Abstract
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.
Footnotes
↵
The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This research was supported by the National Institutes of Health National Eye Institute [Grants EY01730, EY019478, EY015399, EY08061]; the Spanish Ministerio de Ciencia y Tecnología [Grant SAF 2007-63880-FEDER]; and the Xunta de Galicia [Grant PGIDIT07PXIBIB3174174PR].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.109.060038
-
ABBREVIATIONS:
- atRA
- all-trans-retinoic acid
- RAR
- retinoic acid receptor
- RXR
- retinoid X receptor
- RetSat
- retinol saturase
- atROL
- all-trans-retinol
- DROL
- all-trans-13,14-dihydroretinol
- DRA
- all-trans-13,14-dihydroretinoic acid
- PPAR
- peroxisome proliferator-activated receptor
- HPLC
- high-performance liquid chromatography
- DMSO
- dimethyl sulfoxide
- ERR
- estrogen related receptor
- FRET
- fluorescence resonance energy transfer
- CMV
- cytomegalovirus
- TTNPB
- 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid
- HEK
- human embryonic kidney
- PBS
- phosphate-buffered saline
- CRABP
- cellular retinoic acid binding protein
- GFP
- green fluorescent protein
- RBP4
- retinol-binding protein 4
- SRC-1
- steroid receptor coactivator
- DMF
- dimethylformamide.
- Received August 3, 2009.
- Accepted September 21, 2009.
- © 2009 The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|