title: Statin induction of liver fatty acid-binding protein (L-FABP) gene expression is peroxisome proliferator-activated receptor-alpha-dependent.
abstract: 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 PPARalpha 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 PPARalpha-null animals demonstrating the direct implication of PPARalpha in L-FABP regulation by statin treatment. Statin treatment resulted in a rise in PPARalpha mRNA levels both in vitro and in vivo and activated the mouse PPARalpha promoter in a reporter assay. Altogether, these data demonstrate that L-FABP expression is up-regulated by statins through a mechanism involving PPARalpha. Moreover, PPARalpha might be a statin target gene. These effects might contribute to the triglyceride/non-esterified fatty acid-lowering properties of statins.
authors.affiliation: Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation, UMR 5170 Centre Europeen des Sciences du Gout CNRS/Institut National de la Recherche Agronomique/Université de Bourgogne, F-21000 Dijon, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Landrier
authors.forename: Charles
authors.initials: C
authors.lastname: Thomas
authors.forename: Jacques
authors.initials: J
authors.lastname: Grober
authors.forename: Hélène
authors.initials: H
authors.lastname: Duez
authors.forename: Frédéric
authors.initials: F
authors.lastname: Percevault
authors.forename: Maâmar
authors.initials: M
authors.lastname: Souidi
authors.forename: Christine
authors.initials: C
authors.lastname: Linard
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Philippe
authors.initials: P
authors.lastname: Besnard
mesh_terms: D000818:Animals; D001483:Base Sequence; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000235:genetics*; D050556:Fatty Acid-Binding Proteins; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D047493:PPAR alpha / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; C493319:FABP1 protein, human; C493320:Fabp1 protein, mouse; C493321:Fabp1 protein, rat; D050556:Fatty Acid-Binding Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047493:PPAR alpha; D011743:Pyrimidines; D012333:RNA, Messenger; C006253:pirinixic acid; D019821:Simvastatin