P450 CYP2C epoxygenase and CYP4A omega-hydroxylase mediate ciprofibrate-induced PPARalpha-dependent peroxisomal proliferation.
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) alpha subtype of nuclear receptors and involve transcriptional activation of the metabolic pathways involved in lipid oxidative metabolism, transport, and disposition. omega-Hydroxylated-eicosatrienoic acids (HEETs), products of the sequential metabolism of arachidonic acid (AA) by the cytochrome P450 CYP2C epoxygenase and CYP4A omega-hydroxylase gene subfamilies, have been identified as potent and high-affinity ligands of PPARalpha in vitro and as PPARalpha activators in transient transfection assays. Using isolated rat hepatocytes in culture, we demonstrate that specific inhibition of either the CYP2C epoxygenase or the CYP4A omega-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 PPARalpha ligands and that the P450 AA monooxygenases participate in ciprofibrate-induced peroxisomal proliferation and the activation of PPARalpha downstream targets.
Gatica
Arnaldo
A
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.
Aguilera
Mauricio C
MC
Contador
David
D
Loyola
Gloria
G
Pinto
Claudio O
CO
Amigo
Ludwig
L
Tichauer
Juan E
JE
Zanlungo
Silvana
S
Bronfman
Miguel
M
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D058607:Fibric Acids; D022781:Hepatocytes / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D008024:Ligands; D047493:PPAR alpha / Q000378:metabolism*; D020675:Peroxisomes / Q000502:physiology*; D051381:Rats
D058607:Fibric Acids; D006893:Hydroxyeicosatetraenoic Acids; D008024:Ligands; D047493:PPAR alpha; C400322:cytochrome P-450 CYP2C subfamily; D016718:Arachidonic Acid; D002995:Clofibric Acid; D003577:Cytochrome P-450 Enzyme System; D042926:Cytochrome P-450 CYP4A; C019304:ciprofibrate