Vitamin A and retinoid signaling: genomic and nongenomic effects

Vitamin A or retinol is arguably the most multifunctional vitamin in the human body, as it is essential from embryogenesis to adulthood. The pleiotropic effects of vitamin A are exerted mainly by one active metabolite, all-trans retinoic acid (atRA), which regulates the expression of a battery of target genes through several families of nuclear receptors (RARs, RXRs, and PPARβ/δ), polymorphic retinoic acid (RA) response elements, and multiple coregulators. It also involves extranuclear and nontranscriptional effects, such as the activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of several actors of RA signaling. However, vitamin A itself proved recently to be active and RARs to be present in the cytosol to regulate translation and cell plasticity. These new concepts expand the scope of the biologic functions of vitamin A and RA. Vitamin A or retinol is arguably the most multifunctional vitamin in the human body, as it is essential from embryogenesis to adulthood. The pleiotropic effects of vitamin A are exerted mainly by one active metabolite, all-trans retinoic acid (atRA), which regulates the expression of a battery of target genes through several families of nuclear receptors (RARs, RXRs, and PPARβ/δ), polymorphic retinoic acid (RA) response elements, and multiple coregulators. It also involves extranuclear and nontranscriptional effects, such as the activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of several actors of RA signaling. However, vitamin A itself proved recently to be active and RARs to be present in the cytosol to regulate translation and cell plasticity. These new concepts expand the scope of the biologic functions of vitamin A and RA. Vitamins are essential organic molecules that an organism depends on for survival. The main characteristics of a vitamin are that it cannot be synthesized by the organism and thus must be obtained from the diet. Vitamin A is arguably the most multifunctional vitamin in the human body and is provided as preformed vitamin A in foods of animal origin (liver) and as provitamin A carotenoids found in plant-derived foods (1Harrison E.H. Mechanisms involved in the intestinal absorption of dietary vitamin A and provitamin A carotenoids.Biochim. Biophys. Acta. 2012; 1821: 70-77Crossref PubMed Scopus (161) Google Scholar). Vitamin A or retinol is essential for human survival at every point, from embryogenesis to adulthood (2Clagett-Dame M. DeLuca H.F. The role of vitamin A in mammalian reproduction and embryonic development.Annu. Rev. Nutr. 2002; 22: 347-381Crossref PubMed Scopus (344) Google Scholar, 3Clagett-Dame M. Knutson D. Vitamin A in reproduction and development.Nutrients. 2011; 3: 385-428Crossref PubMed Scopus (190) Google Scholar). Such an important role has been revealed by both experimental approaches and clinical observations. Indeed deficiency of vitamin A leads to neonatal growth retardation and a large array of congenital malformations collectively referred to as the fetal “vitamin A deficiency” (VAD) syndrome. Moreover, in adults, vitamin A is well known to be essential for several functions, such as vision, immunity, and reproduction. However, new biologic functions for vitamin A are continuously being discovered in new fields such as lipid metabolism, insulin response, energy balance and the nervous system. It is well documented that most of these pleiotropic functions are not exerted by retinol itself but by active metabolites. Among these metabolites is 11-cis-retinaldehyde (11cRAL), which is involved in phototransduction through binding opsin to form rhodopsin and cone pigments. In fact, the predominant endogenous active metabolite is all-trans retinoic acid (atRA), which regulates the expression of a battery of target genes involved in cell growth and differentiation, development, and homeostasis. Moreover, in keeping with its antiproliferative activity, retinoic acid (RA) is used in the treatment of certain cancers (4Altucci L. Gronemeyer H. The promise of retinoids to fight against cancer.Nat. Rev. Cancer. 2001; 1: 181-193Crossref PubMed Google Scholar). Basically, RA mobilizes to the nucleus through binding to small intracellular lipid-binding proteins. The resulting complex channels RA to specific nuclear receptors, the so-called retinoic acid receptors (RAR), which work as ligand-dependent regulators of transcription and transduce the RA signal in vivo as heterodimers with retinoic X receptors (RXR) (5McKenna N.J. EMBO retinoids 2011: mechanisms, biology and pathology of signaling by retinoic acid and retinoic acid receptors.Nucl. Recept. Signal. 2012; 10: e003Crossref PubMed Scopus (20) Google Scholar, 6Mark M. Ghyselinck N.B. Chambon P. Function of retinoic acid receptors during embryonic development.Nucl. Recept. Signal. 2009; 7: e002Crossref PubMed Scopus (249) Google Scholar). Therefore, vitamin A/RA is considered as the paradigm of the link between vitamin, nutrition, homeostasis, and development via the regulation of gene expression. During the last decade, this scenario became more complicated with the discovery that RA also has extranuclear, nontranscriptional effects, such as the activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which influences the expression of RA target genes via phosphorylation processes. Moreover, other studies revealed that RA activates not only RARs but also other nuclear receptors, such as the peroxisome proliferator-activated receptors (PPAR). Finally, vitamin A/retinol proved recently to be active and to activate the Janus kinase/STAT5 signaling pathway. Remarkably, these two last novel effects result in the regulation of genes that are not direct RAR targets, thus increasing the widespread nature of the biologic functions of vitamin A/RA, especially in the field of energy balance. Finally, there is unexpected role of RARs in translation, out of the nucleus. In this review, we highlight that the spectrum of activities of vitamin A and RA is much broader and more complex than previously suspected due to the diversity of their receptors and to the large spectrum of their extranuclear and nontranscriptional effects. We also attempt to recapitulate how all these effects crosstalk and/or cooperate with each other to expand the scope of vitamin A and RA functions. Vitamin A or retinol is composed of a β-ionone ring, a polyunsaturated side chain, and a polar end group (7Curley Jr, R.W. Retinoid chemistry: synthesis and application for metabolic disease.Biochim. Biophys. Acta. 2012; 1821: 3-9Crossref PubMed Scopus (11) Google Scholar) (Fig. 1). This chemical structure makes it poorly soluble in water but easily transferable through membrane lipid bilayers. In fact, vitamin A exerts its effects via oxidized metabolites, and the pleiotropicity of its effects is generated through the multiplicity of its active metabolites and of its targets. Vitamin A is essential for vision. In the eye, its active metabolite is 11-cis-retinaldehyde (11cRAL) (for review, see Ref. 8Kusakabe T.G. Takimoto N. Jin M. Tsuda M. Evolution and the origin of the visual retinoid cycle in vertebrates.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2009; 364: 2897-2910Crossref PubMed Scopus (0) Google Scholar). It is present in the photoreceptor cells of the retina and belongs to the visual pigment responsible for sensing light (Fig. 1). 11cRAL works as a chromophore and binds opsin, a G protein. Visual perception starts with the absorption of a photon, which induces isomerization of 11cRAL to 11-trans retinaldehyde (11tRARL). Then 11tRAL is released from opsin and the 11-cis chromophore is regenerated for sustained vision. The most important biologically active metabolite of vitamin A is atRA (Fig. 1). Today, several compounds that do not fit with the chemical structure of RA but are much more active in several assays have been synthesized. Now, retinol, RA, other active metabolites and active synthetic compounds are grouped as “retinoids” (9Sporn M.B. Roberts A.B. Goodman D.S. he Retinoids: Biology, Chemistry, and Medicine. 2nd edition. Raven Press Ltd., New York1994Google Scholar). Today, it is well admitted that RA binds and activates RARs. However, the existence of a physiological RXR ligand is still being investigated. Indeed RXRs cannot bind atRA, and although its 9-cis isomer (9cRA) was initially considered as a bona fide RXR ligand (10Heyman R.A. Mangelsdorf D.J. 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Thus endogenous 9cRA exists and is physiological relevant. Nevertheless, RXR can bind a series of flexible fatty acids, including the unsaturated fatty acid docosahexanoic acid (DHA), oleic acid, phytanic acid, and honokiol, strongly suggesting the involvement of this receptor as a sensor of the cellular metabolic status (16Pérez E. Bourguet W. Gronemeyer H. de Lera A.R. Modulation of RXR function through ligand design.Biochim. Biophys. Acta. 2012; 1821: 57-69Crossref PubMed Scopus (125) Google Scholar). Moreover synthetic “rexinoids” have been designed and have confirmed that binding of a ligand to the RXR partner modulates the functions of the RXR/RAR heterodimers (16Pérez E. Bourguet W. Gronemeyer H. de Lera A.R. Modulation of RXR function through ligand design.Biochim. Biophys. Acta. 2012; 1821: 57-69Crossref PubMed Scopus (125) Google Scholar). In the cytosol, RA is well known to bind the cellular retinoic acid-binding protein CRABPII, which belongs to the intracellular lipid binding proteins iLBP family. It is a small cytosolic protein, which specifically associates with RA with subnanomolar affinities. Upon binding of RA, CRABPII mobilizes to the nucleus, where it associates with RARs through direct protein-protein interactions (17Budhu A.S. Noy N. 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.Mol. Cell. Biol. 2002; 22: 2632-2641Crossref PubMed Scopus (218) Google Scholar, 18Delva L. Bastie J.N. Rochette-Egly C. Kraiba R. Balitrand N. Despouy G. Chambon P. Chomienne C. Physical and functional interactions between cellular retinoic acid binding protein II and the retinoic acid-dependent nuclear complex.Mol. Cell. Biol. 1999; 19: 7158-7167Crossref PubMed Google Scholar, 19Dong D. 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In the unliganded state, the hydrophobic surface of the RARα subtype can bind corepressors, such as nuclear receptor corepressor (NCoR) or silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), which are genetic paralogs. In fact, SMRT would be the RAR-favored corepressor, and multiple protein variants are produced by alternative splicing. The majority of the SMRT variants possess at least two receptor interaction domains (RID), which contain an extended α helical box with an LxxI/HIxxxI/L motif (55Perissi V. Staszewski L.M. McInerney E.M. Kurokawa R. Krones A. Rose D.W. Lambert M.H. Milburn M.V. Glass C.K. Rosenfeld M.G. Molecular determinants of nuclear receptor-corepressor interaction.Genes Dev. 1999; 13: 3198-3208Crossref PubMed Scopus (403) Google Scholar). Through one of these domains, SMRT docks with the hydrophobic groove found at the surface of the RARα LBD and generated by H3 and H4. However, according to recent structural studies, efficient interaction also requires an antiparallel β-sheet interface involving N-terminal flanking residues of the corepressor RID and an extended β-strand conformation of the receptor H11 (56le Maire A. Teyssier C. Erb C. Grimaldi M. Alvarez S. de Lera A.R. Balaguer P. Gronemeyer H. Royer C.A. Germain P. et al.A unique secondary-structure switch controls constitutive gene repression by retinoic acid receptor.Nat. Struct. Mol. Biol. 2010; 17: 801-807Crossref PubMed Scopus (106) Google Scholar) (Fig. 3A). This interface removes H12 and unmasks the hydrophobic groove for binding of the RID α helix. Note that the region that maps C-terminal to H12 would also help stabilize H12 in an open conformation co