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The deubiquitinating enzyme cylindromatosis mitigates nonalcoholic steatohepatitis

Nature Medicine volume 24, pages 213–223 (2018)Cite this article

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Abstract

Nonalcoholic steatohepatitis (NASH) is a common clinical condition that can lead to advanced liver diseases. Lack of effective pharmacotherapies for NASH is largely attributable to an incomplete understanding of its pathogenesis. The deubiquitinase cylindromatosis (CYLD) plays key roles in inflammation and cancer. Here we identified CYLD as a suppressor of NASH in mice and in monkeys. CYLD is progressively degraded upon interaction with the E3 ligase TRIM47 in proportion to NASH severity. We observed that overexpression of Cyld in hepatocytes concomitantly inhibits lipid accumulation, insulin resistance, inflammation and fibrosis in mice with NASH induced in an experimental setting. Mechanistically, CYLD interacts directly with the kinase TAK1 and removes its K63-linked polyubiquitin chain, which blocks downstream activation of the JNK–p38 cascades. Notably, reconstitution of hepatic CYLD expression effectively reverses disease progression in mice with dietary or genetically induced NASH and in high-fat diet–fed monkeys predisposed to metabolic syndrome. Collectively, our findings demonstrate that CYLD mitigates NASH severity and identify the CYLD–TAK1 axis as a promising therapeutic target for management of the disease.

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Figure 1: CYLD is downregulated in fatty livers.
Figure 2: TRIM47 mediates the degradation of CYLD in NAFLD.
Figure 3: Hepatocyte-specific Cyld knockout exacerbates HFD-induced insulin resistance, hepatic steatosis and inflammation.
Figure 4: CYLD functions in NAFLD via inactivating the TAK1–JNK–p38 signaling pathway.
Figure 5: CYLD inhibits TAK1 activation through deubiquitination.
Figure 6: Hepatic CYLD overexpression improves HFD-induced hepatic steatosis, insulin resistance and inflammation in mice and monkeys.

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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. Rao, M. Guo and R. Zhang (Institute of Model Animal of Wuhan University) for their assistance in monkey experiments. 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 81630011; H.L.), the National Science and Technology Support Project (no. 2014BAI02B01 and 2015BAI08B01; H.L.), the National Key Research and Development Program (no. 2013YQ030923-05 (H.L.) and no. 2016YFF0101500 (Z.-G.S.)), the National Natural Science Foundation of China (no. 81770053 (Z.-G.S.) and no. 91729303 (L.C.)), the Key Collaborative Project of the National Natural Science Foundation (no. 91639304; H.L.) and the National Institutes of Health (no. DK048873, DK056626 and DK103046; D.E.C.).

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Author notes

  1. Yan-Xiao Ji, Zan Huang, Xia Yang and Xiaozhan Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China

    Yan-Xiao Ji, Lin Cai, Peng Zhang & Hongliang Li

  2. Institute of Model Animal of Wuhan University, Wuhan, China

    Yan-Xiao Ji, Xia Yang, Xiaozhan Wang, Ling-Ping Zhao, Pi-Xiao Wang, Xiao-Jing Zhang, Lin Cai, Peng Zhang, Yue-Xin Lu, Lan Bai, Mao-Mao Gao, Song Tian, Yong Wang, Zhi-Xiang Huang, Xue-Yong Zhu, Yan Zhang, Jun Gong, Zhi-Gang She & Hongliang Li

  3. Basic Medical School, Wuhan University, Wuhan, China

    Yan-Xiao Ji, Xia Yang, Xiaozhan Wang, Ling-Ping Zhao, Pi-Xiao Wang, Lin Cai, Peng Zhang, Yue-Xin Lu, Mao-Mao Gao, Song Tian, Xue-Yong Zhu, Yan Zhang, Jun Gong, Zhi-Gang She, Feng Li & Hongliang Li

  4. Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China

    Yan-Xiao Ji, Xia Yang, Xiaozhan Wang, Ling-Ping Zhao, Pi-Xiao Wang, Peng Zhang, Yue-Xin Lu, Mao-Mao Gao, Song Tian, Xue-Yong Zhu, Yan Zhang, Jun Gong, Zhi-Gang She & Hongliang Li

  5. College of Life Sciences, Wuhan University, Wuhan, China

    Zan Huang, Huan Zhao & Jun Gong

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

    Xiaozhan Wang, Pi-Xiao Wang, Xiao-Jing Zhang, Lan Bai, Zhi-Gang She & Hongliang Li

  7. Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York, USA

    Michele Alves-Bezerra & David E Cohen

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  1. Yan-Xiao Ji
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Contributions

Y.-X.J., Z.H., X.Y. and X.W. designed and performed the experiments, analyzed data and wrote the manuscript; L.-P.Z. performed molecular experiments, analyzed data and wrote the manuscript; P.-X.W. performed animal experiments and analyzed data; X.-J.Z., M.A.-B. and L.C. wrote the manuscript and provided important advice for this study; P.Z., Y.-X.L., L.B., M.-M.G. and H.Z. performed biological experiments and analyzed data; S.T. established mouse and monkey NASH models; Y.W. and Z.-X.H. performed the experiments involving monkeys; X.-Y.Z. performed western blot experiments; Y.Z. performed histopathological analysis; J.G. constructed the genetically engineered mice and performed AAV8 construction; Z.-G.S. and F.L. wrote the manuscript and provided important advice for this study; D.E.C. and H.L. designed experiments, wrote the manuscript and supervised the study.

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Correspondence to David E Cohen or Hongliang Li.

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Ji, YX., Huang, Z., Yang, X. et al. The deubiquitinating enzyme cylindromatosis mitigates nonalcoholic steatohepatitis. Nat Med 24, 213–223 (2018). https://doi.org/10.1038/nm.4461

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