Statins increase cytochrome P450 4F3-mediated eicosanoids production in human liver cells: A PXR dependent mechanism
| Autor: | Yolande Amet, Emmanuelle Plée-Gautier, Sophie Goulitquer, Catherine Le Jossic-Corcos, Brigitte Simon, Joseph Antoun, Laurent Corcos, Jean-Pierre Salaün |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Receptors
Steroid Statin medicine.drug_class Mevalonic Acid Peroxisome proliferator-activated receptor Pharmacology Retinoid X receptor Biochemistry Cytochrome P-450 Enzyme System Cell Line Tumor Coenzyme A Ligases Hydroxyeicosatetraenoic Acids medicine Humans Cytochrome P450 Family 4 Lovastatin RNA Messenger RNA Small Interfering Promoter Regions Genetic Sterol Regulatory Element Binding Proteins chemistry.chemical_classification Pregnane X receptor Apolipoprotein A-I biology Pregnane X Receptor Cytochrome P450 Lipid metabolism Sterol regulatory element-binding protein Cholesterol Liver chemistry Enzyme Induction Gene Knockdown Techniques biology.protein Eicosanoids lipids (amino acids peptides and proteins) Hydroxymethylglutaryl-CoA Reductase Inhibitors medicine.drug |
| Zdroj: | Biochemical Pharmacology. 84:571-579 |
| ISSN: | 0006-2952 |
| Popis: | In the present study, the ability of lovastatin, a competitive inhibitor of HMG-CoA reductase, to regulate the gene expression and function of Cytochrome P450 4F3B (CYP4F3B) was examined in the well differentiated HepaRG human hepatoma cell line. Statins induced CYP4F3B mRNA, protein and the production of 20-hydroxyeicosatetraenoic acid (20-HETE), a product of arachidonic acid metabolism and a peroxisome proliferator activated receptor (PPAR) ligand. This response was not dependent on cholesterol shortage or on sterol regulatory element binding protein activation. By both a pharmacological and a siRNA approaches, we demonstrated that recruitment of the Pregnane X Receptor (PXR) was required to mediate CYP4F3 induction by lovastatin. Furthermore, the CYP4F3 gene promoter was transcriptionally activated by PXR, and responded to lovastatin. Finally, the expression of fatty acid-responsive genes was increased in response to the statin or 20-HETE in a CYP4F3-dependent way. We propose that metabolites produced by CYP4F3 could modulate lipid metabolism in response to lovastatin. These results suggest the existence of a novel pathway, operating in liver cells, through which statins could lower lipid levels. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect