TNIP3过表达通过阻碍TAK1激活来抑制非酒精性脂肪

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本期文章:《细胞—代谢》:Volume 31 Issue 4

近日,武汉大学李红良、折志刚和徐海波等研究人员合作发现,TNIP3过表达通过阻碍TAK1激活来抑制非酒精性脂肪性肝炎(NASH)。2020年4月7日,国际知名学术期刊《细胞—代谢》发表了这一成果。

研究人员确定了TNFAIP3相互作用蛋白3(TNIP3)是一种新型的NASH抑制蛋白。肝细胞特异性TNIP3转基因过表达会减弱小鼠两种饮食模型中的NASH。从机理上讲,TNIP3的这种抑制作用不依赖于其作为TNFAIP3抑制蛋白的常规作用。而是,TNIP3直接与TAK1相互作用,并通过E3连接酶TRIM8抑制TAK1在肝细胞中的泛素化和激活,以响应代谢应激。值得注意的是,腺病毒介导的TNIP3在肝脏中的表达基本上阻断了NASH在小鼠中的进程。这些结果表明,TNIP3可能是NASH治疗的潜在治疗靶标。

 

据介绍,由于其发生率迅速增加但缺乏经过批准的药物来治疗,NASH已成为临床难题。进一步阐明NASH的分子机制可能会鉴定出这种疾病的潜在药物靶标。

 

附:英文原文

Title: TNFAIP3 Interacting Protein 3 Overexpression Suppresses Nonalcoholic Steatohepatitis by Blocking TAK1 Activation

Author: Dan Liu, Peng Zhang, Junjie Zhou, Rufang Liao, Yan Che, Mao-Mao Gao, Jiaqi Sun, Jingjing Cai, Xu Cheng, Yongping Huang, Guopeng Chen, Hongyu Nie, Yan-Xiao Ji, Xiao-Jing Zhang, Zan Huang, Haibo Xu, Zhi-Gang She, Hongliang Li

Issue&Volume: 2020/04/07

Abstract: Nonalcoholic steatohepatitis (NASH) is an unmet clinical challenge due to the rapidincrease in its occurrence but the lack of approved drugs to treat it. Further unravelingof the molecular mechanisms underlying NASH may identify potential successful drugtargets for this condition. Here, we identified TNFAIP3 interacting protein 3 (TNIP3)as a novel inhibitor of NASH. Hepatocyte-specific TNIP3 transgenic overexpressionattenuates NASH in two dietary models in mice. Mechanistically, this inhibitory effectof TNIP3 is independent of its conventional role as an inhibitor of TNFAIP3. Rather,TNIP3 directly interacts with TAK1 and inhibits its ubiquitination and activationby the E3 ligase TRIM8 in hepatocytes in response to metabolic stress. Notably, adenovirus-mediatedTNIP3 expression in the liver substantially blocks NASH progression in mice. Theseresults suggest that TNIP3 may be a promising therapeutic target for NASH management.

DOI: 10.1016/j.cmet.2020.03.007

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30122-4

期刊信息

Cell Metabolism:《细胞—代谢》,创刊于2005年。隶属于细胞出版社,最新IF:22.415
官方网址:https://www.cell.com/cell-metabolism/home
投稿链接:https://www.editorialmanager.com/cell-metabolism/default.aspx

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