title: The 4'-hydroxyl group of resveratrol is functionally important for direct activation of PPARα.
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 α (PPARα). Our previous study in mice showed that resveratrol-mediated protection of the brain against stroke requires activation of PPARα; however, the molecular mechanisms involved in this process remain unknown. Here, we evaluated the chemical basis of the resveratrol-mediated activation of PPARα 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 PPARα ligand-binding domain and an analysis of the activation of PPARα 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 PPARα. Activation of PPARα by 5 μM 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 μM) than resveratrol analogs trans-4-hydroxystilbene and 4-PAP (IC50 = 27-28 μM), 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 μM resveratrol has a higher agonistic activity of PPARα than these analogs, suggesting that there is a feedforward activation loop of PPARα by resveratrol, which may be involved in the long-term effects of resveratrol in vivo.
authors: Department of Food Science & Nutrition, Nara Women's University, Nara, Japan.
authors: Yoshie
authors: Y
authors: Takizawa
authors: Department of Food Science & Nutrition, Nara Women's University, Nara, Japan.
authors: Rieko
authors: R
authors: Nakata
authors: Showa University School of Pharmacy, Tokyo, Japan.
authors: Kiyoshi
authors: K
authors: Fukuhara
authors: Medicinal Chemistry Research Laboratories, Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan.
authors: Hiroshi
authors: H
authors: Yamashita
authors: Medicinal Chemistry Research Laboratories, Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan.
authors: Hideo
authors: H
authors: Kubodera
authors: Department of Food Science & Nutrition, Nara Women's University, Nara, Japan.
authors: Hiroyasu
authors: H
authors: Inoue
mesh_terms: D000818:Animals; D055786:Gene Knockout Techniques; D006878:Hydroxides / Q000737:chemistry*; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D047493:PPAR alpha / Q000737:chemistry / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011487:Protein Conformation; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D006878:Hydroxides; D047493:PPAR alpha; D010726:Phosphodiesterase Inhibitors; D013267:Stilbenes; C031356:hydroxide ion; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol