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Journal of Lipid Research, Vol. 49, 2135-2141, October 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

CYP4F3B is induced by PGA₁ in human liver cells: a regulation of the 20-HETE synthesis

Joseph Antoun^*, Sophie Goulitquer^*, Yolande Amet^*, Yvonne Dreano^*, Jean-Pierre Salaun^*,, Laurent Corcos^*, and Emmanuelle Plée-Gautier^1,*

^* Equipe d'Accueil-948, Faculté de Médecine, Université de Bretagne Occidentale, 29238 Brest, France
Centre National de la Recherche Scientifique - Unité Mixte de Recherche 7139 Station Biologique, 29682 Roscoff, Cedex, France
INSERM U-613, Faculté de Médecine, 29238 Brest, France

J.A. was supported by a fellowship from the Conseil Régional de Bretagne. This study has been conducted under the Programme de Recherche d'Intérêt Régional (n° A3CBL9) from the Conseil Régional de Bretagne (France) and supported by the Ministère de l'Education Nationale de l'Enseignement Supérieur et de la Recherche, the medical Faculty, the University Hospital and the University of Brest, the INSERM, and the Ligue Régionale Contre le Cancer.

Published, JLR Papers in Press, June 19, 2008.

¹ To whom correspondence should be addressed. e-mail: emmanuelle.plee-gautier{at}univ-brest.fr

The regulation of the human liver-specific cytochrome P450 4F3B (CYP4F3B) isoform, a splice variant of the CYP4F3 gene with strong substrate specificity for long chain fatty acids, is yet an unsolved question. This report provides the first evidence that CYP4F3B is uniquely induced by prostaglandin A₁ (PGA₁) in human hepatocyte-like HepaRG cells and leads to the synthesis of 20-hydroxy-eicosatetraenoic acids (HETEs). Real time PCR, immunoblot analysis with a specific antipeptide antibody, and determination of fatty acid -hydroxylase activity demonstrate that PGA₁ treatment strongly increases expression of CYP4F3B. This induction drives the production of 20-HETE (19-fold increase). SiRNA-mediated-silencing of CYP4F3 suppresses both 20-HETE synthesis and PGA₁ induced 20-HETE production. Taken together, these results provide evidence that CYP4F3B is the key enzyme to produce 20-HETE by -hydroxylation of arachidonic acid in liver cells. Since 20-HETE is a potent activator of PPAR and an important inflammatory mediator, CYP4F3B may exert important functions in lipid homeostasis and in inflammatory diseases.

Supplementary key words cytochrome P450 • human hepatoma cells • HepaRG • fatty acid hydroxylase • prostaglandin • inflammation

Abbreviations: AA, arachidonic acid; CYP, cytochrome P450; EET, epoxyeicosatrienoic acid; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HETE, hydroxy-eicosatetraenoic acids; LTB4, leukotriene B4; NICI, negative ion chemical ionization; PG, prostaglandin; PPAR, peroxisome proliferator-activated receptor; SIM, single ion monitoring; Z9(10)-EpSTA, 9,10-epoxystearic acid

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