TY - JOUR T1 - 15-hydroxyeicosatetraenoic acid (15-HETE) is a preferential PPARβ/δ agonist JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.109.060541 SP - mol.109.060541 AU - Simone Naruhn AU - Wolfgang Meissner AU - Till Adhikary AU - Kerstin Kaddatz AU - Thomas Klein AU - Bernhard Watzer AU - Sabine Muller-Brusselbach AU - Rolf Muller Y1 - 2009/01/01 UR - http://molpharm.aspetjournals.org/content/early/2009/11/10/mol.109.060541.abstract N2 - Peroxisome proliferator-activated receptors (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 PPARβ/δ in vivo, competes with synthetic agonists in a PPARβ/δ ligand binding assay in vitro and triggers the interaction of PPARβ/δ with co-activator peptides. These agonistic effects were also seen with PPARα and PPARγ, 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 PPARβ/δ dependent manner, and conversely, that inhibition of 15-HETE synthesis reduces PPARβ/δ transcriptional activity. Consistent with its function as an agonistic ligand, 15-HETE triggers profound changes in chromatin associated PPARβ/δ complexes in vivo, including the recruitment of the coactivator CBP. Both, 15R-HETE and 15S-HETE, are similarly potent at inducing PPARβ/δ coactivator binding and transcriptional activation, indicating that 15-HETE enantiomers generated by different pathways function as PPARβ/δ agonists.The American Society for Pharmacology and Experimental Therapeutics ER -