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;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), CAR␤ (constitutive androstane receptor), PXR (pregnane X receptor), and SXR (steroid and Xenobiotic receptor)] with brief updates on recent progress for FXR, PPAR␥, and LXR␣. 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. RXR heterodimers and ligand dependenceAlthough inherently promising, not all orphans (and perhaps only a few) can be expected to represent unidentified endocrine systems. Therefore, a central and critical problem is identifying which of the many orphan receptors are good candidates to be ligand responsive. An interesting feature of the known, nonsteroidal ligand-activated nuclear receptors is that they all require heterodimerization with RXR, for high-affinity DNA binding. We and others speculated that RXR heterodimerization might be a ...

Regulatory network of lipid-sensing nuclear receptors: roles for CAR, PXR, LXR, and FXR

“…Since some of the CYPs that are regulated by PXR and CAR are involved in steroid metabolism, it is not surprising that the activities of both xenosenors are also modulated by steroids [38]: PXR is activated by pregnanes, progesterone and glucocorticoids [4,5] whereas androstane metabolites, estrogens and progesterone affect CAR activity both positively and negatively [10,[39][40][41].…”

“…In patients, long-term -7 -treatment with rifampicin, a strong human PXR activator, phenobarbital or other anti-convulsants interferes with the bioavailability and therapeutic efficacy of coadministrated corticosteroids and steroid-based oral contraceptives [38,43]. The effect of drugs and xenobiotics on endogenous steroid levels is less clear because of highly efficient compensatory mechanisms that control steroidogenesis and metabolism.…”

Phosphorylation of human estrogen receptor α at serine 118 by two distinct signal transduction pathways revealed by phosphorylation-specific antisera

“…The superfamily includes receptors for androgen, glucocorticoid, progesterone, vitamin D3, thyroid hormone and retinoic acid, as well as receptors activated by peroxisome proliferators, bile acid-, prostaglandin-and benzoate-activated receptors (Blumberg and Evans, 1998;Makishima et al, 1999;Mangelsdorf et al, 1995;Parks et al, 1999;Wang et al, 1999). ERa is required for regulating the development and in the maintenance of the female and male reproductive systems, in bone maintenance and in the cardiovascular system, as well as being signi®cant for certain brain functions (e.g.…”

Liver X receptor is a regulator of orphan nuclear receptor NOR-1 gene transcription in adipocytes

“…23 Over the past 10 years as ligands for many of these receptors have been discovered, including the oxysterols for the LXRs, the remaining members of this 'orphan' class have come to be recognized as a special group the regulation of which is largely driven by their rapid and transient expression in response to intracellular signals. 24 For example, Ruis et al 15 identified a set of three cAMP response elements in the NOR-1 promoter that increases gene transcription in response to cAMP levels.…”