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Updated: Apr 30, 2026
10:51
Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
Published on: November 15, 2013
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Resveratrol and its metabolites bind to PPARs
E Calleri1, G Pochetti2, K S S Dossou3
1Dipartimento di Scienze del Farmaco, Università degli Studi di Pavia, 27100 Pavia, Italy.
Summary
Resveratrol directly interacts with PPARγ and PPARα, acting as an antagonist. This polyphenol and its metabolites bind to PPARs, influencing their activity and potentially explaining off-target effects.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Resveratrol is a polyphenol known to modulate signaling proteins.
- Off-target effects of resveratrol have been linked to peroxisome proliferator-activated receptors (PPARs).
- Direct evidence for resveratrol's interaction with PPARs was previously lacking.
Purpose of the Study:
- To investigate the direct interaction between resveratrol and its metabolites with PPAR transcription factors.
- To determine the binding affinities and molecular interactions of resveratrol with PPARγ and PPARα.
- To elucidate the functional consequences of resveratrol binding to PPARs.
Main Methods:
- Bioaffinity chromatography using immobilized PPARγ and PPARα ligand-binding domains (LBDs).
- Isothermal titration calorimetry to quantify binding affinities.
- X-ray crystallography to determine the molecular structure of resveratrol bound to PPARγ-LBD.
- Transactivation assays in HepG2 cells to assess functional activity.
Main Results:
- Resveratrol, resveratrol 3-O-glucuronide, and resveratrol 4-O-glucuronide bound to PPARγ-LBD with microM affinities.
- Resveratrol bound to PPARα-LBD with microM affinity.
- X-ray crystallography confirmed resveratrol binding to the PPARγ-LBD in a manner similar to known ligands.
- Resveratrol acted as a PPAR antagonist, displacing known agonists (rosiglitazone and Wy-14643) with specific IC50 values.
Conclusions:
- Resveratrol directly interacts with PPARγ and PPARα.
- Resveratrol and its metabolites can bind to PPARs, influencing their transcriptional activity.
- Resveratrol functions as a PPAR antagonist, not an agonist, through direct binding.
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