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Metabolic modulation of acetaminophen-induced hepatotoxicity by osteopontin

Cellular & Molecular Immunology volume 16, pages 483–494 (2019)Cite this article

Abstract

Induction of osteopontin (OPN), a well-known pro-inflammatory molecule, has been observed in acetaminophen (APAP)-induced hepatotoxicity. However, the precise cell source for OPN induction and its role during APAP-induced hepatotoxicity has not been fully explored. By employing a hepatotoxic mouse model induced by APAP overdose, we demonstrate that both serum and hepatic OPN levels were significantly elevated in response to APAP treatment. Our in vivo and in vitro studies clearly indicated that the induced expression of hepatic OPN was mainly located in necrosis areas and produced by dying or dead hepatocytes. Functional experiments showed that OPN deficiency protected against the APAP-induced liver injury by inhibiting the toxic APAP metabolism via reducing the expression of the cytochrome P450 family 2 subfamily E member 1 (CYP2E1). Interestingly, this inhibition of CYP2E1 expression did not occur in unfasted Opn−/− mice, but was significant in fasted Opn−/− mice and maintained for 2 hours after APAP challenge in fasted Opn−/− mice. In addition, despite the early protective role of OPN deficiency on APAP-induced hepatotoxicity, OPN deficiency retarded injury resolution by sensitizing hepatocytes to apoptosis and impairing liver regeneration. Finally, we demonstrated that a siRNA-mediated transient hepatic Opn knockdown could sufficiently and significantly protect animals from APAP-induced hepatotoxicity and death. In conclusion, this study clearly defines the cell source of OPN induction in response to APAP treatment, provides a novel insight into the metabolic role of OPN to APAP overdose, and suggests an Opn-targeted therapeutic strategy for the treatment or prevention of APAP-induced hepatotoxicity.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81670562 and 31300742 to X.K., 81670598 to Q.X., 81372233 to H.W., and 81673935 to X.S.) and a grant from the Shanghai Municipal Education Commission (Gaofeng Clinical Medicine Grant Support (20171911) to X.K., National Science and Technology major grant (2017ZX10203204-006-005) to X.K., and the Shanghai Health Bureau Key Joint Efforts Foundation (2013ZYJB001) to Q.X.).

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Author notes

  1. These authors contributed equally: Yankai Wen, Chenchen Wang, Jinyang Gu.

Authors and Affiliations

  1. Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Yankai Wen, Chenchen Wang, Chang Yu, Ying Tong, Qiang Xia & Xiaoni Kong

  2. School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

    Yankai Wen & Chang Yu

  3. Department of Transplantation, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Jinyang Gu

  4. Department of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China

    Kaixia Wang & Xuehua Sun

  5. Department of Rehabilitation Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China

    Yun Sun

  6. Department of Hyperbaric Oxygen, The First Affiliated Hospital, Zhejiang University, Hangzhou, China

    Yun Sun

  7. State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    Hailong Wu

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  1. Yankai Wen
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Correspondence to Qiang Xia or Xiaoni Kong.

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Wen, Y., Wang, C., Gu, J. et al. Metabolic modulation of acetaminophen-induced hepatotoxicity by osteopontin. Cell Mol Immunol 16, 483–494 (2019). https://doi.org/10.1038/s41423-018-0033-z

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