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-transretinol 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) ␣ and ␥, respectively. Expression of RetSat in adipose tissue is also required for PPAR␥ 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)-alltrans-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 RARcontrolled 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.

Macrophages Engulfing Apoptotic Cells Produce Nonclassical Retinoids To Enhance Their Phagocytic Capacity

“…This pathway also involves RALDHs and produces 13,14-dihydro-retinoic acids, which act also as low-affinity RAR ligands (40)(41)(42). We found that retinol saturase is expressed in the thymus, and its expression is induced after in vivo apoptosis induction, indicating that this alternative pathway might be involved in the formation of the novel retinoids.…”

“…Dihydroretinol can be converted further via RALDHs to dihydro-retinoic acids (41), which can also act as low-affinity RAR ligands (42). We therefore investigated whether retinol saturase is expressed in the thymus and whether its expression is enhanced after in vivo apoptosis induction.…”

Lipophilic Micronutrients and Adipose Tissue Biology

“…RetSat catalyzes the synthesis of ATRA to all- trans -13,14-dihydroretinol, which can be further converted to all- trans -13,14-dihydroretinoic acid, which is an RAR ligand [78,79], but that has a lower transactivation efficiency compared with ATRA in vivo . Interestingly, RetSat is necessary for 3T3-L1 adipocyte differentiation, and the expression level of RetSat is diminished in the adipose tissue of obese individuals [80], while RetSat knock-out animals have increased adiposity [81].…”

Enzymatic intracrine regulation of white adipose tissue

“…Oxidized metabolites of RA. RA is metabolized by cytochrome P450 enzymes and its oxidized metabolites also activate RAR [141, 142]; however, the function of these RA derivatives in adipose tissue has not been reported.…”