Fibroblast growth factor 21 protects against acetaminophen-induced hepatotoxicity by potentiating peroxisome proliferator-activated receptor coactivator protein-1α-mediated antioxidant capacity in mice

Authors

  • Dewei Ye,

    1. State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China
    2. Department of Medicine, University of Hong Kong, Hong Kong, China
    3. Department of Pharmacology & Pharmacy, University of Hong Kong, Hong Kong, China
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    • These authors contributed equally to this work.

  • Yudong Wang,

    1. State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China
    2. Department of Medicine, University of Hong Kong, Hong Kong, China
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    • These authors contributed equally to this work.

  • Huating Li,

    1. Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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  • Weiping Jia,

    1. Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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  • Kwan Man,

    1. Department of Surgery, University of Hong Kong, Hong Kong, China
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  • Chung Mau Lo,

    1. Department of Surgery, University of Hong Kong, Hong Kong, China
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  • Yu Wang,

    1. State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China
    2. Department of Pharmacology & Pharmacy, University of Hong Kong, Hong Kong, China
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  • Karen S.L. Lam,

    Corresponding author
    1. State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China
    2. Department of Medicine, University of Hong Kong, Hong Kong, China
    • Address reprint requests to: Prof. Aimin Xu or Prof. Karen S.L. Lam, State Key Laboratory of Pharmaceutical Biotechnology, and Department of Medicine, University of Hong Kong, Room L8-39, Lab Block, 21 Sassoon Road, Hong Kong. E-mail: amxu@hku.hk or ksllam@hku.hk; fax: +852-28162095.

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  • Aimin Xu

    Corresponding author
    1. State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, China
    2. Department of Medicine, University of Hong Kong, Hong Kong, China
    3. Department of Pharmacology & Pharmacy, University of Hong Kong, Hong Kong, China
    • Address reprint requests to: Prof. Aimin Xu or Prof. Karen S.L. Lam, State Key Laboratory of Pharmaceutical Biotechnology, and Department of Medicine, University of Hong Kong, Room L8-39, Lab Block, 21 Sassoon Road, Hong Kong. E-mail: amxu@hku.hk or ksllam@hku.hk; fax: +852-28162095.

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  • Potential conflict of interest: Nothing to report.

  • Supported by Collaborative Research Fund (HKU2/CRF/12R and HKU3/CRF/11R) from the Research Grant Council of Hong Kong, the National Basic Research Program of China (2011CB504004 and 2010CB945500), Young Scientists Fund of National Natural Science Foundation (81200292), and Theme-Based Research Scheme grant T12-705/11 from the Research Grant Council of Hong Kong.

  • See Editorial on Page 792

Abstract

Acetaminophen (APAP) overdose is a leading cause of drug-induced hepatotoxicity and acute liver failure worldwide, but its pathophysiology remains incompletely understood. Fibroblast growth factor 21 (FGF21) is a hepatocyte-secreted hormone with pleiotropic effects on glucose and lipid metabolism. This study aimed to investigate the pathophysiological role of FGF21 in APAP-induced hepatotoxicity in mice. In response to APAP overdose, both hepatic expression and circulating levels of FGF21 in mice were dramatically increased as early as 3 hours, prior to elevations of the liver injury markers alanine aminotransferase (ALT) and aspartate aminotransferase (AST). APAP overdose-induced liver damage and mortality in FGF21 knockout (KO) mice were markedly aggravated, which was accompanied by increased oxidative stress and impaired antioxidant capacities as compared to wild-type (WT) littermates. By contrast, replenishment of recombinant FGF21 largely reversed APAP-induced hepatic oxidative stress and liver injury in FGF21 KO mice. Mechanistically, FGF21 induced hepatic expression of peroxisome proliferator-activated receptor coactivator protein-1α (PGC-1α), thereby increasing the nuclear abundance of nuclear factor erythroid 2-related factor 2 (Nrf2) and subsequent up-regulation of several antioxidant genes. The beneficial effects of recombinant FGF21 on up-regulation of Nrf2 and antioxidant genes and alleviation of APAP-induced oxidative stress and liver injury were largely abolished by adenovirus-mediated knockdown of hepatic PGC-1α expression, whereas overexpression of PGC-1α was sufficient to counteract the increased susceptibility of FGF21 KO mice to APAP-induced hepatotoxicity. Conclusion: The marked elevation of FGF21 by APAP overdose may represent a compensatory mechanism to protect against the drug-induced hepatotoxicity, by enhancing PGC-1α/Nrf2-mediated antioxidant capacity in the liver. (Hepatology 2014;60:977–989)

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