Statin induction of liver fatty acid-binding protein (L-FABP) gene expression is peroxisome proliferator-activated receptor-alpha-dependent.
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.
Landrier
Jean-François
JF
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.
Thomas
Charles
C
Grober
Jacques
J
Duez
Hélène
H
Percevault
Frédéric
F
Souidi
Maâmar
M
Linard
Christine
C
Staels
Bart
B
Besnard
Philippe
P
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*
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