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.

中文翻译：

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去泛素化酶TNFAIP3介导肝ASK1的失活并改善非酒精性脂肪性肝炎。

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，也是治疗该病的有希望的靶标。然而，ASK1激活的潜在机制仍不清楚，因此该激酶的内源性调节剂仍然开放，可以用作潜在的治疗靶标。在筛选与NASH相关的ASK1相互作用的蛋白质时，我们确定了去泛素化酶肿瘤坏死因子α诱导的蛋白3（TNFAIP3）是ASK1活化的关键内源性抑制剂，我们发现TNFAIP3直接与ASK1相互作用并使其在ASK1中去泛素化。肝细胞。Tnfaip3的肝细胞特异性消融加重了小鼠的非酒精性脂肪性肝病和NASH相关表型，包括葡萄糖代谢异常，脂质积累和炎症增强，以ASK1依赖性方式存在。相反，在小鼠和非人类灵长类NASH模型中，肝中的转基因或腺相关病毒介导的TNFAIP3基因递送基本上阻止了疾病的发作和发展。这些结果表明，TNFAIP3在NASH的发病机理中是ASK1过度活化的功能上重要的内源性抑制剂，并将其确定为NASH治疗的潜在新分子靶标。