Chan Jeannie, Kushwaha Rampratap S, Vandeberg Jane F, Vandeberg John L
Department of Genetics and Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, TX 78245-0549, USA.
Metabolism. 2008 Dec;57(12):1645-54. doi: 10.1016/j.metabol.2008.07.019.
Partially inbred lines of laboratory opossums differ in plasma low-density lipoprotein cholesterol concentration and cholesterol absorption on a high-cholesterol diet. The aim of the present studies was to determine whether ezetimibe inhibits cholesterol absorption and eliminates the differences in plasma cholesterol and hepatic cholesterol metabolism between high and low responders on a high-cholesterol diet. Initially, we determined that the optimum dose of ezetimibe was 5 mg/(kg d) and treated 6 high- and 6 low-responding opossums with this dose (with equal numbers of controls) for 3 weeks while the opossums consumed a high-cholesterol and low-fat diet. Plasma and low-density lipoprotein cholesterol concentrations decreased significantly (P < .05) in treated but not in untreated high-responding opossums. Plasma cholesterol concentrations increased slightly (P < .05) in untreated low responders but not in treated low responders. The percentage of cholesterol absorption was significantly higher in untreated high responders than in other groups. Livers from high responders with or without treatment were significantly (P < .01) heavier than livers from low responders with or without treatment. Hepatic cholesterol concentrations in untreated high responders were significantly (P < .05) higher than those in low responders with or without treatment (P < .001). The gall bladder bile cholesterol concentrations in untreated high responders were significantly (P < .05) lower than those in other groups. A decrease in biliary cholesterol in low responders treated with ezetimibe was associated with a decrease in hepatic expression of ABCG5 and ABCG8. These studies suggest that ezetimibe decreases plasma cholesterol levels in high responders mainly by decreasing cholesterol absorption and increasing biliary cholesterol concentrations. Because ezetimibe's target is NPC1L1 and NPC1L1 is expressed in the intestine of opossums, its effect on cholesterol absorption may be mediated by inhibiting NPC1L1 function in the intestine.
实验室负鼠的部分近交系在高胆固醇饮食下，血浆低密度脂蛋白胆固醇浓度和胆固醇吸收存在差异。本研究的目的是确定依泽替米贝是否能抑制胆固醇吸收，并消除高胆固醇饮食下高反应者和低反应者之间血浆胆固醇及肝脏胆固醇代谢的差异。最初，我们确定依泽替米贝的最佳剂量为5毫克/（千克·天），并以该剂量治疗6只高反应负鼠和6只低反应负鼠（每组有相同数量的对照），持续3周，期间负鼠食用高胆固醇和低脂肪饮食。治疗后的高反应负鼠血浆和低密度脂蛋白胆固醇浓度显著降低（P <.05），而未治疗的高反应负鼠则无此变化。未治疗的低反应负鼠血浆胆固醇浓度略有升高（P <.05），而治疗后的低反应负鼠则无此变化。未治疗的高反应负鼠的胆固醇吸收百分比显著高于其他组。无论是否接受治疗，高反应负鼠的肝脏重量均显著（P <.01）高于低反应负鼠的肝脏。未治疗的高反应负鼠肝脏胆固醇浓度显著（P <.05）高于接受或未接受治疗的低反应负鼠（P <.001）。未治疗的高反应负鼠胆囊胆汁胆固醇浓度显著（P <.05）低于其他组。依泽替米贝治疗的低反应负鼠胆汁胆固醇的降低与ABCG5和ABCG8肝脏表达的降低有关。这些研究表明，依泽替米贝主要通过降低胆固醇吸收和增加胆汁胆固醇浓度来降低高反应者的血浆胆固醇水平。由于依泽替米贝的靶点是NPC1L1，且NPC1L1在负鼠肠道中表达，其对胆固醇吸收的影响可能是通过抑制肠道中NPC1L1的功能来介导的。
