15-hydroxyeicosatetraenoic acid is a preferential peroxisome proliferator-activated receptor beta/delta 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 PPARbeta/delta in vivo, competes with synthetic agonists in a PPARbeta/delta ligand binding assay in vitro, and triggers the interaction of PPARbeta/delta with coactivator peptides. These agonistic effects were also seen with PPARalpha and PPARgamma, 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 PPARbeta/delta-dependent manner and, conversely, that inhibition of 15-HETE synthesis reduces PPARbeta/delta transcriptional activity. Consistent with its function as an agonistic ligand, 15-HETE triggers profound changes in chromatin-associated PPARbeta/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 PPARbeta/delta coactivator binding and transcriptional activation, indicating that 15-HETE enantiomers generated by different pathways function as PPARbeta/delta agonists.
Naruhn
Simone
S
Institut für Molekularbiologie und Tumorforschung, Philipps-Universität Marburg, 35032 Marburg, Germany.
Meissner
Wolfgang
W
Adhikary
Till
T
Kaddatz
Kerstin
K
Klein
Thomas
T
Watzer
Bernhard
B
Müller-Brüsselbach
Sabine
S
Müller
Rolf
R
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005347:Fibroblasts / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D047494:PPAR delta / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D048068:PPAR-beta / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology
D006893:Hydroxyeicosatetraenoic Acids; D047494:PPAR delta; D048068:PPAR-beta; D015534:Trans-Activators; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid