Abstract
Nonalcoholic steatohepatitis (NASH) is a progressive disease that is often accompanied by metabolic syndrome and poses a high risk of severe liver damage. However, no effective pharmacological treatment is currently available for NASH. Here we report that CASP8 and FADD-like apoptosis regulator (CFLAR) is a key suppressor of steatohepatitis and its metabolic disorders. We provide mechanistic evidence that CFLAR directly targets the kinase MAP3K5 (also known as ASK1) and interrupts its N-terminus-mediated dimerization, thereby blocking signaling involving ASK1 and the kinase MAPK8 (also known as JNK1). Furthermore, we identified a small peptide segment in CFLAR that effectively attenuates the progression of steatohepatitis and metabolic disorders in both mice and monkeys by disrupting the N-terminus-mediated dimerization of ASK1 when the peptide is expressed from an injected adenovirus-associated virus 8–based vector. Taken together, these findings establish CFLAR as a key suppressor of steatohepatitis and indicate that the development of CFLAR-peptide-mimicking drugs and the screening of small-molecular inhibitors that specifically block ASK1 dimerization are new and feasible approaches for NASH treatment.
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Change history
26 July 2017
In the version of this article initially published, the authors inadvertently left out information in the Online Methods section regarding a second injection of AAV8-CFLAR(S1) 7 weeks after the first injection in the monkey experiments to ensure stable expression of CFLAR(S1) in the livers of the monkeys that received the injections. This correction does not change any results or conclusions of the paper. The error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We thank L. Ma (Wuhan University), a biostatistical expert, for his help with the statistical analyses in our present study and L. Zhang (Chinese Academy of Medical Sciences) for the Jnk1-KO (B6.129S1-Mapk8) and Jnk2-KO (B6.129S2-Mapk9) mice. 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 2016YFF0101504 (Z.-G.S.)).
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P.-X.W., Y.-X.J. and X.-J.Z. contributed equally to this work, and designed and performed experiments, analyzed data and wrote the manuscript; L.-P.Z., Z.-Z.Y., P.Z., L.-J.S. and X.Y. performed experiments, analyzed data and provided useful advice on the manuscript; J.F., S.T. and Y.W. performed the experiments with monkeys; X.-Y.Z. performed western blot experiments; J.G. and X.Z. constructed the genetically engineered mice used in this study; Q.-F.W. established the mouse models of NASH; J.L., L.W. and Q.X. performed the PET experiments; Z.-G.S., Z.W. and Z.H. helped design the project and edited the manuscript; and H.L. supervised the study, designed experiments and wrote the manuscript.
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Wang, PX., Ji, YX., Zhang, XJ. et al. Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates. Nat Med 23, 439–449 (2017). https://doi.org/10.1038/nm.4290
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DOI: https://doi.org/10.1038/nm.4290
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