摘要：SummaryThis work investigates the relationship between high-glucose (HG) culture, CpG methylation of genes involved in cell signaling pathways, and the regulation of carbohydrate and lipid metabolism in hepatocytes. The results indicate that HG leads to an increase in nuclear 25-hydroxycholesterol (25HC), which specifically activates DNA methyltransferase-1 (DNMT1), and regulates gene expression involved in intracellular lipid metabolism. The results show significant increases in5mCpG levels in at least 2,225 genes involved in 57 signaling pathways. The hypermethylated genes directly involved in carbohydrate and lipid metabolism are of PI3K, cAMP, insulin, insulin secretion, diabetic, and NAFLD signaling pathways. The studies indicate a close relationship between the increase in nuclear 25HC levels and activation of DNMT1, which may regulate lipid metabolism via DNA CpG methylation. Our results indicate an epigenetic regulation of hepatic cell metabolism that has relevance to some common diseases such as non-alcoholic fatty liver disease and metabolic syndrome.Graphical AbstractDisplay OmittedHighlights•High glucose induces lipids accumulation via epigenetic regulation•High glucose induces lipids accumulation via DNA CpG methylation in promoter regions•High glucose induces lipid accumulation by inhibiting multiple signaling pathways•25-Hydroxycholesterol is an endogenous agonist of DNMT1, an epigenetic regulatorBiological Sciences; Molecular Genetics; Systems Biology
