Center for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Pharmacogenet Genomics. 2011 Nov;21(11):741-50. doi: 10.1097/FPC.0b013e32834a5585.
With particular emphasis on interactions between cholesterol homeostasis and drug metabolism we investigate the transcriptome of human primary hepatocytes treated by two commonly prescribed cholesterol lowering drugs atorvastatin and rosuvastatin and by rifampicin that serves as an outgroup as well as a model substance for induction of nuclear pregnane X receptor.
Hepatocytes from human donors have been treated with rosuvastatin, atorvastatin, and rifampicin for 12, 24, and 48 h. Expression profiling with cholesterol and drug metabolism enriched low density Steroltalk cDNA and whole genome Affymetrix HG-U133 Plus 2.0 arrays has been applied. Differential expression (DE) of genes and gene set enrichment analysis of KEGG pathways were performed. Lists of differentially expressed genes and gene sets were cross-compared. Selected genes were confirmed by quantitative real-time PCR.
Statins lead to: (a) upregulation of cholesterol-related genes indicating an increased LDL uptake and storage of esterified cholesterol, elevated bile acid/drug export and lower capacity to form HDL; (b) perturbation of genes in glucose and fatty acid homeostasis, influencing acetyl-CoA pools, promoting gluconeogenesis and glucose export; (c) elevated expression of ADIPOR2 suggesting increased sensitivity to adiponectin; (d) perturbations in genes of lipoprotein particle formation, differently for each statin; (e) perturbed expression of many metabolic genes that are directly controlled by nuclear receptors constitutive androstan and/or pregnane X.
These data provide a novel global insight into hepatic effects of statins, offering biochemical explanations for higher blood glucose in statin-treated patients, and for drug-induced secondary fatty liver disease.
特别强调胆固醇稳态与药物代谢之间的相互作用，我们研究了人原代肝细胞在两种常用降胆固醇药物阿托伐他汀和瑞舒伐他汀以及利福平（作为分组药物以及核孕烷 X 受体诱导的模型物质）处理后的转录组。
用人源供体的原代肝细胞，用瑞舒伐他汀、阿托伐他汀和利福平处理 12、24 和 48 小时。应用胆固醇和药物代谢物富集低密度甾醇 cDNA 和全基因组 Affymetrix HG-U133 Plus 2.0 芯片进行表达谱分析。对基因的差异表达（DE）和 KEGG 途径的基因集富集分析进行了分析。对差异表达基因列表和基因集进行了交叉比较。通过定量实时 PCR 验证了选定的基因。
他汀类药物导致：（a）胆固醇相关基因的上调，表明 LDL 摄取和酯化胆固醇的储存增加，胆汁酸/药物的外排增加，形成 HDL 的能力降低；（b）葡萄糖和脂肪酸稳态的基因受到干扰，影响乙酰辅酶 A 池，促进糖异生和葡萄糖输出；（c）ADIPOR2 基因的表达升高，表明对脂联素的敏感性增加；（d）不同的他汀类药物对脂蛋白颗粒形成的基因产生干扰；（e）许多代谢基因的表达受到干扰，这些基因直接受核受体组成型雄烷和/或孕烷 X 控制。
这些数据为他汀类药物对肝脏的影响提供了新的全面认识，为他汀类药物治疗患者的血糖升高和药物引起的继发性脂肪肝提供了生化解释。
