The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis
Peng Zhang, Pi-Xiao Wang, Ling-Ping Zhao, Xin Zhang, Yan-Xiao Ji, Xiao-Jing Zhang, Chun Fang, Yue-Xin Lu, Xia Yang, Mao-Mao Gao, Yan Zhang, Song Tian, Xue-Yong Zhu, Jun Gong, Xin-Liang Ma, Feng Li, Zhihua Wang, Zan Huang, Zhi-Gang She & Hongliang Li

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.

中国国是世界肝病大国，全国超过3亿人存在不同程度的非酒精性脂肪肝，可进一步发展为肝硬化，甚至肝癌、肝衰竭，同时增加多种心脑血管和代谢性疾病患病风险。然而，国际上尚无针对非酒精性脂肪肝的临床用药。肝脏切除和肝脏移植成为治疗晚期肝病的主要手段，但手术过程中不可避免的肝脏缺血再灌注损伤极大限制了肝脏手术的开展和救治效果。

本次发表的两篇论文中，“The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis”（《去泛素化酶TNFAIP3通过抑制肝脏ASK1活性缓解非酒精性脂肪肝炎》）阐释了一条新的非酒精性脂肪肝病发展内在的抑制途径。博士后张鹏、王丕晓、博士生赵玲萍为共同第一作者，李红良和折志刚教授为共同通讯作者。（论文链接：https://www.nature.com/articles/nm.4453）