Evidence for direct binding of fatty acids and eicosanoids to human peroxisome proliferators-activated receptor α

The alpha isoform of peroxisome proliferators-activated receptor (PPAR) is activated by fatty acids, their metabolites, and the fibrate class of lipid-lowering agents. To test the ability of these activators to directly bind the ligand-binding domain of human PPAR alpha, we performed a competitive binding assay using radiolabeled [H-3]KRP-297, a known ligand for human PPAR alpha. Long-chain fatty acids and eicosanoids were even more potent ligands for human PPAR alpha than the hitherto most potent PPAR alpha ligand WY-14,643. Moreover, these natural ligands avidly activated this receptor in a transient transcriptional assay. This study provides the direct evidence that human PPAR alpha is activated through the direct binding of fatty acids and eicosanoids, as well as of a fibrate, to its ligand-binding domain. (C) 1999 Academic Press.