Vitamin A or retinol is required at many stages during vertebrate development and remains crucial for the body homeostasis in the adult organism. Most of its numerous activities are due to the action of all-trans retinoic acid (atRA) and its 9-cis isomer (9-cis RA). Two classes of receptors convey the activity of retinoic acid (RA). The retinoic acid receptors (RARs) bind atRA and 9-cis RA. This class is well-characterized for its predominant but not exclusive role in embryogenesis and organogenesis (reviewed in Mark et al., 2006). The second class corresponds to the rexinoid receptors (RXRs), which bind 9-cis RA only. Both RARs and RXRs belong to the nuclear receptor superfamily, the largest class of transcription factors. Within this family, RXRs occupy a particular place as they are obligatory DNA-binding partners for a number of other nuclear receptors. RXRs work in three different configurations: (1) as a structural component of the heterodimer complex, required for DNA binding but not acting as a receptor per se, these are the so-called "nonpermissive" heterodimers; (2) as both a structural and a functional component of the heterodimer, allowing 9-cis RA to signal through the corresponding heterodimer, forming the so-called permissive heterodimers; and (3) as conveyers of a 9-cis RA signal, independently of other nuclear receptors, by forming functional homodimers. However, one lingering question about RXR signaling concerns the true nature of the endogenous ligand, as will be discussed herein.

The present chapter is focused on the properties of RXR-containing tran-scriptional complexes, more particularly those playing a role in metabolic regulation. After positioning RXR among the nuclear receptor superfamily, we will discuss the three major signaling pathways involved in metabolism that are sensitive to RXR activation, that is, LXR:RXR, FXR:RXR, and PPAR:RXR pathways. The third and last part is focused on RXR signaling and its potential-specific role in metabolic regulations. Indeed, while the nature of the endogenous ligand for RXR is still in question, RXR synthetic ligands are already in use in clinical trials for their antitumorigenic activity. Experimental data also indicated a potential use in the treatment of metabolic diseases such as the type 2 diabetes. However, an extended understanding of RXR activities is still necessary to envisage the potential and safe therapeutic applications of synthetic RXR ligands.


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