Shimin An1, Ling-Ping Zhao2,3, Li-Jun Shen3,4, Siyuan Wang1, Kuo Zhang1, Yu Qi1, Jilin Zheng1, Xiao-Jing Zhang2,3,4, Xue-Yong Zhu2,3,4, Rong Bao3, Ling Yang2,3,4, Yue-Xin Lu2,3, Zhi-Gang She2,3,4, Yi-Da Tang1. 1. Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 2. Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China. 3. The Institute of Model Animals of Wuhan University, Wuhan, China. 4. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low-grade inflammation. However, the pathogenic mechanism of NAFLD is poorly understood, which hinders the exploration of possible treatments. Here, we report that ubiquitin-specific protease 18 (USP18), a member of the deubiquitinating enzyme family, plays regulatory roles in NAFLD progression. Expression of USP18 was down-regulated in the livers of nonalcoholic steatohepatitis patients and high-fat diet (HFD)-induced or genetically obese mice. When challenged with HFD, hepatocyte-specific USP18 transgenic mice exhibited improved lipid metabolism and insulin sensitivity, whereas mice knocked out of USP18 expression showed adverse trends regarding hepatic steatosis and glucose metabolic disorders. Furthermore, the concomitant inflammatory response was suppressed in USP18-hepatocyte-specific transgenic mice and promoted in USP18-hepatocyte-specific knockout mice treated with HFD. Mechanistically, hepatocyte USP18 ameliorates hepatic steatosis by interacting with and deubiquitinating transforming growth factorβ-activated kinase 1 (TAK1), which inhibits TAK1 activation and subsequently suppresses the downstream c-Jun N-terminal kinase and nuclear factor kappa B signaling pathways. This is further validated by alleviated steatotic phenotypes and highly activated insulin signaling in HFD-fed USP18-hepatocyte-specific knockout mice administered a TAK1 inhibitor. The therapeutic effect of USP18 on NAFLD relies on its deubiquitinating activity because HFD-fed mice injected with active-site mutant USP18 failed to inhibit hepatic steatosis. CONCLUSION: USP18 associates with and deubiquitinates TAK1 to protect against hepatic steatosis, insulin resistance, and the inflammatory response. (Hepatology 2017;66:1866-1884).
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low-grade inflammation. However, the pathogenic mechanism of NAFLD is poorly understood, which hinders the exploration of possible treatments. Here, we report that ubiquitin-specific protease 18 (USP18), a member of the deubiquitinating enzyme family, plays regulatory roles in NAFLD progression. Expression of USP18 was down-regulated in the livers of nonalcoholic steatohepatitispatients and high-fat diet (HFD)-induced or genetically obesemice. When challenged with HFD, hepatocyte-specific USP18transgenic mice exhibited improved lipid metabolism and insulin sensitivity, whereas mice knocked out of USP18 expression showed adverse trends regarding hepatic steatosis and glucose metabolic disorders. Furthermore, the concomitant inflammatory response was suppressed in USP18-hepatocyte-specific transgenic mice and promoted in USP18-hepatocyte-specific knockout mice treated with HFD. Mechanistically, hepatocyte USP18 ameliorates hepatic steatosis by interacting with and deubiquitinating transforming growth factorβ-activated kinase 1 (TAK1), which inhibits TAK1 activation and subsequently suppresses the downstream c-Jun N-terminal kinase and nuclear factor kappa B signaling pathways. This is further validated by alleviated steatotic phenotypes and highly activated insulin signaling in HFD-fed USP18-hepatocyte-specific knockout mice administered a TAK1 inhibitor. The therapeutic effect of USP18 on NAFLD relies on its deubiquitinating activity because HFD-fed mice injected with active-site mutant USP18 failed to inhibit hepatic steatosis. CONCLUSION:USP18 associates with and deubiquitinates TAK1 to protect against hepatic steatosis, insulin resistance, and the inflammatory response. (Hepatology 2017;66:1866-1884).