Abstract
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.
Highlights
Vitamin A or retinol is arguably the most multifunctional vitamin in the human body, as it is essential from embryogenesis to adulthood
The predominant endogenous active metabolite is alltrans retinoic acid, which regulates the expression of a battery of target genes involved in cell growth and differentiation, development, and homeostasis
Retinol that was associated to the “retinol-binding protein (RBP)” and that was bound to the cell surface signaling receptor stimulated by retinoic acid 6 (Stra6) was found to activate the Janus kinases (JAK)/signal transducer and activator of transcription 5 (STAT5) signaling cascade [126,127,128] (Fig. 5B)
Summary
Vitamin A or retinol is composed of a -ionone ring, a polyunsaturated side chain, and a polar end group [7] (Fig. 1). RA binding activates the nuclear translocation of FABP5, which delivers the ligand to the PPAR/␦ subtype (but not to the other PPARs) [21,22,23] These observations raised a novel paradigm, according to which RA can alternatively activate two different types of nuclear receptors, RARs and PPAR/␦, depending on the relative expression levels of CRABPII and FABP5 (Fig. 1). Like RARs, PPARs belong to the superfamily of nuclear receptors and regulate the expression of target genes as heterodimers with RXRs. There are three main subtypes, PPAR␣ (NR1C1), PPAR␥ (NR1C3), and PPAR/␦ (NR1C2), which are encoded by separate genes and display structural characteristics very similar to those of RARs [45, 46]. The in vivo relevance of such observations remains to be determined
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