FATTY-ACIDS, EICOSANOIDS, AND HYPOLIPIDEMIC AGENTS IDENTIFIED AS LIGANDS OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS BY COACTIVATOR-DEPENDENT RECEPTOR-LIGAND ASSAY

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormon e receptors controlling the expression of genes involved in lipid home ostasis. PPARs activate gene transcription in response to a variety of compounds including hypolipidemic drugs as well as natural fatty acid s. From the plethora of PPAR activators, Scatchard analysis of recepto r-ligand interactions has thus far identified only four ligands, These are the chemotactic agent leukotriene B-4 and the hypolipidemic drug Wy 14,643 for. the alpha-subtype and a prostaglandin J2 metabolite and synthetic antidiabetic thiazolidinediones for the gamma-subtype, Base d on the hypothesis that ligand binding to PPAR would induce interacti ons of the receptor with transcriptional coactivators, we have develop ed a novel ligand sensor assay, termed coactivator-dependent receptor ligand assay (CARLA), With CARLA we have screened several natural and synthetic candidate ligands and have identified naturally occurring fa tty acids and metabolites as well as hypolipidemic drugs as bona fide ligands of the three PPAR subtypes from Xenopus laevis, Our results;su ggest that PPARs, by their ability to interact with a number of struct urally diverse compounds, have acquired unique ligand-binding properti es among the superfamily of nuclear receptors that are compatible with their biological activity.