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Statin induction of Liver Fatty Acid-Binding Protein (L-FABP) gene expression is peroxisome proliferator-activated receptor-- dependent.

 Jean-François Landrier, Charles Thomas, Jacques Grober, Hélène Duez, Frédéric Percevault, Maâmar Souidi, Christine Linard, Bart Staels and Philippe Besnard1The Journal of Biological Chemistry 2004;279: 45512-45518)

Document type > *Article de revue

Keywords > lipids, statine

Research Unit > IRSN/DRPH/SRBE/LRTOX

Authors > LINARD Christine, SOUIDI Maâmar

Publication Date > 01/10/2004

Summary

 Statins are drugs widely used in humans to correct hypercholesterolemia. This action takes place through a cholesterol-mediated activation of the transcription factor sterol responsive element-binding protein-2 leading to changes in expression of genes responsible for cholesterol balance. Statin therapy also improves blood triglyceride (TG) and non esterified fatty acid (NEFA) levels, but the origin of this effect remains more elusive. Since liver fatty acid-binding protein (L-FABP) is known to play a role in influx of long-chain fatty acids into hepatocytes, we hypothesized that it might be a target for statins contributing by this way to the hypolipidemic action of these drugs. In line with this assumption, simvastatin was found to induce L-FABP mRNA levels in rat hepatocytes in dose-dependent manner. Progressive 5’-deletion analysis of rat L-FABP promoter revealed that the peroxisome proliferator-activated receptor (PPAR)-responsive element located in position -67/-55 was responsible for the statin-mediated transactivation of reporter gene. Synergic induction of simvastatin and PPARa agonist Wy14,649 on L-FABP expression (mRNA and protein) was found in rat Fao hepatoma cell line. This effect, reproduced in wild-type mice, was fully abolished in PPARa null animals demonstrating the direct implication of PPARa in this regulation. Statin treatment led to a rise in PPARa mRNA levels both in vitro and in vivo. CAT reporter gene driven by mouse PPARa promoter was transactived by simvastatin. Collectively, these data demonstrated that L-FABP expression is up-regulated by statins via a cascade involving PPARa. They also suggest that PPARa might be a statins target gene what might greatly contribute to the TG/NEFA-lowering properties of these drugs. 

 


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