A recent study led by Dr. YING Hao’s group from Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences (CAS), established a critical role of fat mass and obesity-associated (FTO) in insulin-regulated hepatic lipogenesis and provided a potential strategy for treating nonalcoholic fatty liver disease (NAFLD). This work entitled “Aberrant elevation of FTO levels promotes liver steatosis by decreasing the m6A methylation and increasing the stability of SREBF1 and ChREBP mRNAs” was published online in Journal of Molecular Cell Biology on Nov. 10^th, 2022.   

NAFLD has emerged as the most common chronic liver disease. N6-methyladenosine (m6A) is the most abundant epigenetic modification found in at least a quarter of mammalian mRNAs, while the demethylation is processed by fat mass and obesity-associated (FTO) and AlkB homolog 5 (ALKBH5). Recent evidence suggests that m6A methylation may play a critical role in the regulation of hepatic triglyceride metabolism. FTO has long been associated with obesity according to early Genome-Wide Association Studies and plays a regulatory role in adipogenesis. 

This study demonstrated that hepatic FTO could demethylate and stabilize SREBF1 and ChREBP mRNA, resulting in an elevation of both SREBP1c and ChREBP protein levels, and consequently upregulating the transcription of key lipogenic enzymes responsible for hepatic lipogenesis.  

Moreover, insulin could induce the expression of hepatic FTO, which in turn mediated the lipogenic effect of insulin. Furthermore, inhibition of FTO could reduce hepatic lipogenesis and lipid accumulation, implicating a potential strategy for treating NAFLD.  

Zhili TANG, a Ph.D. student at SINH was the first author, Dr. YING Hao, LI Zhuoyang, and JIANG Jingjing were the corresponding authors of this article. This study was supported by grants from the Ministry of Science and Technology, National Natural Science Foundation of China, CAS, as well as the core facilities of SINH. 

Schematic of FTO signaling pathway. (Image provided by Dr. YING’s group)