| Research Abstract |
We used a coactivator-dependent receptor ligand interaction assay (CARLA), which is a semifunctional in vitro assay, to determine whether or not the 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 in the CARLA, and that bezafibrate induced transcriptional activation of PPARα/RXRα. Although the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors cerivastatin and fluvastatin were not ligands for these three nuclear receptors in the CARLA, they induced transcriptional activation of PPARα/RXRα. Moreover, cerivastatin and fluvastatin 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 decreases the transactivation of NF-κB.
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