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J. Biol. Chem., Vol. 279, Issue 44, 45512-45518, October 29, 2004

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Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor--dependent^*

Jean-François Landrier, Charles Thomas, Jacques Grober, Hélène Duez, Frédéric Percevault, Maâmar Souidi¶, Christine Linard¶, Bart Staels, and Philippe Besnard||

From the Physiologie de la Nutrition, Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation (ENSBANA), UMR 5170 Centre Europeen des Sciences du Gout CNRS/Institut National de la Recherche Agronomique/Université de Bourgogne, 1 Esplanade Erasme, F-21000, Dijon, France, UR545 INSERM, Institut Pasteur de Lille, 1 Rue Calmette, F-59019, and Faculté de Pharmacie, Université de Lille 2, Lille, France, and ^¶Institut de Radioprotection, Département de RadioProtection de l'Homme, Institut de Radioprotection et de Surete Nucleaire B.P. N° 17, F-92262, Fontenay-aux-Roses Cedex, France

Statins are drugs widely used in humans to treat hypercholesterolemia. Statins act by inhibiting cholesterol synthesis resulting in the activation of the transcription factor sterol-responsive element-binding protein-2 that controls the expression of genes involved in cholesterol homeostasis. Statin therapy also decreases plasma triglyceride and non-esterified fatty acid levels, but the mechanism behind this effect remains more elusive. Liver fatty acid-binding protein (L-FABP) plays a role in the influx of long-chain fatty acids into hepatocytes. Here we show that L-FABP is a target for statins. In rat hepatocytes, simvastatin treatment induced L-FABP mRNA levels in a dose-dependent manner. Moreover, L-FABP promoter activity was induced by statin treatment. Progressive 5'-deletion analysis revealed that the peroxisome proliferator-activated receptor (PPAR)-responsive element located at position –67/–55 was responsible for the statin-mediated transactivation of the rat L-FABP promoter. Moreover, treatment with simvastatin and the PPAR agonist Wy14,649 resulted in a synergistic induction of L-FABP expression (mRNA and protein) in rat Fao hepatoma cells. This effect was also observed in vivo in wild-type mice but not in PPAR-null animals demonstrating the direct implication of PPAR in L-FABP regulation by statin treatment. Statin treatment resulted in a rise in PPAR mRNA levels both in vitro and in vivo and activated the mouse PPAR promoter in a reporter assay. Altogether, these data demonstrate that L-FABP expression is up-regulated by statins through a mechanism involving PPAR. Moreover, PPAR might be a statin target gene. These effects might contribute to the triglyceride/non-esterified fatty acid-lowering properties of statins.

Received for publication, July 6, 2004 , and in revised form, August 25, 2004.

^* This work was supported by funds from the Conseil Régional de Bourgogne (to P. B.) and the Leducq Foundation (to B. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Physiologie de la Nutrition, ENSBANA, 1 Esplanade Erasme, F-21000 Dijon, France. Tel./Fax: 33-03-80-39-66-91; E-mail: pbesnard{at}u-bourgogne.fr.

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