METTL3-m6A-Rubicon axis inhibits autophagy in nonalcoholic fatty liver disease.

Abstract N6-methyladenosine (m6A) mRNA modification plays critical roles in various biological events and involves in multiple complex diseases. However, the role of m6A modification in autophagy in nonalcoholic fatty liver disease (NAFLD) remains largely unknown. Here, we report that m6A modification was increased in livers of NAFLD mouse models and in free fatty acids (FFAs)-treated hepatocytes, and the abnormal m6A modification was attributed to the upregulation of methyltransferase like 3 (METTL3) induced by lipotoxicity. Knockdown of METTL3 promoted hepatic autophagic flux and lipid drops (LDs) clearance, while overexpression METTL3 inhibited these process. Mechanistically, METTL3 directly bound to Rubicon mRNA and mediated the m6A modification. While YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), as a partner of METTL3, interacted with the m6A-marked Rubicon mRNA and promoted its stability. Subsequently, RUBICON inhibited autophagosome-lysosome fusion and further blocked LDs clearance. Together, our results showed a critical role of METTL3 and YTHDF1 in regulating lipid metabolism via autophagy pathway and provided a novel insight into m6A mRNA methylation in NAFLD.