期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 290, 期 1, 页码 131-139出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1006/bbrc.2001.6141
关键词
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin); fibrate; coactivator-dependent receptor-ligand interaction assay (CARLA); cAMP-response element-binding protein (CREB)-binding protein (CBP/p300); bezafibrate; peroxisome proliferator-activated receptor alpha (PPAR alpha); sterol regulatory element-binding protein-1 (SREBP-1); nuclear factor kappa B (NF kappa B)
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 PPARa, 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. (C) 2002 Elsevier Science.
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