High Glucose Induces Lipid Accumulation via 25-Hydroxycholesterol DNA-CpG Methylation
Yaping Wang,
Lanming Chen,
William M. Pandak,
Douglas Heuman,
Phillip B. Hylemon,
Shunlin Ren
Affiliations
Yaping Wang
College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China; Department of Internal Medicine, Virginia Commonwealth University/McGuire VA Medical Centre, Research 151, 1201 Broad Rock Boulevard, Richmond, VA 23249, USA
Lanming Chen
College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China
William M. Pandak
Department of Internal Medicine, Virginia Commonwealth University/McGuire VA Medical Centre, Research 151, 1201 Broad Rock Boulevard, Richmond, VA 23249, USA
Douglas Heuman
Department of Internal Medicine, Virginia Commonwealth University/McGuire VA Medical Centre, Research 151, 1201 Broad Rock Boulevard, Richmond, VA 23249, USA
Phillip B. Hylemon
Department of Internal Medicine, Virginia Commonwealth University/McGuire VA Medical Centre, Research 151, 1201 Broad Rock Boulevard, Richmond, VA 23249, USA
Shunlin Ren
Department of Internal Medicine, Virginia Commonwealth University/McGuire VA Medical Centre, Research 151, 1201 Broad Rock Boulevard, Richmond, VA 23249, USA; Corresponding author
Summary: 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 5mCpG 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.
