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Journal of Lipid Research, Vol. 48, 924-934, April 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

P450 CYP2C epoxygenase and CYP4A -hydroxylase mediate ciprofibrate-induced PPAR-dependent peroxisomal proliferation

Arnaldo Gatica^*, Mauricio C. Aguilera^*, David Contador^*, Gloria Loyola^*, Claudio O. Pinto^*, Ludwig Amigo, Juan E. Tichauer, Silvana Zanlungo and Miguel Bronfman^1,*

^* Centro de Regulación Celular y Patología and Millennium Institute for Fundamental and Applied Biology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Casilla 114-D, Santiago, Chile
Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Casilla 114-D, Santiago, Chile

Published, JLR Papers in Press, January 17, 2007.

¹ To whom correspondence should be addressed. e-mail: mbronfman{at}bio.puc.cl

Peroxisomal proliferators, such as ciprofibrate, are used extensively as effective hypolipidemic drugs. The effects of these compounds on lipid metabolism require ligand binding activation of the peroxisome proliferator-activated receptor (PPAR) subtype of nuclear receptors and involve transcriptional activation of the metabolic pathways involved in lipid oxidative metabolism, transport, and disposition. -Hydroxylated-eicosatrienoic acids (HEETs), products of the sequential metabolism of arachidonic acid (AA) by the cytochrome P450 CYP2C epoxygenase and CYP4A -hydroxylase gene subfamilies, have been identified as potent and high-affinity ligands of PPAR in vitro and as PPAR activators in transient transfection assays. Using isolated rat hepatocytes in culture, we demonstrate that specific inhibition of either the CYP2C epoxygenase or the CYP4A -hydroxylase abrogates ciprofibrate-induced peroxisomal proliferation, whereas inhibition of other eicosanoid-synthesizing pathways had no effect. Conversely, overexpression of the rat liver CYP2C11 epoxygenase leads to spontaneous peroxisomal proliferation, an effect that is reversed by a CYP inhibitor. Based on these results, we propose that HEETs may serve as endogenous PPAR ligands and that the P450 AA monooxygenases participate in ciprofibrate-induced peroxisomal proliferation and the activation of PPAR downstream targets.

Supplementary key words P450 monooxygenases • -hydroxylated-eicosatrienoic acids • peroxisome proliferator-activated receptor

Abbreviations: AA, arachidonic acid; ADAPS, alkyl-dihydroxyacetone phosphate synthase; Ad-EPOX, adenoviral epoxygenase vector; Ad-ßgal, adenoviral ß-galactosidase vector; AOX, acyl-coenzyme A oxidase; CoASH, Coenzyme A; DDMS, N-methylsulfonyl-12,12-dibromododec-11-enamide; EET, epoxyeicosatrienoic acid; HEET, -hydroxylated-eicosatrienoic acid; HNF-4, hepatic nuclear factor-4; PMP70, peroxisomal membrane protein; PP, peroxisome proliferator; PPAR, peroxisome proliferator-activated receptor ; PPOH, 6-(2-propargyloxyphenyl) hexanoic acid; PPRE, peroxisome proliferator response element

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