PT - JOURNAL ARTICLE AU - Alexander R. Moise AU - Susana Alvarez AU - Marta Domínguez AU - Rosana Alvarez AU - Marcin Golczak AU - Glenn P. Lobo AU - Johannes von Lintig AU - Angel R. de Lera AU - Krzysztof Palczewski TI - Activation of Retinoic Acid Receptors by Dihydroretinoids AID - 10.1124/mol.109.060038 DP - 2009 Dec 01 TA - Molecular Pharmacology PG - 1228--1237 VI - 76 IP - 6 4099 - http://molpharm.aspetjournals.org/content/76/6/1228.short 4100 - http://molpharm.aspetjournals.org/content/76/6/1228.full SO - Mol Pharmacol2009 Dec 01; 76 AB - Vitamin A-derived metabolites act as ligands for nuclear receptors controlling the expression of a number of genes. Stereospecific saturation of the C13-C14 double bond of all-trans-retinol by the enzyme, retinol saturase (RetSat), leads to the production of (R)-all-trans-13,14-dihydroretinol. In liver and adipose tissue, expression of RetSat is controlled by peroxisome proliferator-activated receptors (PPAR) α and γ, respectively. Expression of RetSat in adipose tissue is also required for PPARγ activation and adipocyte differentiation, but the involved mechanism is poorly understood. In this study, we examined the potential of (R)-all-trans-13,14-dihydroretinol and its metabolites to control gene transcription via nuclear receptors. Using a cell-based transactivation assay to screen 25 human nuclear receptors for activation, we found that dihydroretinoids have a narrow transcriptional profile limited primarily to activation of retinoic acid receptors (RARs). Although (R)-all-trans-13,14-dihydroretinoic acid exhibited comparable potency to retinoic acid in promoting the interaction of RARs with a coactivator peptide in vitro, its potency in activating RAR-controlled genes in cell-based assays was much lower than that of retinoic acid. As an explanation for the weak RAR agonist activity of dihydroretinoids in cell-based assays, we propose that both delivery of ligand to the nucleus and RAR activation favor retinoic acid over dihydroretinoids. Discrimination between the cognate ligand, retinoic acid, and close analogs such as dihydroretinoids, occurs at multiple levels and may represent a mechanism to modulate retinoid-dependent physiological processes.© 2009 The American Society for Pharmacology and Experimental Therapeutics