Aberrant elevation of FTO levels promotes liver steatosis by decreasing the m6A methylation and increasing the stability of SREBF1 and ChREBP mRNAs

• DOI: 10.1093/jmcb/mjac061
• Publication Date: 2022-11-10T05:29:13Z
• Authors: Zhili Tang; Chao Sun; Ying Yan; Zhoumin Niu; Yuying Li; Xi Xu; Jing Zhang; Yuting Wu; Yan Li; Li Wang; Cheng Hu; Zhuoyang Li; Jingjing Jiang; Hao Ying
• Keywords: Lipogenesis; Carbohydrate-responsive element-binding protein; Steatosis

ABSTRACT Previous studies have indicated an association of fat mass and obesity-associated (FTO) with nonalcoholic fatty liver disease (NAFLD), the most common chronic worldwide. This study aimed to decipher complex role FTO in hepatic lipid metabolism. We found that a decrease N6-methyladenosine (m6A) RNA methylation mice fed high-fat diet (HFD) was accompanied by increase expression. Overexpression promoted triglyceride accumulation upregulating expression lipogenic genes. Mechanistical revealed could stabilize mRNAs sterol regulatory element binding transcription factor 1 (SREBF1) carbohydrate responsive protein (ChREBP), two master factors, demethylating m6A sites. Knockdown either SREBF1 or ChREBP attenuated effect FTO, suggesting they are bona fide effectors for regulating lipogenesis. Insulin stimulate through mechanism involving action intranuclear insulin receptor beta, while knockdown abrogated insulin. Inhibition entacapone decreased SREBF1, ChREBP, downstream genes, ameliorating steatosis HFD-fed mice. Thus, our established critical both insulin-regulated lipogenesis pathogenesis NAFLD provided potential strategy treating NAFLD.