The 4′-Hydroxyl Group of Resveratrol Is Functionally Important for Direct Activation of PPARα

Long-term moderate consumption of red wine is associated with a reduced risk of developing lifestyle-related diseases such as cardiovascular disease and cancer. Therefore, resveratrol, a constituent of grapes and various other plants, has attracted substantial interest. This study focused on one molecular target of resveratrol, the peroxisome proliferator activated receptor alpha (PPAR alpha). Our previous study in mice showed that resveratrol-mediated protection of the brain against stroke requires activation of PPARa; however, the molecular mechanisms involved in this process remain unknown. Here, we evaluated the chemical basis of the resveratrol-mediated activation of PPARa by performing a docking mode simulation and examining the structure-activity relationships of various polyphenols. The results of experiments using the crystal structure of the PPARa ligand-binding domain and an analysis of the activation of PPARa by a resveratrol analog 4-phenylazophenol (4-PAP) in vivo indicate that the 4'-hydroxyl group of resveratrol is critical for the direct activation of PPAR alpha. Activation of PPARa by 5 mu M resveratrol was enhanced by rolipram, an inhibitor of phosphodiesterase (PDE) and forskolin, an activator of adenylate cyclase. We also found that resveratrol has a higher PDE inhibitory activity (IC50 = 19 mu M) than resveratrol analogs trans-4-hydroxystilbene and 4-PAP (IC50 = 27-28 mu M), both of which has only 4'-hydroxyl group, indicating that this 4'-hydroxyl group of resveratrol is not sufficient for the inhibition of PDE. This result is consistent with that 10 mu M resveratrol has a higher agonistic activity of PPARa than these analogs, suggesting that there is a feedforward activation loop of PPARa by resveratrol, which may be involved in the long-term effects of resveratrol in vivo.