Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor-α-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.
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Submitted on : Tuesday, December 18, 2018 - 3:22:09 PM
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Jean-François Landrier, Charles Thomas, Jacques Grober, Hélène Duez, Frédéric Percevault, et al.. Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor-α-dependent. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2004, 279 (44), pp.45512-45518. ⟨10.1074/jbc.M407461200⟩. ⟨hal-01959211⟩

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