Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFkappaB.
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Inoue I, Itoh F, Aoyagi S, Tazawa S, Kusama H, Akahane M, Mastunaga T, Hayashi K, Awata T, Komoda T, Katayama S
Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFkappaB.
Biochem Biophys Res Commun. 2002 Jan 11;290(1):131-9.
- PubMed ID
- 11779144 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Clinofibrate Peroxisome proliferator-activated receptor alpha Protein Humans UnknownNot Available Details Clinofibrate Peroxisome proliferator-activated receptor delta Protein Humans UnknownNot Available Details Clinofibrate Peroxisome proliferator-activated receptor gamma Protein Humans UnknownNot Available Details Fenofibric acid Peroxisome proliferator-activated receptor delta Protein Humans UnknownUnknownDetails Fenofibric acid Peroxisome proliferator-activated receptor gamma Protein Humans UnknownNot Available Details Rosiglitazone Peroxisome proliferator-activated receptor alpha Protein Humans UnknownNot Available Details Rosiglitazone Peroxisome proliferator-activated receptor delta Protein Humans UnknownNot Available Details Troglitazone Peroxisome proliferator-activated receptor alpha Protein Humans UnknownNot Available Details Troglitazone Peroxisome proliferator-activated receptor delta Protein Humans UnknownNot Available Details