Chapter 278 - Identification of Ligands for Orphan Nuclear Receptors

Abstract

The nuclear receptors comprise a superfamily of transcription factors that are activated by small, lipophilic chemicals including the classic steroid, retinoid, and thyroid hormones. There are 48 members of this family encoded by the human genome, far more receptors than established lipophilic hormones. The work of a number of laboratories has shown that many of the remaining members of the family function as metabolic sensors, linking physiological levels of intracellular metabolites to the transcriptional regulation of key biochemical pathways. This chapter highlights recent progress that has been made in the identification of ligands for orphan nuclear receptors. With the exception of the hepatocyte nuclear receptor 4 (HNF4, NR2A) and estrogen related receptor (ERR; NR3B) subtypes, all of the receptors discussed in this review bind to their cognate DNA response elements as heterodimers with the 9-cis retinoic acid receptors (RXR, NR2B). Recent studies with HNF4 raise the possibility that some orphan nuclear receptors have high constitutive levels of transcriptional activity because they bind irreversibly to their lipophilic ligands. The availability of natural and synthetic ligands will aid tremendously in unraveling the biological functions of these orphan nuclear receptors.