Fibrate and Statin Synergistically Increase the Transcriptional Activities of PPARα/RXRα and Decrease the Transactivation of NFκB

In this study, we used a coactivator-dependent receptor–ligand interaction assay (CARLA), which is a semifunctional in vitro assay, to determine whether hypolipidemic drugs are ligands for the three peroxisome proliferator-activated receptor isotypes (PPARα, δ, and γ). We also evaluated the transcriptional activities of the three PPAR isotypes by transient transfection assays. We found that bezafibrate was a ligand for PPARα, δ, and γ in the CARLA and that bezafibrate induced transcriptional activation of PPARα/RXRα, PPARδ/RXRα, and PPARγ/RXRα. Although the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors cerivastatin, fluvastatin, and pitavastatin were not ligands for these three nuclear receptors in the CARLA, they induced transcriptional activation of PPARα/RXRα, PPARδ/RXRα, and PPARγ2/RXRα. Moreover, cerivastatin, fluvastatin, and pitavastatin synergistically and dose-dependently increased the transcriptional activation of PPARα/RXRα induced by bezafibrate. In addition, the cerivastatin-induced transcriptional activation of PPARα/RXRα was decreased by addition of mevalonate, farnesol, geranylgeraniol, or cholesterol and by co-transfection with sterol regulatory element-binding protein-1 (SREBP-1). Moreover, concomitant administration of statins and fibrates also decreased the transactivation of nuclear factor κB (NFκB) and the activation of NFκB by mitogen-activated protein kinase kinase kinase (MEKK) also decreased the transactivation of PPARα/RXRα.