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. doi: 10.1006/bbrc.2001.6141.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Fluvastatin
  • 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

Substances

  • Anticholesteremic Agents
  • CCAAT-Enhancer-Binding Proteins
  • DNA, Complementary
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Fatty Acids, Monounsaturated
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Hypolipidemic Agents
  • Indoles
  • Ligands
  • NF-kappa B
  • Nuclear Proteins
  • Pyridines
  • Quinolines
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Recombinant Fusion Proteins
  • Retinoid X Receptors
  • SREBF1 protein, human
  • Sterol Regulatory Element Binding Protein 1
  • Trans-Activators
  • Transcription Factors
  • Fluvastatin
  • cerivastatin
  • Mitogen-Activated Protein Kinase Kinases
  • pitavastatin
  • Bezafibrate