Department of Endocrinology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan Road 2, Guangzhou 510080, China.
Department of Geriatrics, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
Mol Ther. 2022 Feb 2;30(2):932-946. doi: 10.1016/j.ymthe.2021.09.016. Epub 2021 Sep 20.
N6-methyladenosine (mA) mRNA modification plays critical roles in various biological events and is involved in multiple complex diseases. However, the role of mA modification in autophagy in nonalcoholic fatty liver disease (NAFLD) remains largely unknown. Here, we report that mA modification was increased in livers of NAFLD mouse models and in free fatty acid (FFA)-treated hepatocytes, and the abnormal mA modification was attributed to the upregulation of methyltransferase like 3 (METTL3) induced by lipotoxicity. Knockdown of METTL3 promoted hepatic autophagic flux and clearance of lipid droplets (LDs), while overexpression of METTL3 inhibited these processes. Mechanistically, METTL3 directly bound to Rubicon mRNA and mediated the mA modification, while YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), as a partner of METTL3, interacted with the mA-marked Rubicon mRNA and promoted its stability. Subsequently, RUBICON inhibited autophagosome-lysosome fusion and further blocked clearance of LDs. Taken together, our results showed a critical role of METTL3 and YTHDF1 in regulating lipid metabolism via the autophagy pathway and provided a novel insight into mA mRNA methylation in NAFLD.
N6-甲基腺苷（mA）mRNA 修饰在各种生物事件中发挥着关键作用，并参与多种复杂疾病。然而，mA 修饰在非酒精性脂肪性肝病（NAFLD）自噬中的作用在很大程度上尚不清楚。在这里，我们报告说，mA 修饰在 NAFLD 小鼠模型和游离脂肪酸（FFA）处理的肝细胞中增加，异常的 mA 修饰归因于脂毒性诱导的甲基转移酶样 3（METTL3）的上调。METTL3 的敲低促进了肝自噬流和脂滴（LDs）的清除，而过表达 METTL3 则抑制了这些过程。在机制上，METTL3 直接与 Rubicon mRNA 结合并介导 mA 修饰，而 YTH N6-甲基腺苷 RNA 结合蛋白 1（YTHDF1）作为 METTL3 的伴侣，与 mA 标记的 Rubicon mRNA 相互作用并促进其稳定性。随后，RUBICON 抑制自噬体-溶酶体融合，进一步阻止 LDs 的清除。总之，我们的研究结果表明，METTL3 和 YTHDF1 在通过自噬途径调节脂质代谢方面起着关键作用，并为 NAFLD 中 mA mRNA 甲基化提供了新的见解。
