¹UCSF, San Francisco, CA, USA

Abstract

Cytochrome P450 (CYP) eicosanoids regulate vascular tone, renal tubular transport, cellular proliferation and inflammation. CYP epoxygenases produce stereo- and regioisomeric epoxyeicosatrienoic acids (EETs) which are hydrated by soluble epoxide hydrolase (sEH) into dihydroxyeicosatrienoic acids (DHETs). CYP epoxygenases and sEH are selectively induced or repressed upon activation of peroxisome proliferator-activated receptor alpha (PPAR|[alpha]|) by fatty acids and xenobiotics. We hypothesize that CYP eicosanoids can bind to and activate PPAR|[alpha]|, thereby regulating their own levels as well as the levels of PPAR|[alpha]| target genes. In transactivation assays, 14,15-DHET was the most potent activator of PPAR|[alpha]|. In addition, 14,15-DHET strongly activated PPAR|[gamma]|. EETs also activated PPAR|[alpha]| and PPAR|[gamma]| but were half as potent as 14,15-DHET. Gel shift assays showed that EETs and DHETs induced PPAR|[alpha]|-specific binding to its response element. The effects of 14,15-DHET on fatty acid metabolism were examined in HepG2 cells by RT-PCR. Expression of acyl-CoA synthetase was increased 3-fold, and carnitine palmitoyltransferase 1A increased 2-fold. In contrast, hydroxy methylglutaryl CoA expression was unaffected. In conclusion, 14,15-DHET has been identified as a potent endogenous activator of PPAR|[alpha]| and plays a role in the regulation of fatty acid metabolism in the human liver. Funded by NIH grants HL53994 and GM07175 and a predoctoral fellowship from the PhRMA Foundation.