Peroxisome proliferator-activated receptors and reverse endocrinology

Abstract

This chapter discusses the peroxisome proliferator-activated receptors (PPAR). Members of the nuclear receptor family, which includes the steroid, retinoid, and thyroid hormone receptors, function as ligand-activated transcription factors and have critical roles in nearly every aspect of vertebrate development and adult physiology. In addition to the receptors with known hormones, the nuclear receptor family includes many members that lack identified hormones. The identification of these so-called “orphan receptors” suggested that there might be additional hormones yet to be discovered and opened the era of “reverse endocrinology”. Historically, novel endocrine signaling pathways were discovered based upon their effects on physiological and developmental processes. The isolated hormone was then used to identify its partner receptor. In reverse endocrinology, this path is inverted. The orphan receptor is used to screen for novel small molecule ligands, either natural or synthetic, that modulate its transcriptional activity. The ligand, in turn, is used as a chemical tool to dissect the role of the receptor in physiology and pathophysiology. Over the past several years, reverse endocrinology has been used to link a number of orphan receptors to ligands and biological activities. Among the orphan nuclear receptors for which ligands have been identified and used to unravel their biology are the peroxisome proliferator-activated receptors (PPAR) as fatty acid and eicosanoid receptors; the liver X receptors (LXR) as oxysterol receptors; the farnesoid X receptor (FXR) as a bile acid receptor; and, the pregnane X receptor (PXR) as a xenobiotic and bile acid receptor.