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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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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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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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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DOI: https://doi.org/10.1038/nm.4461
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