Article

The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis

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Abstract

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.

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Acknowledgements

We thank H.-B. Shu (Medical Research Institute, Wuhan University) for providing ubiquitin and several of its derivative plasmids. We thank Y. Wang (University of California, Los Angeles) for his helpful suggestions regarding this research and for editing the manuscript. This work was supported by grants from the National Science Fund for Distinguished Young Scholars (no. 81425005, H.L.), the Key Project of the National Natural Science Foundation (no. 81330005 and no. 81630011, H.L.), the National Science and Technology Support Project (no. 2014BAI02B01 and no. 2015BAI08B01, H.L.), the National Key Research and Development Program (no. 2013YQ030923-05, H.L.; no. 2016YFF0101500, Z.-G.S.), the National Natural Science Foundation of China (no. 81770053, Z.-G.S.) and the Key Collaborative Project of the National Natural Science Foundation (no. 91639304, H.L. and Z.-G.S.).

Author information

Author notes

    • Peng Zhang
    • , Pi-Xiao Wang
    • , Ling-Ping Zhao
    •  & Xin Zhang

    These authors contributed equally to this work.

    • Peng Zhang

    Present address: Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China.

Affiliations

  1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.

    • Peng Zhang
    • , Xiao-Jing Zhang
    • , Zhihua Wang
    • , Zhi-Gang She
    •  & Hongliang Li
  2. Institute of Model Animals of Wuhan University, Wuhan, China.

    • 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
    • , Zan Huang
    • , Zhi-Gang She
    •  & Hongliang Li
  3. Basic Medical School, Wuhan University, Wuhan, China.

    • Peng Zhang
    • , Pi-Xiao Wang
    • , Ling-Ping Zhao
    • , Yan-Xiao Ji
    • , Chun Fang
    • , Yue-Xin Lu
    • , Xia Yang
    • , Mao-Mao Gao
    • , Yan Zhang
    • , Song Tian
    • , Xue-Yong Zhu
    • , Jun Gong
    • , Feng Li
    • , Zan Huang
    • , Zhi-Gang She
    •  & Hongliang Li
  4. Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.

    • Peng Zhang
    • , Pi-Xiao Wang
    • , Ling-Ping Zhao
    • , Yan-Xiao Ji
    • , Chun Fang
    • , Yue-Xin Lu
    • , Xia Yang
    • , Mao-Mao Gao
    • , Yan Zhang
    • , Song Tian
    • , Xue-Yong Zhu
    • , Jun Gong
    • , Zan Huang
    • , Zhi-Gang She
    •  & Hongliang Li
  5. College of Life Sciences, Wuhan University, Wuhan, China.

    • Xin Zhang
    • , Jun Gong
    •  & Zan Huang
  6. Medical Science Research Center, Zhongnan Hospital, Wuhan, China.

    • Yan-Xiao Ji
    •  & Hongliang Li
  7. Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

    • Xin-Liang Ma

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Contributions

P.Z., P.-X.W., L.-P.Z. and X.Z. designed and performed experiments, analyzed data and wrote the manuscript; Y.-X.J., X.-J.Z., C.F., Y.-X.L., X.Y. and M.-M.G. performed experiments, analyzed data and provided useful advice regarding the manuscript; Y.Z. performed histology experiments; J.G. constructed the genetically engineered mice used in this study; S.T. established mouse NASH models and performed mouse experiments; X.-Y.Z. performed western blot analysis; X.-L.M., F.L., Z.W. and Z.H. helped design the project and edited the manuscript; Z.-G.S. and H.L. designed experiments, wrote the manuscript and supervised the study.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Zhi-Gang She or Hongliang Li.

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