PT  - JOURNAL ARTICLE
AU  - Naruhn, Simone
AU  - Meissner, Wolfgang
AU  - Adhikary, Till
AU  - Kaddatz, Kerstin
AU  - Klein, Thomas
AU  - Watzer, Bernhard
AU  - Müller-Brüsselbach, Sabine
AU  - Müller, Rolf
TI  - 15-Hydroxyeicosatetraenoic Acid Is a Preferential Peroxisome Proliferator-Activated Receptor β/δ Agonist
AID  - 10.1124/mol.109.060541
DP  - 2010 Feb 01
TA  - Molecular Pharmacology
PG  - 171--184
VI  - 77
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/77/2/171.short
4100  - http://molpharm.aspetjournals.org/content/77/2/171.full
SO  - Mol Pharmacol2010 Feb 01; 77
AB  - 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 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 coactivator 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 cAMP response element-binding protein binding protein. 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.