RT Journal Article
SR Electronic
T1 15-Hydroxyeicosatetraenoic Acid Is a Preferential Peroxisome Proliferator-Activated Receptor β/δ Agonist
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 171
OP 184
DO 10.1124/mol.109.060541
VO 77
IS 2
A1 Simone Naruhn
A1 Wolfgang Meissner
A1 Till Adhikary
A1 Kerstin Kaddatz
A1 Thomas Klein
A1 Bernhard Watzer
A1 Sabine Müller-Brüsselbach
A1 Rolf Müller
YR 2010
UL http://molpharm.aspetjournals.org/content/77/2/171.abstract
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.