Non-alcoholic 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 -methyladenosine (m A) RNA methylation is the most common internal modification in eukaryotic mRNA; however, its role in the progression of obesity-associated NAFLD has not been investigated. In the present study, via m A-sequencing and RNA-sequencing, we found that both the m 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), a m A reader, was markedly downregulated in the livers of obese mice and NAFLD patients. Suppression of Ythdc2 in the livers of lean mice led to TG accumulation, whereas ectopic overexpression of Ythdc2 in the livers of obese mice improved liver steatosis and insulin resistance. Mechanistically, we found that Ythdc2 could bind to the mRNA of lipogenic genes, including sterol regulatory element-binding protein 1c (Srebp-1c), fatty acid synthase (Fasn), stearoyl-CoA desaturase 1 (Scd1) and acetyl-CoA carboxylase 1 (Acc1), to decrease their mRNA stability and inhibit gene expression. CONCLUSION: Our findings describe an important role of the m A reader Ythdc2 for regulation of hepatic lipogenesis and TG homeostasis, which might provide a potential target for treating obesity-related NAFLD.This article is protected by copyright. All rights reserved.
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