Activation of Retinoic Acid Receptors by Dihydroretinoids

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.

[1]  Krzysztof Palczewski,et al.  Stereospecificity of retinol saturase: absolute configuration, synthesis, and biological evaluation of dihydroretinoids. , 2008, Journal of the American Chemical Society.

[2]  K. Palczewski,et al.  Specificity of zebrafish retinol saturase: formation of all-trans-13,14-dihydroretinol and all-trans-7,8- dihydroretinol. , 2007, Biochemistry.

[3]  T. Jessell,et al.  Regional differences in retinoid release from embryonic neural tissue detected by an in vitro reporter assay. , 1992, Development.

[4]  Krzysztof Palczewski,et al.  Metabolism and Transactivation Activity of 13,14-Dihydroretinoic Acid* , 2005, Journal of Biological Chemistry.

[5]  Lucia Altucci,et al.  Nuclear receptors in cell life and death , 2001, Trends in Endocrinology & Metabolism.

[6]  Stefan Engeli,et al.  Retinol saturase promotes adipogenesis and is downregulated in obesity , 2009, Proceedings of the National Academy of Sciences.

[7]  W. Driever,et al.  RBP4 disrupts vitamin A uptake homeostasis in a STRA6-deficient animal model for Matthew-Wood syndrome. , 2008, Cell metabolism.

[8]  P. Chambon,et al.  Cloning of murine alpha and beta retinoic acid receptors and a novel receptor gamma predominantly expressed in skin. , 1989, Nature.

[9]  R. Tsien,et al.  Ligand-dependent interactions of coactivators steroid receptor coactivator-1 and peroxisome proliferator-activated receptor binding protein with nuclear hormone receptors can be imaged in live cells and are required for transcription. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Gregor Eichele,et al.  9-cis retinoic acid is a high affinity ligand for the retinoid X receptor , 1992, Cell.

[11]  Krzysztof Palczewski,et al.  Identification of All-trans-Retinol:All-trans-13,14-dihydroretinol Saturase* , 2004, Journal of Biological Chemistry.

[12]  P. Ping,et al.  A Membrane Receptor for Retinol Binding Protein Mediates Cellular Uptake of Vitamin A , 2007, Science.

[13]  Krzysztof Palczewski,et al.  G protein-coupled receptor rhodopsin. , 2006, Annual review of biochemistry.

[14]  Michael Albers,et al.  A Novel Principle for Partial Agonism of Liver X Receptor Ligands , 2006, Journal of Biological Chemistry.

[15]  K. Palczewski,et al.  Metabolic Basis of Visual Cycle Inhibition by Retinoid and Nonretinoid Compounds in the Vertebrate Retina* , 2008, Journal of Biological Chemistry.

[16]  P. A. Peterson,et al.  Ligand-dependent regulation of intracellular protein transport: effect of vitamin a on the secretion of the retinol-binding protein , 1983, The Journal of cell biology.

[17]  S. Lee,et al.  Identification and characterization of a novel mouse peroxisome proliferator-activated receptor alpha-regulated and starvation-induced gene, Ppsig. , 2008, The international journal of biochemistry & cell biology.

[18]  M. Stallcup,et al.  Nuclear receptor-binding sites of coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1): multiple motifs with different binding specificities. , 1998, Molecular Endocrinology.

[19]  P. Chambon,et al.  Physical and Functional Interactions between Cellular Retinoic Acid Binding Protein II and the Retinoic Acid-Dependent Nuclear Complex , 1999, Molecular and Cellular Biology.

[20]  I. P. López,et al.  High-fat feeding period affects gene expression in rat white adipose tissue , 2005, Molecular and Cellular Biochemistry.

[21]  A. Martí,et al.  Gene expression changes in rat white adipose tissue after a high-fat diet determined by differential display. , 2004, Biochemical and biophysical research communications.

[22]  P. Chambon,et al.  Cloning of murine α and β retinoic acid receptors and a novel receptor γ predominantly expressed in skin , 1989, Nature.

[23]  R. Rodriguez,et al.  A noncommercial dual luciferase enzyme assay system for reporter gene analysis. , 2000, Analytical biochemistry.

[24]  H. Nau,et al.  2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters the endogenous metabolism of all-trans-retinoic acid in the rat , 2003, Archives of Toxicology.

[25]  P. Lemotte,et al.  Characterization of synthetic retinoids with selectivity for retinoic acid or retinoid X nuclear receptors. , 1996, Biochimica et biophysica acta.

[26]  D. Goodman,et al.  Retinol-binding protein: the transport protein for vitamin A in human plasma. , 1968, The Journal of clinical investigation.

[27]  G. Casari,et al.  Identification of Farnesoid X Receptor β as a Novel Mammalian Nuclear Receptor Sensing Lanosterol , 2003, Molecular and Cellular Biology.

[28]  D. Goodman,et al.  Fluorescence studies of human plasma retinol-binding protein and of the retinol-binding protein-prealbumin complex. , 1972, Biochimica et biophysica acta.

[29]  G. Eichele,et al.  The endogenous retinoid metabolite S‐4‐oxo‐9‐cis‐13,14‐dihydro‐retinoic acid activates retinoic acid receptor signalling both in vitro and in vivo , 2009, The FEBS journal.

[30]  A. Budhu,et al.  Direct Channeling of Retinoic Acid between Cellular Retinoic Acid-Binding Protein II and Retinoic Acid Receptor Sensitizes Mammary Carcinoma Cells to Retinoic Acid-Induced Growth Arrest , 2002, Molecular and Cellular Biology.

[31]  K. Nakanishi,et al.  Intracellular signaling by 14-hydroxy-4,14-retro-retinol. , 1991, Science.

[32]  Pierre Chambon,et al.  A human retinoic acid receptor which belongs to the family of nuclear receptors , 1987, Nature.

[33]  V. Giguère,et al.  Identification of a receptor for the morphogen retinoic acid , 1987, Nature.

[34]  U. Cogan,et al.  Binding affinities of retinol and related compounds to retinol binding proteins. , 1976, European journal of biochemistry.

[35]  F. Chytil,et al.  Specificity of cellular retinol-binding protein for compounds with vitamin A activity , 1975, Nature.

[36]  D. Goodman.  PLASMA RETINOL‐BINDING PROTEIN * , 1980, Annals of the New York Academy of Sciences.

[37]  G Wald,et al.  Visual Excitation and Blood Clotting , 1965, Science.