigated the functional metabolic effects of mitochondrial overexpression of CpG (MSssI) and GpC (MCviPI) DNA methyltransferases in relation to gene expression and (mito)epigenetic signatures. Overall, the results show that mitochondrial GpC and to a lesser extent CpG methylation increase bile acid metabolic gene expression, inducing cholestasis by mito-nuclear epigenetic reprogramming. Moreover, increased expression of metabolic nuclear receptors in both MSssI and MCviPI cells promote mitochondrial swelling and induce basal overactivation of mitochondrial respiration which favours lipid accumulation and metabolic-stress induced mitophagy and autophagy stress responses. Altogether GpC and CpG mitochondrial induce a metabolic challenging environment that is similar to mitochondrial dysfunction in the progression of MASLD.

2023-12-08 | GSE241526 | GEO

Mitochondrial GpC and CpG DNA hypermethylation cause metabolic stress induced mitophagy and cholestophagy

Project description:Mitochondrial GpC and CpG DNA hypermethylation cause metabolic stress induced mitophagy and cholestophagy

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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.

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Transcription profiling of Bos taurus CD14+ purified bovine monoctye stimulation with CpG ODN 2007 vs. GpC ODN 2007, CpG 2007 vs. Control, GpC 2007 vs. Control and Media vs Control (

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Mitochondrial GpC and CpG DNA hypermethylation cause metabolic stress induced mitophagy and cholestophagy [RNA-seq]

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Project description:Background & Aims:The prevalence of metabolic dysfunction-associated liver disease (MASLD) has been strongly increasing over the last decades. As MASLD is often associated with more severe disease states, such as metabolic dysfunction-associated steato-hepatitis (MASH), insulin resistance and type 2 diabetes, the increasing number of patients will contribute to an epidemic rise in metabolic abnormalities and end stage liver diseases. Despite the high demand, there are still no FDA-approved pharmaceutical treatments for MASLD due to low efficacy and high toxicity of the targets pursued, indicating a lack of appropriate pre-clinical models for selection and validation. To facilitate earlier stop-go decisions for continued target development, we have established and extensively characterized a primary human steatoticin vitrohepatocyte model system that could guide treatment strategies for MASLD. Methods:Cryopreserved primary human hepatocytes of different donors varying in sex and ethnicity were cultured with free fatty acids (FFA) in a 3D collagen sandwich system for 7 days and the development of MASLD was followed by assessing classical hepatocellular functions. As aproof-of-concept, the effects of Firsocostat (GS-0976) onin vitroMASLD phenotypes were evaluated. Results:Incubation with FFA induced known MASLD pathologies, including steatosis, insulin resistance, mitochondrial dysfunction, inflammation and alterations in prominent human gene signatures similar to patients with MASLD/MASH, indicating the recapitulation of human MASLD in this system. As the application of Firsocostat rescued clinically observed fatty liver disease pathologies, it highlights the ability of thein vitrosystem to test drug efficacy and potentially characterize their mode of action. Conclusions:Altogether, our human MASLDin vitromodel system could guide the development and validation of novel targets and drugs for the treatment of MASLD.

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