FTO-mediated m^(6)A demethylation of ULK1 mRNA promotes autophagy and activation of hepatic stellate cells in liver fibrosis  

作　　者：Tingjuan Huang Chunhong Zhang Junjie Ren Qizhi Shuai Xiaonan Li Xuewei Li Jun Xie Jun Xu 

机构地区：[1]Shanxi Key Laboratory of Birth Defect and Cell Regeneration,Department of Biochemistry and Molecular Biology,Shanxi Medical University,Taiyuan 030001,China [2]Department of Gastroenterology and Hepatology,the First Hospital of Shanxi Medical University,Taiyuan 030001,China [3]Department of Cancer Radiotherapy Department,Shanxi Provincial People’s Hospital,Taiyuan 030001,China [4]Department of Hepatopancreatobiliary Surgery,the First Hospital of Shanxi Medical University,Taiyuan 030001,China

出　　处：《Acta Biochimica et Biophysica Sinica》2024年第10期1509-1520,共12页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the Fundamental Research Program of Shanxi Province(No.20210302124615);the Research Fund for the Doctor Program of Shanxi Province(No.SD1913);the Research Fund for the Doctor Program of Shanxi Medical University(No.XD1913);the National Natural Science Foundation of China(No.82203221).

摘　　要：The activation of hepatic stellate cells(HSCs)is central to the occurrence and development of liver fibrosis.Our previous studies showed that autophagy promotes HSC activation and ultimately accelerates liver fibrosis.Unc-51-like autophagy activating kinase 1(ULK1)is an autophagic initiator in mammals,and N6-methyladenosine(m^(6)A)modification is closely related to autophagy.In this study,we find that the m^(6)A demethylase fat mass and obesityassociated protein(FTO),which is the m^(6)A methylase with the most significant difference in expression,is upregulated during HSC activation and bile duct ligation(BDL)-induced hepatic fibrosis.Importantly,we identify that FTO overexpression aggravates HSC activation and hepatic fibrosis via autophagy.Mechanistically,compared with other autophagy-related genes,ULK1 is a target of FTO because FTO mainly mediates the m^(6)A demethylation of ULK1 and upregulates its expression,thereby enhancing autophagy and the activation of HSCs.Notably,the m^(6)A reader YTH domain-containing protein 2(YTHDC2)decreases ULK1 mRNA level by recognizing them^(6)A binding site and ultimately inhibiting autophagy and HSC activation.Taken together,our findings highlight m^(6)A-dependent ULK1 as an essential regulator of HSC autophagy and reveal that ULK1 is a novel potential therapeutic target for hepatic fibrosis treatment.

关 键 词：AUTOPHAGY hepatic stellate cells FTO m^(6)A methylation ULK1 

分 类 号：R575.2[医药卫生—消化系统]