Resveratrol and Its Metabolites Bind to PPARs

Authors

  • Dr. Enrica Calleri,

    1. Dipartimento di Scienze del Farmaco, Università degli Studi di Pavia, Viale Taramelli 12, 27100 Pavia (Italy)
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    • These authors contributed equally to this work.

  • Dr. Giorgio Pochetti,

    1. Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Montelibretti, 00015 Monterotondo Stazione, Roma (Italy)
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    • These authors contributed equally to this work.

  • Dr. Katina S. S. Dossou,

    1. Biomedical Research Center, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224-6825 (USA)
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  • Dr. Antonio Laghezza,

    1. Dipartimento di Farmacia–Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Via Orabona 4, 70126 Bari (Italy)
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  • Dr. Roberta Montanari,

    1. Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Montelibretti, 00015 Monterotondo Stazione, Roma (Italy)
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  • Davide Capelli,

    1. Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Montelibretti, 00015 Monterotondo Stazione, Roma (Italy)
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  • Dr. Ellen Prada,

    1. Dipartimento di Scienze del Farmaco, Università degli Studi di Pavia, Viale Taramelli 12, 27100 Pavia (Italy)
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  • Dr. Fulvio Loiodice,

    1. Dipartimento di Farmacia–Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, Via Orabona 4, 70126 Bari (Italy)
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  • Dr. Gabriella Massolini,

    1. Dipartimento di Scienze del Farmaco, Università degli Studi di Pavia, Viale Taramelli 12, 27100 Pavia (Italy)
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  • Dr. Michel Bernier,

    1. Biomedical Research Center, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224-6825 (USA)
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  • Dr. Ruin Moaddel

    Corresponding author
    1. Biomedical Research Center, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224-6825 (USA)
    • Biomedical Research Center, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224-6825 (USA)===

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Abstract

Resveratrol, a modulator of several signaling proteins, can exert off-target effects involving the peroxisome proliferator-activated receptor (PPAR) transcription factors. However, evidence for the direct interaction between this polyphenol and PPARs is lacking. Here, we addressed the hypothesis that resveratrol and its metabolites control aspects of PPAR transcriptional activity through direct interaction with PPARs. Bioaffinity chromatographic studies with the immobilized ligand-binding domains (LBDs) of PPARγ and PPARα and isothermal titration calorimetry allowed the binding affinities of resveratrol, resveratrol 3-O-glucuronide, resveratrol 4-O-glucuronide, and resveratrol 3-O-sulfate to both PPAR-LBDs to be determined. Interaction of resveratrol, resveratrol 3-O-glucuronide, and resveratrol 4-O-glucuronide with PPARγ-LBD occurred with binding affinities of 1.4, 1.1, and 0.8 μM, respectively, although only resveratrol bound to the PPARα-LBD with a binding affinity of 2.7 μM. Subsequently, X-ray crystallographic studies were carried out to characterize resveratrol binding to the PPARγ-LBD at the molecular level. The electron density map from the crystal structure of the complex between PPARγ-LBD and resveratrol revealed the presence of one molecule of resveratrol bound to the LBD of PPARγ, with the ligand occupying a position close to that of other known PPARγ ligands. Transactivation assays were also performed in HepG2 cells, with the results showing that resveratrol was not a PPAR agonist but instead was able to displace rosiglitazone from PPARγ and Wy-14643 from PPARα with IC50 values of (27.4±1.8) μM and (31.7±2.5) μM, respectively. We propose that resveratrol acts as a PPAR antagonist through its direct interaction with PPARγ and PPARα.

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