TNFAIP3 Interacting Protein 3 Overexpression Suppresses Nonalcoholic Steatohepatitis by Blocking TAK1 Activation
TNFAIP3 Interacting Protein 3 Overexpression Suppresses Nonalcoholic Steatohepatitis by Blocking TAK1 Activation
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TNFAIP3 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
DOI：
10.1016/j.cmet.2020.03.007
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发表时间：
2020-04-07
期刊：
影响因子：
29
通讯作者：
Li, Hongliang
中科院分区：
文献类型：
--
作者：
Liu, Dan;Zhang, Peng;Li, Hongliang
非酒精性脂肪性肝炎(NASH)是临床上尚未解决的挑战，因为它的发病率迅速增加，但缺乏批准的药物来治疗它。进一步解开NASH背后的分子机制可能会确定治疗这种疾病的潜在成功药物靶点。在这里，我们确定了TNFAIP3相互作用蛋白3(TNIP3)是一种新的NASH抑制因子。肝细胞特异性TNIP3转基因过表达可减轻两种饮食模型小鼠的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，并抑制其泛素化和肝细胞中E3连接酶TRIM8对代谢应激的激活。值得注意的是，腺病毒介导的TNIP3在肝脏中的表达显著阻止了小鼠的NASH进展。这些结果表明，TNIP3可能是NASH治疗的一个有前途的治疗靶点。
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.