P450CYP2C epoxygenase and CYP4A omega-hydroxylase mediate ciprofibrate-induced PPAR alpha-dependent peroxisomal proliferation

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dc.contributor.authorGatica, Arnaldo
dc.contributor.authorAguilera, Mauricio C.
dc.contributor.authorContador, David
dc.contributor.authorLoyola, Gloria
dc.contributor.authorPinto, Claudio O.
dc.contributor.authorAmigo, Ludwig
dc.contributor.authorTichauer, Juan E.
dc.contributor.authorZanlungo, Silvana
dc.contributor.authorBronfman, Miguel
dc.date.accessioned2024-01-10T12:07:20Z
dc.date.available2024-01-10T12:07:20Z
dc.date.issued2007
dc.description.abstractPeroxisomal 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 PPAR alpha in vitro and as PPAR alpha 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 PPAR alpha ligands and that the P450 AA monooxygenases participate in ciprofibrate-induced peroxisomal proliferation and the activation of PPAR alpha downstream targets.
dc.fechaingreso.objetodigital2024-05-15
dc.format.extent11 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1194/jlr.M700002-JLR200
dc.identifier.eissn1539-7262
dc.identifier.issn0022-2275
dc.identifier.pubmedidMEDLINE:17234604
dc.identifier.urihttps://doi.org/10.1194/jlr.M700002-JLR200
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/76271
dc.identifier.wosidWOS:000245627100018
dc.information.autorucCiencias Biológicas;Bronfman M;S/I;98819
dc.information.autorucMedicina;Zanlungo S;S/I;72650
dc.issue.numero4
dc.language.isoen
dc.nota.accesocontenido completo
dc.pagina.final934
dc.pagina.inicio924
dc.publisherAMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
dc.revistaJOURNAL OF LIPID RESEARCH
dc.rightsacceso abierto
dc.subjectP450 monooxygenases
dc.subjectomega-hydroxylated-eicosatrienoic acids
dc.subjectperoxisome proliferator-activated receptor alpha
dc.subjectACTIVATED RECEPTOR-ALPHA
dc.subjectACYL-COA OXIDASE
dc.subjectEPOXYEICOSATRIENOIC ACIDS EETS
dc.subjectARACHIDONIC-ACID
dc.subjectFATTY-ACIDS
dc.subjectGENE-EXPRESSION
dc.subjectHYPOLIPIDEMIC DRUGS
dc.subjectCYTOCHROMES P450
dc.subjectRAT-LIVER
dc.subjectBIOCHEMICAL-CHARACTERIZATION
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleP450CYP2C epoxygenase and CYP4A omega-hydroxylase mediate ciprofibrate-induced PPAR alpha-dependent peroxisomal proliferation
dc.typeartículo
dc.volumen48
sipa.codpersvinculados98819
sipa.codpersvinculados72650
sipa.indexWOS
sipa.indexScopus
sipa.trazabilidadCarga SIPA;09-01-2024
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