Agellon Luis B, Drover Victor A B, Cheema Sukhinder K, Gbaguidi G Franck, Walsh Annemarie
Department of Biochemistry and Canadian Institutes of Health Research Group in Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
J Biol Chem. 2002 Jun 7;277(23):20131-4. doi: 10.1074/jbc.C200105200. Epub 2002 Apr 19.
Dietary cholesterol has been shown to have a stimulatory effect on the murine cholesterol 7alpha-hydroxylase gene (Cyp7a1), but its effect on human cholesterol 7alpha-hydroxylase gene (CYP7A1) expression in vivo is not known. A transgenic mouse strain harboring the human CYP7A1 gene and homozygous for the disrupted murine Cyp7a1 gene was created. Cholesterol feeding increased the expression of the endogenous modified Cyp7a1 allele but failed to stimulate the human CYP7A1 transgene. In transfected hepatoma cells, 25-hydroxycholesterol increased murine Cyp7a1 gene promoter activity, whereas the human CYP7A1 gene promoter was unresponsive. Electrophoretic mobility shift assays demonstrated the interaction of the liver X receptor alpha (LXRalpha): retinoid X receptor (RXR) heterodimer, a transcription factor complex that is activated by oxysterols, with the murine Cyp7a1 gene promoter, whereas no binding to the human CYP7A1 gene promoter was detected. The results demonstrate that the human CYP7A1 gene is not stimulated by dietary cholesterol in the intact animal, and this is attributable to the inability of the CYP7A1 gene promoter to interact with LXRalpha:RXR.
膳食胆固醇已被证明对小鼠胆固醇7α-羟化酶基因（Cyp7a1）有刺激作用，但其对人体胆固醇7α-羟化酶基因（CYP7A1）体内表达的影响尚不清楚。构建了一种携带人CYP7A1基因且小鼠Cyp7a1基因纯合缺失的转基因小鼠品系。喂食胆固醇可增加内源性修饰的Cyp7a1等位基因的表达，但未能刺激人CYP7A1转基因。在转染的肝癌细胞中，25-羟胆固醇可增加小鼠Cyp7a1基因启动子活性，而人CYP7A1基因启动子无反应。电泳迁移率变动分析表明，肝脏X受体α（LXRα）：视黄酸X受体（RXR）异二聚体（一种被氧化甾醇激活的转录因子复合物）与小鼠Cyp7a1基因启动子相互作用，而未检测到与人CYP7A1基因启动子的结合。结果表明，在完整动物中，膳食胆固醇不会刺激人CYP7A1基因，这是由于CYP7A1基因启动子无法与LXRα：RXR相互作用。
