The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis
The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis
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去泛素化酶 TNFAIP3 介导肝脏 ASK1 失活并改善非酒精性脂肪性肝炎
DOI：
10.1038/nm.4453
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发表时间：
2018-01-01
期刊：
影响因子：
82.9
通讯作者：
Li, Hongliang
中科院分区：
文献类型：
--
作者：
Zhang, Peng;Wang, Pi-Xiao;Li, Hongliang
肝细胞中凋亡信号调节激酶1（ASK1）的激活是非酒精性脂肪性肝炎（NASH）进展的关键过程，也是治疗该疾病的有希望的靶点。然而，ASK1激活的机制尚不清楚，因此该激酶的内源性调节剂仍有待开发作为潜在的治疗靶点。在NASH背景下筛选与ASK1相互作用的蛋白质时，我们鉴定了脱泛素化酶肿瘤坏死因子α诱导蛋白3（TNFAIP3）作为ASK1激活的关键内源性抑制因子，我们发现TNFAIP3直接与肝细胞中的ASK1相互作用并使其脱泛素化。Tnfaip3的肝细胞特异性消融以ASK1依赖性方式加剧了小鼠中非酒精性脂肪肝疾病和NASH相关表型，包括葡萄糖代谢障碍，脂质积聚和炎症增强。相反，在NASH的小鼠和非人灵长类动物模型中，转基因或腺相关病毒介导的TNFAIP3基因在肝脏中的递送基本上阻断了疾病的发作和进展。这些结果暗示TNFAIP3作为NASH发病机制中ASK 1超活化的功能重要的内源性抑制剂，并将其鉴定为NASH治疗的潜在新分子靶点。
Activation of apoptosis signal-regulating kinase 1 (ASK1) in hepatocytes is a key process in the progression of nonalcoholic steatohepatitis (NASH) and a promising target for treatment of the condition. However, the mechanism underlying ASK1 activation is still unclear, and thus the endogenous regulators of this kinase remain open to be exploited as potential therapeutic targets. In screening for proteins that interact with ASK1 in the context of NASH, we identified the deubiquitinase tumor necrosis factor alpha-induced protein 3 (TNFAIP3) as a key endogenous suppressor of ASK1 activation, and we found that TNFAIP3 directly interacts with and deubiquitinates ASK1 in hepatocytes. Hepatocyte-specific ablation of Tnfaip3 exacerbated nonalcoholic fatty liver disease-and NASH-related phenotypes in mice, including glucose metabolism disorders, lipid accumulation and enhanced inflammation, in an ASK1-dependent manner. In contrast, transgenic or adeno-associated virus-mediated TNFAIP3 gene delivery in the liver in both mouse and nonhuman primate models of NASH substantially blocked the onset and progression of the disease. These results implicate TNFAIP3 as a functionally important endogenous suppressor of ASK1 hyperactivation in the pathogenesis of NASH and identify it as a potential new molecular target for NASH therapy.