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The transrepressive activity of peroxisome proliferator-activated receptor alpha is necessary and sufficient to prevent liver fibrosis in mice

Authors

  • Michal Pawlak,

    1. European Genomic Institute for Diabetes, Lille, France
    2. INSERM UMR1011, F-59000, Lille, France
    3. University Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • Eric Baugé,

    1. European Genomic Institute for Diabetes, Lille, France
    2. INSERM UMR1011, F-59000, Lille, France
    3. University Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • William Bourguet,

    1. CNRS UMR 5048, CBS, Montpellier, France
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  • Karolien De Bosscher,

    1. Cytokine Receptor Lab, Nuclear Receptor Signaling Unit, VIB Department of Medical Protein Research, VIB, Ghent University, Ghent, Belgium
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  • Fanny Lalloyer,

    1. European Genomic Institute for Diabetes, Lille, France
    2. INSERM UMR1011, F-59000, Lille, France
    3. University Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • Anne Tailleux,

    1. European Genomic Institute for Diabetes, Lille, France
    2. INSERM UMR1011, F-59000, Lille, France
    3. University Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • Corinna Lebherz,

    1. Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany
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  • Philippe Lefebvre,

    1. European Genomic Institute for Diabetes, Lille, France
    2. INSERM UMR1011, F-59000, Lille, France
    3. University Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • Bart Staels

    Corresponding author
    1. European Genomic Institute for Diabetes, Lille, France
    2. INSERM UMR1011, F-59000, Lille, France
    3. University Lille 2, Lille, France
    4. Institut Pasteur de Lille, Lille, France
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  • Potential conflict of interest: Nothing to report.

  • M.P. was supported, in part, by a fellowship from the French Ministry for Education and Research. This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale, the European Genomic Institute for Diabetes (ANR-10-LABX-46), Région Nord-Pas de Calais, FEDER, and Cost Action BM0602. B.S. is a member of the Institut Universitaire de France. B.S. and K.D.B. are part of a research community on nuclear receptors supported by FWO-Vlaanderen (FWO-WOG).

Abstract

Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and strongly associated with central obesity, dyslipidemia, and insulin resistance. According to the multiple-hit model of NAFLD pathogenesis, lipid accumulation drives nonalcoholic steatohepatitis (NASH) initiation by triggering oxidative stress, lipotoxicity, and subsequent activation of hepatic inflammatory responses that may progress, in predisposed individuals, to fibrosis and cirrhosis. While there is an unmet therapeutical need for NASH and fibrosis, recent preclinical studies showed that peroxisome proliferator-activated receptor (PPAR)-α agonism can efficiently oppose these symptoms. To dissect the relative contribution of antisteatotic versus anti-inflammatory PPAR-α activities in counteracting dietary-induced liver fibrosis, we used a PPAR-α mutant lacking its DNA-binding-dependent activity on fatty acid metabolism. Liver-specific expression of wild-type or a DNA-binding-deficient PPAR-α in acute and chronic models of inflammation were used to study PPAR-α's anti-inflammatory versus metabolic activities in NASH and fibrosis. Pharmacologically activated PPAR-α inhibited hepatic inflammatory responses and the transition from steatosis toward NASH and fibrosis through a direct, anti-inflammatory mechanism independent of its lipid handling properties. Conclusion: The transrepression activity of PPAR-α on chronic liver inflammation is sufficient to prevent progression of NASH to liver fibrosis. Dissociated PPAR-α agonists, selectively modulating PPAR-α transrepression activity, could thus be an option to prevent NASH and fibrosis progression. (Hepatology 2014;60:1593–1606)

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