FATTY-ACIDS AND EICOSANOIDS REGULATE GENE-EXPRESSION THROUGH DIRECT INTERACTIONS WITH PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA AND RECEPTOR-GAMMA

Peroxisome proliferator-activated receptors (PPARs) alpha and gamma ar e key regulators of lipid homeostasis and are activated by a structura lly diverse group of compounds including fatty acids, eicosanoids, and hypolipidemic drugs such as fibrates and thiazolidinediones. While th iazolidinediones and 15-deoxy-Delta(12,14)-prostaglandin J(2) have bee n shown to bind to PPAR gamma, it has remained unclear whether other a ctivators mediate their effects through direct interactions with the P PARs or via indirect mechanisms, Here, we describe a novel fibrate, de signated GW2331, that is a high-affinity ligand for both PPAR alpha an d PPAR gamma, Using GW2331 as a radioligand in competition binding ass ays, we shown that certain mono- and polyunsaturated fatty acids bind directly to PPAR alpha and PARA gamma at physiological concentrations, and that the eicosanoids S(S)-hydroxyeicosatetraenoic acid and 15-deo xy-Delta(12,14) -prostaglandin J(2) can function as subtype-selective ligands for PPAR alpha: and PPAR gamma, respectively. These data provi de evidence that PPARs serve as physiological sensors of lipid levels and suggest a molecular mechanism whereby dietary fatty acids can modu late lipid homeostasis.