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Aberrant elevation of FTO levels promotes liver steatosis by decreasing the m6A methylation and increasing the stability of SREBF1 and ChREBP mRNAs 
Zhili Tang1,2 , Chao Sun1 , Ying Yan1 , Zhoumin Niu1 , Yuying Li1 , Xi Xu3 , Jing Zhang3 , Yuting Wu1 , Yan Li4 , Li Wang4 , Cheng Hu5 , Zhuoyang Li1,* , Jingjing Jiang3,* , Hao Ying1,2,6,*
1CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, and Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200031, China
2Innovation Center for Intervention of Chronic Disease and Promotion of Health, Shanghai 200031, China
3Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200031, China
4State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China
5Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
6Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing 100021, China
*Correspondence to:Zhuoyang Li , Jingjing Jiang , Hao Ying ,
J Mol Cell Biol, Volume 14, Issue 9, September 2022, mjac061,
Keyword: FTO, m6A, SREBF1, ChREBP, lipogenesis, NAFLD

Previous studies have indicated an association of fat mass and obesity-associated (FTO) with nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide. This study aimed to decipher the complex role of FTO in hepatic lipid metabolism. We found that a decrease in N6-methyladenosine (m6A) RNA methylation in the liver of mice fed with a high-fat diet (HFD) was accompanied by an increase in FTO expression. Overexpression of FTO in the liver promoted triglyceride accumulation by upregulating the expression of lipogenic genes. Mechanistical studies revealed that FTO could stabilize the mRNAs of sterol regulatory element binding transcription factor 1 (SREBF1) and carbohydrate responsive element binding protein (ChREBP), two master lipogenic transcription factors, by demethylating m6A sites. Knockdown of either SREBF1 or ChREBP attenuated the lipogenic effect of FTO, suggesting that they are bona fide