Gene

Leptin

Molecular biology

Methyltransferase

Biology

Messenger RNA

Steatosis

Endocrinology

Lipogenesis

Fatty acid synthase

Biochemistry

Fatty liver

Leptin receptor

Nonalcoholic fatty liver disease

Methylation

Internal medicine

Gene knockdown

Lipid metabolism

Medicine

Chemistry

Obesity

N6-Methyladenosine

Disease

Hepatology

Background and Aims Nonalcoholic fatty liver disease (NAFLD) is characterized by accumulation of excessive triglycerides (TGs) in hepatocytes. Obesity is a major risk factor for developing fatty liver, although the intracellular molecular basis remains largely unclear. N 6 ‐methyladenosine (m 6 A) RNA methylation is the most common internal modification in eukaryotic mRNA. Approach and Results In the present study, by m 6 A sequencing and RNA sequencing, we found that both m 6 A enrichment and mRNA expression of lipogenic genes were significantly increased in leptin‐receptor–deficient db/db mice. Importantly, our results showed that YT521‐B homology domain‐containing 2 (Ythdc2), an m 6 A reader, was markedly down‐regulated in livers of obese mice and NAFLD patients. Suppression of Ythdc2 in livers of lean mice led to TG accumulation, whereas ectopic overexpression of Ythdc2 in livers of obese mice improved liver steatosis and insulin resistance. Mechanistically, we found that Ythdc2 could bind to mRNA of lipogenic genes, including sterol regulatory element‐binding protein 1c, fatty acid synthase, stearoyl‐CoA desaturase 1, and acetyl‐CoA carboxylase 1, to decrease their mRNA stability and inhibit gene expression. Conclusions Our findings describe an important role of the m 6 A reader, Ythdc2, for regulation of hepatic lipogenesis and TG homeostasis, which might provide a potential target for treating obesity‐related NAFLD.

N6‐Methyladenosine Reader Protein YT521‐B Homology Domain‐Containing 2 Suppresses Liver Steatosis by Regulation of mRNA Stability of Lipogenic Genes