INSERM U613-ECLA, Faculté de Médecine, Université de Bretagne Occidentale, 29238 Brest, France.
Biochem Pharmacol. 2012 Aug 15;84(4):571-9. doi: 10.1016/j.bcp.2012.05.012. Epub 2012 May 23.
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.
在本研究中，我们考察了洛伐他汀（HMG-CoA 还原酶的竞争性抑制剂）调节细胞色素 P450 4F3B（CYP4F3B）基因表达和功能的能力，该基因在分化良好的 HepaRG 人肝癌细胞系中表达。他汀类药物诱导 CYP4F3B mRNA、蛋白的表达，并产生 20-羟二十碳四烯酸（20-HETE），这是花生四烯酸代谢产物和过氧化物酶体增殖物激活受体（PPAR）配体。该反应不依赖于胆固醇缺乏或固醇调节元件结合蛋白的激活。通过药理学和 siRNA 方法，我们证明了妊娠相关 X 受体（PXR）的募集对于洛伐他汀诱导 CYP4F3B 是必需的。此外，CYP4F3B 基因启动子可被 PXR 转录激活，并对洛伐他汀作出反应。最后，脂肪酸反应基因的表达可通过 CYP4F3B 依赖的方式响应他汀类药物或 20-HETE 增加。我们提出，CYP4F3 产生的代谢物可能会调节肝脏细胞中的脂质代谢以响应洛伐他汀。这些结果表明他汀类药物可能通过一种新的途径降低脂质水平。
