Peroxisome proliferator-activated receptor alpha induction of uncoupling protein 2 protects against acetaminophen-induced liver toxicity

Authors

  • Andrew D. Patterson,

    1. Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD
    2. Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA
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  • Yatrik M. Shah,

    1. Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD
    2. Department of Molecular and Integrative Physiology and Internal Medicine, Division of Gastroenterology, University of Michigan School of Medicine, Ann Arbor, MI
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  • Tsutomu Matsubara,

    1. Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD
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  • Kristopher W. Krausz,

    1. Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD
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  • Frank J. Gonzalez

    Corresponding author
    1. Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD
    • Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814===

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    • fax: 301-496-8419


  • Potential conflict of interest: Nothing to report.

Abstract

Acetaminophen (APAP) overdose causes acute liver failure in humans and rodents due in part to the destruction of mitochondria as a result of increased oxidative stress followed by hepatocellular necrosis. Activation of the peroxisome proliferator-activated receptor alpha (PPARα), a member of the nuclear receptor superfamily that controls the expression of genes encoding peroxisomal and mitochondrial fatty acid β-oxidation enzymes, with the experimental ligand Wy-14,643 or the clinically used fibrate drug fenofibrate, fully protects mice from APAP-induced hepatotoxicity. PPARα-humanized mice were also protected, whereas Ppara-null mice were not, thus indicating that the protection extends to human PPARα and is PPARα-dependent. This protection is due in part to induction of the PPARα target gene encoding mitochondrial uncoupling protein 2 (UCP2). Forced overexpression of UCP2 protected wildtype mice against APAP-induced hepatotoxicity in the absence of PPARα activation. Ucp2-null mice, however, were sensitive to APAP-induced hepatotoxicity despite activation of PPARα with Wy-14,643. Protection against hepatotoxicity by UCP2-induction through activation of PPARα is associated with decreased APAP-induced c-jun and c-fos expression, decreased phosphorylation of JNK and c-jun, lower mitochondrial H2O2 levels, increased mitochondrial glutathione in liver, and decreased levels of circulating fatty acyl-carnitines. These studies indicate that the PPARα target gene UCP2 protects against elevated reactive oxygen species generated during drug-induced hepatotoxicity and suggest that induction of UCP2 may also be a general mechanism for protection of mitochondria during fatty acid β-oxidation. (HEPATOLOGY 2012;56:281–290)

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