Orphan nuclear receptors—new ligands and new possibilities: Figure 1.

Abstract

Nuclear hormone receptors comprise a large superfamily of ligand-modulated transcription factors that, in part, mediate response to steroids, retinoids and thyroid hormones and play key roles in development and body physiology (for review, see Beato et al. 1995; Kastner et al. 1995; Mangelsdorf and Evans 1995; Mangelsdorf et al. 1995; Enmark and Gustaffson 1996; Willy and Mangelsdorf 1998). Ten years ago the first orphan nuclear receptors were isolated, raising the first portents toward a new era in physiology (Giguere et al. 1988). Although structurally related to the known receptors, no physiological ligands or activators were known for these orphan receptors which are more numerous (19 families) than receptors with known ligands (10 families). Orphan receptors represent a diverse and ancient component of the nuclear receptor superfamily, being found in nearly all animal species examined. Orphan nuclear receptors provide a unique and, until recently, largely untapped resource to uncover regulatory systems that impact on both health and human disease. Shortly after their isolation, strategies were devised to identify orphan ligands using the receptor as a screening target. This process, referred to as ‘reverse endocrinology,’ has led previously to the identification of ligands for RXRs [9-cis retinoic acid receptors (RARs), a.k.a. retinoid X receptors], PPARs (peroxisome proliferator-activated receptors), FXRs (farnesoid X receptors), and LXRs (liver X receptors). In a review eight years ago, Bert O’Malley predicted that the field of orphan receptors would provide much excitement for the future (O’Malley 1990). The promise of orphan receptors is that they provide an opportunity to identify not only novel ligands but perhaps unsuspected classes of ligands and potentially new principles of physiology. Because all known receptors are important in the treatment of human disease, their signaling pathways have direct implications for drug discovery. The purpose of this review is to highlight advances made on four new orphan receptor-mediated signaling pathways [BXR (benzoate X receptor), CARb (constitutive androstane receptor), PXR (pregnane X receptor), and SXR (steroid and Xenobiotic receptor)] with brief updates on recent progress for FXR, PPARg, and LXRa. To restrict the scope of the review, we will focus only on orphans forming heterodimers with RXR and studies that have been reported in the last year. We will emphasize what has been learned about the nature of the ligands, new modes of regulation, insights into physiology, and potential new drug targets.