Statin induction of liver fatty acid-binding protein (L-FABP) gene expression is peroxisome proliferator-activated receptor-alpha-dependent

• Published in: The Journal of biological chemistry Vol. 279; no. 44; pp. 45512 - 45518
• Main Authors: Landrier, Jean-François, Thomas, Charles, Grober, Jacques, Duez, Hélène, Percevault, Frédéric, Souidi, Maâmar, Linard, Christine, Staels, Bart, Besnard, Philippe
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 29.10.2004
• Subjects: Animals; Base Sequence; Caco-2 Cells; Carrier Proteins - genetics; Fatty Acid-Binding Proteins; Food and Nutrition; Gene Expression Regulation - drug effects; Hepatocytes - metabolism; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Life Sciences; Mice; Molecular Sequence Data; PPAR alpha - genetics; PPAR alpha - physiology; Promoter Regions, Genetic; Pyrimidines - pharmacology; Rats; RNA, Messenger - analysis; Simvastatin - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M407461200

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.