肿瘤坏死因子-α诱导蛋白 3 相互作用蛋白 3 过表达通过阻断 TAK1 激活抑制非酒精性脂肪性肝炎。

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

机构信息

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Basic Medical School, Wuhan University, Wuhan 430071, China; Institute of Model Animal, Wuhan University, Wuhan 430071, China.

Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Institute of Model Animal, Wuhan University, Wuhan 430071, China.

出版信息

Cell Metab. 2020 Apr 7;31(4):726-740.e8. doi: 10.1016/j.cmet.2020.03.007.

DOI:10.1016/j.cmet.2020.03.007

PMID:32268115

Abstract

Nonalcoholic steatohepatitis (NASH) is an unmet clinical challenge due to the rapid increase in its occurrence but the lack of approved drugs to treat it. Further unraveling of the molecular mechanisms underlying NASH may identify potential successful drug targets for this condition. Here, we identified TNFAIP3 interacting protein 3 (TNIP3) as a novel inhibitor of NASH. Hepatocyte-specific TNIP3 transgenic overexpression attenuates NASH in two dietary models in mice. Mechanistically, this inhibitory effect of TNIP3 is independent of its conventional role as an inhibitor of TNFAIP3. Rather, TNIP3 directly interacts with TAK1 and inhibits its ubiquitination and activation by the E3 ligase TRIM8 in hepatocytes in response to metabolic stress. Notably, adenovirus-mediated TNIP3 expression in the liver substantially blocks NASH progression in mice. These results suggest that TNIP3 may be a promising therapeutic target for NASH management.

摘要

非酒精性脂肪性肝炎（NASH）是一个未满足的临床挑战，因为其发病率迅速增加，但缺乏批准用于治疗的药物。进一步阐明 NASH 的分子机制可能会为这种疾病确定潜在的有效药物靶点。在这里，我们鉴定出 TNFAIP3 相互作用蛋白 3（TNIP3）是 NASH 的一种新型抑制剂。肝细胞特异性 TNIP3 转基因过表达可减轻两种饮食模型中小鼠的 NASH。从机制上讲，TNIP3 的这种抑制作用与其作为 TNFAIP3 抑制剂的传统作用无关。相反，TNIP3 直接与 TAK1 相互作用，并在代谢应激下抑制其在肝细胞中的泛素化和激活，由 E3 连接酶 TRIM8 介导。值得注意的是，腺病毒介导的肝脏中 TNIP3 的表达可显著阻止小鼠 NASH 的进展。这些结果表明，TNIP3 可能是 NASH 治疗的一个有希望的治疗靶点。