Hepatocyte glutathione S-transferase mu 2 prevents non-alcoholic steatohepatitis by suppressing ASK1 signaling

脂肪性肝炎 脂肪肝 ASK1 激酶 化学 酒精性肝病 癌症研究 肝细胞 蛋白激酶A 细胞生物学 生物 医学 内科学 疾病 生物化学 细胞周期蛋白依赖激酶2 体外 肝硬化
作者
Tian Lan,Yufeng Hu,Fengjiao Hu,Haonan Li,Yinghua Chen,Jing Zhang,Yang Yu,Shuo Jiang,Qiqing Weng,Song Tian,Tengfei Ma,Guizhi Yang,Duosheng Luo,Lexun Wang,Kunping Li,Shenghua Piao,Xianglu Rong,Jiao Guo
出处
期刊:Journal of Hepatology [Elsevier]
卷期号:76 (2): 407-419 被引量:37
标识
DOI:10.1016/j.jhep.2021.09.040
摘要

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. The advanced stage of NAFLD, non-alcoholic steatohepatitis (NASH), has been recognized as a leading cause of end-stage liver injury for which there are no FDA-approved therapeutic options. Glutathione S-transferase Mu 2 (GSTM2) is a phase II detoxification enzyme. However, the roles of GSTM2 in NASH have not been elucidated.Multiple RNA-seq analyses were used to identify hepatic GSTM2 expression in NASH. In vitro and in vivo gain- or loss-of-function approaches were used to investigate the role and molecular mechanism of GSTM2 in NASH.We identified GSTM2 as a sensitive responder and effective suppressor of NASH progression. GSTM2 was significantly downregulated during NASH progression. Hepatocyte GSTM2 deficiency markedly aggravated insulin resistance, hepatic steatosis, inflammation and fibrosis induced by a high-fat diet and a high-fat/high-cholesterol diet. Mechanistically, GSTM2 sustained MAPK pathway signaling by directly interacting with apoptosis signal-regulating kinase 1 (ASK1). GSTM2 directly bound to the N-terminal region of ASK1 and inhibited ASK1 N-terminal dimerization to subsequently repress ASK1 phosphorylation and the activation of its downstream JNK/p38 signaling pathway under conditions of metabolic dysfunction.These data demonstrated that hepatocyte GSTM2 is an endogenous suppressor that protects against NASH progression by blocking ASK1 N-terminal dimerization and phosphorylation. Activating GSTM2 holds promise as a therapeutic strategy for NASH.IIT-2021-277.New therapeutic strategies for non-alcoholic steatohepatitis are urgently needed. We identified that the protein GSTM2 exerts a protective effect in response to metabolic stress. Therapies that aim to increase the activity of GSTM2 could hold promise for the treatment of non-alcoholic steatohepatitis.
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