The 4'-hydroxyl group of resveratrol is functionally important for direct activation of PPAR?.

ABSTRACT: 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 ? (PPAR?). Our previous study in mice showed that resveratrol-mediated protection of the brain against stroke requires activation of PPAR?; however, the molecular mechanisms involved in this process remain unknown. Here, we evaluated the chemical basis of the resveratrol-mediated activation of PPAR? 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 PPAR? ligand-binding domain and an analysis of the activation of PPAR? 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?. Activation of PPAR? by 5 ?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 ?M) than resveratrol analogs trans-4-hydroxystilbene and 4-PAP (IC50 = 27-28 ?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 ?M resveratrol has a higher agonistic activity of PPAR? than these analogs, suggesting that there is a feedforward activation loop of PPAR? by resveratrol, which may be involved in the long-term effects of resveratrol in vivo.

SUBMITTER: Takizawa Y 

PROVIDER: S-EPMC4370454 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature