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Papers In Press, published online ahead of print August 27, 2004
Physiologie de la Nutrition, ENSBANA, Dijon 21000
Corresponding Author: pbesnard{at}u-bourgogne.fr
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 (TG) and non-esterified fatty acid (NEFA) 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
J. Biol. Chem, 10.1074/jbc.M407461200
Submitted on July 6, 2004
Revised on August 25, 2004
Accepted on August 27, 2004
Statin induction of liver fatty acid-binding protein (L-FABP) gene expression is PPAR
-dependent
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 TG/NEFA-lowering properties of statins.
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