Epigenetic Regulation of Hepatic Lipid Metabolism by DNA Methylation

Abstract While extensive investigations have been devoted to the study of genetic pathways related to fatty liver diseases, much less is known about epigenetic mechanisms underlying these disorders. DNA methylation is an epigenetic link between environmental factors (e.g., diets) and complex diseases (e.g., non‐alcoholic fatty liver disease). Here, it is aimed to study the role of DNA methylation in the regulation of hepatic lipid metabolism. A dynamic change in the DNA methylome in the liver of high‐fat diet (HFD)‐fed mice is discovered, including a marked increase in DNA methylation at the promoter of Beta‐klotho ( Klb) , a co‐receptor for the biological functions of fibroblast growth factor (FGF)15/19 and FGF21. DNA methyltransferases (DNMT) 1 and 3A mediate HFD‐induced methylation at the Klb promoter. Notably, HFD enhances DNMT1 protein stability via a ubiquitination‐mediated mechanism. Liver‐specific deletion of Dnmt1 or 3a increases Klb expression and ameliorates HFD‐induced hepatic steatosis. Single‐nucleus RNA sequencing analysis reveals pathways involved in fatty acid oxidation in Dnmt1 ‐deficient hepatocytes. Targeted demethylation at the Klb promoter increases Klb expression and fatty acid oxidation, resulting in decreased hepatic lipid accumulation. Up‐regulation of methyltransferases by HFD may induce hypermethylation of the Klb promoter and subsequent down‐regulation of Klb expression, resulting in the development of hepatic steatosis.