| 15-hydroxyeicosatetraenoic acid is a preferential peroxisome proliferator-activated receptor beta/delta agonist. | |
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MedLine Citation:
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PMID: 19903832 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Simone Naruhn; Wolfgang Meissner; Till Adhikary; Kerstin Kaddatz; Thomas Klein; Bernhard Watzer; Sabine M?ller-Br?sselbach; Rolf M?ller |
Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2009-11-10 |
Journal Detail:
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Title: Molecular pharmacology Volume: 77 ISSN: 1521-0111 ISO Abbreviation: Mol. Pharmacol. Publication Date: 2010 Feb |
Date Detail:
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Created Date: 2010-01-20 Completed Date: 2010-02-11 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 171-84 Citation Subset: IM |
Affiliation:
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Institut f?r Molekularbiologie und Tumorforschung, Philipps-Universit?t Marburg, 35032 Marburg, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals CHO Cells Cricetinae Cricetulus Fibroblasts / chemistry, metabolism Humans Hydroxyeicosatetraenoic Acids / biosynthesis, metabolism, pharmacology* Mice Mice, Knockout Molecular Sequence Data NIH 3T3 Cells PPAR delta / agonists*, genetics, physiology PPAR-beta / agonists*, genetics, physiology Trans-Activators / biosynthesis, genetics, physiology |
| Chemical | |
Reg. No./Substance:
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0/Hydroxyeicosatetraenoic Acids; 0/PPAR delta; 0/PPAR-beta; 0/Trans-Activators; 73945-47-8/15-hydroxy-5,8,11,13-eicosatetraenoic acid |
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