机构：[1]Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.[2]Institute of Model Animal, Wuhan University, Wuhan, China.[3]Basic Medical School, Wuhan University, Wuhan, China.[4]College of Life Sciences, Wuhan University, Wuhan, China.[5]Department of Burns, Tongren Hospital of Wuhan University & Wuhan Third Hospital, Wuhan, China.[6]Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease worldwide but lacks a well-established pharmacological therapy. Here, we aimed to investigate the role of an E3 ligase SH3 domain-containing ring finger 2 (SH3RF2) in NAFLD and to further explore the underlying mechanisms.In this study, we found that SH3RF2 was suppressed in the setting of NAFLD across mice, monkeys, and clinical individuals. Based on a genetic interruption model, we further demonstrated that hepatocyte SH3RF2 markedly deteriorates lipid accumulation in cultured hepatocytes and diet-induced NAFLD mice. Mechanistically, SH3RF2 directly binds to ATP citrate lyase (ACLY), the primary enzyme promoting cytosolic acetyl-CoA production, and promotes its K48-linked ubiquitination-dependent degradation. Consistently, acetyl-CoA was significantly accumulated in Sh3rf2-knockout hepatocytes and livers compared to wild-type controls, leading to enhanced de novo lipogenesis, cholesterol production and resultant lipid deposition.SH3RF2 depletion in hepatocytes is a critical aggravator for NAFLD progression and thus represents a promising therapeutic target for related liver diseases.This article is protected by copyright. All rights reserved.
基金：
National Key R&D Program of China (2016YFF0101504 and 2016YFF0101500 to Z.G.S.), the National Science
Foundation of China (81970364 and 81770053 to Z.G.S; 81970070 to X.J.Z; 81970011 to P.Z; 82070079 to Y.X.J; 82000600 to F.J.H), the Hubei
Provincial Natural Science Foundation of China (2020CFB665 to Y.H), Henan Charity Federation-Hepatobiliary
Care Fund (GDXZ2021005 to
Y.H.) and the Fundamental Research Funds for the Central Universities (2042019kf0134 to Y.C.).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2020]版：
大类|1 区医学
小类|1 区胃肠肝病学
最新[2023]版：
大类|1 区医学
小类|1 区胃肠肝病学
第一作者：
第一作者机构：[1]Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.[2]Institute of Model Animal, Wuhan University, Wuhan, China.
共同第一作者：
通讯作者：
通讯机构：[1]Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.[2]Institute of Model Animal, Wuhan University, Wuhan, China.[3]Basic Medical School, Wuhan University, Wuhan, China.[6]Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.[*1]Department of Cardiology Renmin Hospital of Wuhan University 238 Jiefang Road Wuhan 430060, China[*2]Medical Science Research Center Zhongnan Hospital of Wuhan University 169 Donghu Road Wuhan, 430071, China
推荐引用方式(GB/T 7714)：
Yang Xia,Sun Dating,Xiang Hui,et al.Hepatocyte SH3RF2 Deficiency is a Key Aggravator for Nonalcoholic Fatty Liver Disease.[J].Hepatology (Baltimore, Md.).2021,doi:10.1002/hep.31863.
APA：
Yang Xia,Sun Dating,Xiang Hui,Wang Sichen,Huang Yongping...&She Zhi-Gang.(2021).Hepatocyte SH3RF2 Deficiency is a Key Aggravator for Nonalcoholic Fatty Liver Disease..Hepatology (Baltimore, Md.),,
MLA：
Yang Xia,et al."Hepatocyte SH3RF2 Deficiency is a Key Aggravator for Nonalcoholic Fatty Liver Disease.".Hepatology (Baltimore, Md.) .(2021)
医学