Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFkappaB

• Published in: Biochemical and biophysical research communications 2002-01, Vol.290 (1), p.131
• Main Authors: Inoue, Ikuo, Itoh, Fumiaki, Aoyagi, Shigemi, Tazawa, Shigeki, Kusama, Hiroshi, Akahane, Masuo, Mastunaga, Toshiyuki, Hayashi, Kenji, Awata, Takuya, Komoda, Tugikazu, Katayama, Sigehiro
• Format: Article
• Language: English
• Subjects: Anticholesteremic Agents - pharmacology; Bezafibrate - pharmacology; Blotting, Western; CCAAT-Enhancer-Binding Proteins - metabolism; Cell Nucleus - metabolism; DNA, Complementary - metabolism; DNA-Binding Proteins - metabolism; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors - pharmacology; Fatty Acids, Monounsaturated - pharmacology; Gene Library; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hypolipidemic Agents - pharmacology; Indoles - pharmacology; Ligands; Liver - metabolism; Mitogen-Activated Protein Kinase Kinases - metabolism; Models, Biological; Muscle, Skeletal - metabolism; NF-kappa B - metabolism; Nuclear Proteins - metabolism; Protein Structure, Tertiary; Pyridines - pharmacology; Quinolines - pharmacology; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Retinoic Acid - metabolism; Recombinant Fusion Proteins - metabolism; Retinoid X Receptors; Sequence Analysis, DNA; Sterol Regulatory Element Binding Protein 1; Trans-Activators - metabolism; Transcription Factors - metabolism; Transcription, Genetic; Transcriptional Activation; Transfection
• ISSN: 0006-291X

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 (PPARalpha, delta, and gamma). We also evaluated the transcriptional activities of the three PPAR isotypes by transient transfection assays. We found that bezafibrate was a ligand for PPARalpha, delta, and gamma in the CARLA and that bezafibrate induced transcriptional activation of PPARalpha/RXRalpha, PPARdelta/RXRalpha, and PPARgamma/RXRalpha. 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 PPARalpha/RXRalpha, PPARdelta/RXRalpha, and PPARgamma2/RXRalpha. Moreover, cerivastatin, fluvastatin, and pitavastatin synergistically and dose-dependently increased the transcriptional activation of PPARalpha/RXRalpha induced by bezafibrate. In addition, the cerivastatin-induced transcriptional activation of PPARalpha/RXRalpha 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 kappaB (NFkappaB) and the activation of NFkappaB by mitogen-activated protein kinase kinase kinase (MEKK) also decreased the transactivation of PPARalpha/RXRalpha.