title: Activation of retinoic acid receptors by dihydroretinoids.
abstract: Vitamin A-derived metabolites act as ligands for nuclear receptors controlling the expression of a number of genes. Stereospecific saturation of the C(13)-C(14) 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) alpha and gamma, respectively. Expression of RetSat in adipose tissue is also required for PPARgamma 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.
authors.affiliation: Department of Pharmacology & Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS 66045, USA. alexmoise@ku.edu
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Moise
authors.forename: Susana
authors.initials: S
authors.lastname: Alvarez
authors.forename: Marta
authors.initials: M
authors.lastname: Domínguez
authors.forename: Rosana
authors.initials: R
authors.lastname: Alvarez
authors.forename: Marcin
authors.initials: M
authors.lastname: Golczak
authors.forename: Glenn P
authors.initials: GP
authors.lastname: Lobo
authors.forename: Johannes
authors.initials: J
authors.lastname: von Lintig
authors.forename: Angel R
authors.initials: AR
authors.lastname: de Lera
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
mesh_terms: D002460:Cell Line; D006801:Humans; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000096:biosynthesis* / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma / Q000096:biosynthesis; D013050:Spectrometry, Fluorescence; D015533:Transcriptional Activation / Q000187:drug effects; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C503916:13,14-dihydroretinoic acid; C101326:RBP4 protein, human; D018168:Receptors, Retinoic Acid; D054839:Retinol-Binding Proteins, Plasma; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin