Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
Institute of Model Animals of Wuhan University, Wuhan, China.
Nat Med. 2018 Jan;24(1):84-94. doi: 10.1038/nm.4453. Epub 2017 Dec 11.
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.
激活肝细胞中的凋亡信号调节激酶 1（ASK1）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前途的靶点。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。在筛选与 NASH 背景下与 ASK1 相互作用的蛋白质时，我们鉴定出去泛素化酶肿瘤坏死因子-α诱导蛋白 3（TNFAIP3）是 ASK1 激活的关键内源性抑制剂，并且发现 TNFAIP3 直接在肝细胞中与 ASK1 相互作用并使其去泛素化。在小鼠中，肝细胞特异性敲除 Tnfaip3 以 ASK1 依赖性方式加剧了非酒精性脂肪肝和 NASH 相关表型，包括葡萄糖代谢紊乱、脂质积累和炎症增强。相比之下，在 NASH 的小鼠和非人灵长类动物模型中，通过转基因或腺相关病毒介导的 TNFAIP3 基因传递到肝脏中，可显著阻断疾病的发生和进展。这些结果表明 TNFAIP3 是 NASH 发病机制中 ASK1 过度激活的功能重要内源性抑制剂，并将其鉴定为 NASH 治疗的潜在新分子靶点。
