15-Hydroxyeicosatetraenoic Acid Is a Preferential Peroxisome Proliferator-Activated Receptor β/δ Agonist

Peroxisome proliferator-activated receptor (PPARs) modulate target gene expression in response to unsaturated fatty acid ligands, such as arachidonic acid (AA). Here, we report that the AA metabolite 15-hydroxyeicosatetraenoic acid (15-HETE) activates the ligand-dependent activation domain (AF2) of PPAR beta/delta in vivo, competes with synthetic agonists in a PPAR beta/delta ligand binding assay in vitro, and triggers the interaction of PPAR beta/delta with coactivator peptides. These agonistic effects were also seen with PPAR alpha and PPAR gamma, but to a significantly weaker extent. We further show that 15-HETE strongly induces the expression of the bona fide PPAR target gene Angptl4 in a PPAR beta/delta-dependent manner and, conversely, that inhibition of 15-HETE synthesis reduces PPAR beta/delta transcriptional activity. Consistent with its function as an agonistic ligand, 15-HETE triggers profound changes in chromatin-associated PPAR beta/delta complexes in vivo, including the recruitment of the coactivator cAMP response element- binding protein binding protein. Both 15R-HETE and 15S-HETE are similarly potent at inducing PPAR beta/delta coactivator binding and transcriptional activation, indicating that 15-HETE enantiomers generated by different pathways function as PPAR beta/delta agonists.