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Am J Physiol Heart Circ Physiol 290: H55-H63, 2006. First published August 19, 2005; doi:10.1152/ajpheart.00427.2005
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14,15-Dihydroxyeicosatrienoic acid activates peroxisome proliferator-activated receptor-{alpha}

Xiang Fang,1 Shanming Hu,1 Bingkun Xu,1 Gary D. Snyder,1 Shawn Harmon,1 Jianrong Yao,1 Yi Liu,4 Bhavani Sangras,5 J. R. Falck,5 Neal L. Weintraub,2,3 and Arthur A. Spector1,2

Departments of 1Biochemistry and 2Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa; 3Veterans Administration Medical Center, Iowa City, Iowa; 4Department of Cell Biology and Neuroscience, University of California, Riverside, California; and 5Department of Biochemistry, University of Texas Southwestern Medical School, Dallas, Texas

Submitted 28 April 2005 ; accepted in final form 12 August 2005

Epoxyeicosatrienoic acids (EETs), lipid mediators synthesized from arachidonic acid by cytochrome P-450 epoxygenases, are converted by soluble epoxide hydrolase (SEH) to the corresponding dihydroxyeicosatrienoic acids (DHETs). Originally considered as 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-{alpha} (PPAR{alpha}). We find that among the EET and DHET regioisomers, 14,15-DHET is the most potent PPAR{alpha} activator in a COS-7 cell expression system. Incubation with 10 µM 14,15-DHET produced a 12-fold increase in PPAR{alpha}-mediated luciferase activity, an increase similar to that produced by the PPAR{alpha} agonist Wy-14643 (20 µM). Although 10 µM 14,15-EET produced a threefold 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{alpha}. However, PPAR{alpha} 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 14,15-[3H]DHET from the medium, and the cells also retained a small amount of the DHET formed during incubation with 14,15-[3H]EET. Binding studies indicated that 14,15-[3H]DHET binds to the ligand binding domain of PPAR{alpha} with a Kd of 1.4 µM. Furthermore, 14,15-DHET increased the expression of carnitine palmitoyltransferase 1A, a PPAR{alpha}-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{alpha}.

cytochrome P-450; soluble epoxide hydrolase; 14,15-epoxyeicosatrieonic acid analogs


Address for reprint requests and other correspondence: X. Fang, Dept. of Biochemistry, Univ. of Iowa Carver College of Medicine, Iowa City, IA 52242 (e-mail: xiang-fang{at}uiowa.edu)




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