High Glucose Induces Lipid Accumulation via 25-Hydroxycholesterol DNA-CpG Methylation

Abstract

This 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 in 5m CpG 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.

Cholesterol Metabolites 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: From Discovery to Clinical Usage

“…25HC plays an important role in lipid accumulation in hepatocytes and development of nonalcoholic fatty liver diseases (NAFLD) [ 42 , 43 ]. 25HC regulates excess acetyl CoA for synthesis of lipids as energy storage.…”

“…25HC induces biosynthesis of free fatty acids and triglycerides. Lipid accumulation in hepatocytes induced by high glucose media has been widely used as in vitro model for the study of NAFLD [ 43 , 44 ]. A recent report has shown that, when human hepatocytes were incubated in media containing high glucose levels, 25HC was significantly increased in their nuclei [ 43 ].…”

“…Lipid accumulation in hepatocytes induced by high glucose media has been widely used as in vitro model for the study of NAFLD [ 43 , 44 ]. A recent report has shown that, when human hepatocytes were incubated in media containing high glucose levels, 25HC was significantly increased in their nuclei [ 43 ]. Meanwhile, the high glucose incubation increases CpG (5′—cytosine—phosphate—guanine—3′) methylation and increases in 5m CpG levels in promoter regions and silences the expression of many key genes involved in PI3K, cAMP, insulin, insulin secretion, diabetic, and NAFLD signaling pathways, leading to lipid accumulation [ 43 ].…”

“…A recent report has shown that, when human hepatocytes were incubated in media containing high glucose levels, 25HC was significantly increased in their nuclei [ 43 ]. Meanwhile, the high glucose incubation increases CpG (5′—cytosine—phosphate—guanine—3′) methylation and increases in 5m CpG levels in promoter regions and silences the expression of many key genes involved in PI3K, cAMP, insulin, insulin secretion, diabetic, and NAFLD signaling pathways, leading to lipid accumulation [ 43 ]. Interestingly, the sulfated 25HC, 25HC3S converted the methylated CpG in the regions, which has been shown as a distinct yet potent regulator of cellular functions [ 19 ].…”

“…The function of 25HC and 25HC3S in global regulation indicates that they are epigenetic regulators. Methylation at position 5 of cytosine (5-methylcytosine, 5m C) in DNA promoter regions is an important epigenetic modification that regulates gene expression and other functions of the genome [ 43 ]. Cytosine methylation of CpG in promoter regions is inversely correlated with the transcriptional activity of associated genes as it causes chromatin condensation and thus gene silencing [ 67 ].…”