Statins Activate Human PPAR<i>α</i> Promoter and Increase PPAR<i>α</i> mRNA Expression and Activation in HepG2 Cells

Abstract

Statins increase peroxisome proliferator-activated receptor alpha (PPARalpha) mRNA expression, but the mechanism of this increased PPARalpha production remains elusive. To examine the regulation of PPARalpha production, we examined the effect of 7 statins (atorvastatin, cerivastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) on human PPARalpha promoter activity, mRNA expression, nuclear protein levels, and transcriptional activity. The main results are as follows. (1) Majority of statins enhanced PPARalpha promoter activity in a dose-dependent manner in HepG2 cells transfected with the human PPARalpha promoter. This enhancement may be mediated by statin-induced HNF-4alpha. (2) PPARalpha mRNA expression was increased by statin treatment. (3) The PPARalpha levels in nuclear fractions were increased by statin treatment. (4) Simvastatin, pravastatin, and cerivastatin markedly enhanced transcriptional activity in 293T cells cotransfected with acyl-coenzyme A oxidase promoter and PPARalpha/RXRalpha expression vectors. In summary, these data demonstrate that PPARalpha production and activation are upregulated through the PPARalpha promoter activity by statin treatment.