DNA hypermethylation-induced suppression of ALKBH5 is required for folic acid to alleviate hepatic lipid deposition by enhancing autophagy in an ATG12-dependent manner.

Abstract

Nonalcoholic fatty liver disease (NAFLD) occurs when too much fat builds up in the liver. As a growing worldwide epidemic, NAFLD is strongly linked with multiple metabolic diseases including obesity, insulin resistance, and dyslipidemia. However, very few effective treatments are currently available. Folate, an essential B-group vitamin with important biological functions including DNA and RNA methylation regulation, has been shown to have a protective effect against NAFLD with its underlying mechanism remains largely unclear. Here, we show that administration of folic acid significantly improves glucose tolerance, insulin sensitivity, and dyslipidemia in high-fat diet (HFD) fed mice. Moreover, folic acid treatment significantly inhibits lipid deposition in hepatocytes both in vivo and in vitro. Mechanically, folic acid reduces the expression of m⁶A demethylase AlkB homolog 5 (ALKHB5) via promoter DNA hypermethylation. Decreased ALKBH5 causes increased m⁶A modification and increased expression of ATG12 in a demethylase activity-dependent manner, thereby promoting autophagy and preventing hepatic steatosis. Inhibition of ATG12 induced by overexpression of ALKBH5 could impair autophagy and the inhibitory effect of folic acid on lipid accumulation in hepatocytes. Together, these findings provide novel insights into understanding the protective role of folic acid in the treatment of NAFLD and suggest that folic acid may be a potential agent for combating NAFLD.