Statins increase cytochrome P450 4F3-mediated eicosanoids production in human liver cells: a PXR dependent mechanism.
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.
INSERM U613-ECLA, Faculté de Médecine, Université de Bretagne Occidentale, 29238 Brest, France. emmanuelle.plee-gautier@univ-brest.fr
Emmanuelle
E
Plée-Gautier
Joseph
J
Antoun
Sophie
S
Goulitquer
Catherine
C
Le Jossic-Corcos
Brigitte
B
Simon
Yolande
Y
Amet
Jean-Pierre
JP
Salaün
Laurent
L
Corcos
D016632:Apolipoprotein A-I / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000494:pharmacology; D003066:Coenzyme A Ligases / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D000072470:Cytochrome P450 Family 4; D015777:Eicosanoids / Q000096:biosynthesis*; D004790:Enzyme Induction; D055785:Gene Knockdown Techniques; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000235:genetics; D011987:Receptors, Steroid / Q000378:metabolism*; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism
D016632:Apolipoprotein A-I; D015777:Eicosanoids; D006893:Hydroxyeicosatetraenoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011987:Receptors, Steroid; D051779:Sterol Regulatory Element Binding Proteins; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D008148:Lovastatin; D000072470:Cytochrome P450 Family 4; C465349:CYP4F3 protein, human; D003066:Coenzyme A Ligases; D008798:Mevalonic Acid