Epigenetic Regulation of Peroxisome Proliferator-Activated Receptor Gamma Mediates High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease
| Autor: | Mohamed Zaiou, Thomas V. Fungwe, Khadija Ouguerram, Tahar Hajri, Samuel A. Besong |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
CD36 Antigens medicine.medical_specialty QH301-705.5 CD36 Saturated fat Peroxisome proliferator-activated receptor 030209 endocrinology & metabolism Diet High-Fat Article Epigenesis Genetic 03 medical and health sciences 0302 clinical medicine Non-alcoholic Fatty Liver Disease Internal medicine medicine Animals Epigenetics Biology (General) chemistry.chemical_classification DNA methylation biology Chemistry Fatty liver Fatty acid General Medicine Peroxisome medicine.disease Lipid Metabolism Mice Inbred C57BL PPAR gamma Disease Models Animal 030104 developmental biology Endocrinology high-fat diet Liver biology.protein Hepatocytes non-alcoholic fatty liver disease (NAFLD) epigenetic |
| Zdroj: | Cells Cells, Vol 10, Iss 1355, p 1355 (2021) Volume 10 Issue 6 |
| ISSN: | 2073-4409 |
| Popis: | Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in Western countries and has become a serious public health concern. Although Western-style dietary patterns, characterized by a high intake of saturated fat, is considered a risk factor for NAFLD, the molecular mechanisms leading to hepatic fat accumulation are still unclear. In this study, we assessed epigenetic regulation of peroxisome proliferator-activated receptor γ (PPARγ), modifications of gene expression, and lipid uptake in the liver of mice fed a high-fat diet (HFD), and in hepatocyte culture challenged with palmitic acid. Bisulfate pyrosequencing revealed that HFD reduced the level of cytosine methylation in the pparγ DNA promoter. This was associated with increased expression of the hepatic PPARγ, very low-density lipoprotein receptor (VLDLR) and cluster differentiating 36 (CD36), and enhanced uptake of fatty acids and very low-density lipoprotein, leading to excess hepatic lipid accumulation. Furthermore, palmitic acid overload engendered comparable modifications in hepatocytes, suggesting that dietary fatty acids contribute to the pathogenesis of NAFLD through epigenetic upregulation of PPARγ and its target genes. The significance of epigenetic regulation was further demonstrated in hepatocytes treated with DNA methylation inhibitor, showing marked upregulation of PPARγ and its target genes, leading to enhanced fatty acid uptake and storage. This study demonstrated that HFD-induction of pparγ DNA promoter demethylation increased the expression of PPARγ and its target genes, vldlr and cd36, leading to excess lipid accumulation, an important initiating mechanism by which HFD increased PPARγ and lipid accumulation. These findings provide strong evidence that modification of the pparγ promoter methylation is a crucial mechanism of regulation in NAFLD pathogenesis. |
| Databáze: | OpenAIRE |
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