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1 Biochemistry, University of Iowa, Iowa City, IA, USA
2 Cell Biology and Neuroscience, University of California, Riverside, Riverside, CA, USA
3 Biochemistry, University of Southwestern Medical School, Dallas, TX, USA
4 Internal Medicine, University of Iowa, Iowa City, IA, USA
* To whom correspondence should be addressed. E-mail: xiang-fang{at}uiowa.edu.
Epoxyeicosatrienoic acids (EETs), lipid mediators synthesized from arachidonic acid by cytochrome P450 epoxygenases, are converted by soluble epoxide hydrolase (sEH) to the corresponding dihydroxyeicosatrienoic acids (DHETs). Originally considered inactive degradation products of EETs, DHETs have biological activity in some systems. Here, we examined the capacity of EETs and DHETs to activate peroxisome proliferator-activated receptor (PPAR) a. We find that among the EET and DHET regioisomers, 14,15-DHET is the most potent PPAR
activator in a COS-7 cell expression system. Incubation with 10 µM 14,15-DHET produced a 12-fold increase in PPAR-mediated luciferase activity, an increase similar to that produced by the PPARa agonist Wy-14643 (20 µM). Although 10 µM 14,15-EET produced a 3-fold increase in luciferase activity, this was abrogated by the sEH inhibitor dicyclohexylurea. 14-Hexyloxytetradec-5(Z)-enoic acid, a 14,15-EET analog that cannot be converted to a DHET, did not activate PPAR. However, PPAR was activated by 2-(14,15-epoxyeicosatrienoyl)glycerol, which was hydrolyzed and the released 14,15-EET converted to 14,15-DHET. COS-7 cells incorporated [3H]14,15-DHET from the medium, and the cells also retained a small amount of the DHET formed during incubation with [3H]14,15-EET. Binding studies indicated that [3H]14,15-DHET binds to the ligand binding domain of PPAR with a Kd of 1.4 µM. Furthermore, 14,15-DHET increased the expression of the carnitine palmitoyltransferase 1A, a PPAR-responsive gene, in transfected HepG2 cells. These findings suggest that 14,15-DHET, produced from 14,15-EET by the action of sEH, may function as an endogenous activator of PPAR.
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