REVERSE CHOLESTEROL TRANSPORT IN HUMANS

项目摘要 这项提议的中心假设是胆固醇逆向转运与冠心病有关 (CHD)风险这是补充的概念，减少胆固醇的生物合成与他汀类药物 预防冠心病，但它侧重于全身胆固醇代谢和胆固醇动力学运输， 而不是稳定的循环脂蛋白水平。虽然这是一个古老的想法，但还没有经过充分的检验 因为缺乏合适的方法。在这项提案中，我们将采用创新的稳定同位素， 质谱技术，以研究人类受试者的胆固醇逆向转运。第一个具体目标 是改进静脉注射氘代胆固醇示踪剂的制备，这是研究中的关键限制因素 胆固醇的代谢。第二个目的是使用静脉内示踪剂，沿着不同的 口服示踪剂，将粪便胆固醇分成排泄的内源性胆固醇、未吸收的膳食胆固醇 以及来自肝脏和肠道的新合成胆固醇。测量将在 由代谢厨房提供的受控饮食的消费。快速混合体的池尺寸 胆固醇池将沿着胆固醇催化剂的分数率进行测量。这些直接 胆固醇逆向转运的测量将与血浆生物标志物和代谢相关性相关联。 协变量将确定胆固醇逆向转运与颈动脉内膜中层厚度的关系。 第三个具体目标将使用类似的方法来研究广泛使用的药物的作用机制 依折麦布。将测定内源性胆固醇排泄分数和相关指标的变化 在临床试验中，依折麦布或安慰剂治疗后。这项工作代表了胆固醇的新方向 研究有可能开发新的和补充的方法来降低CHD风险， 添加到饮食和他汀类药物治疗中。

Project Summary The central hypothesis of this proposal is that reverse cholesterol transport is related to coronary heart disease (CHD) risk. It is complementary to the concept that reduction of cholesterol biosynthesis with statin drugs prevents CHD, but it focuses on whole body cholesterol metabolism and kinetic cholesterol transport rather than on static levels of circulating lipoproteins. Although this is an old idea, it has not been adequately tested in humans because of lack of suitable methods. In this proposal we will apply innovative stable isotope and mass spectroscopic technology to study reverse cholesterol transport in human subjects. The first specific aim is to improve the preparation of intravenous deuterated cholesterol tracer, a critical limiting element in the study of whole body cholesterol metabolism. The second aim is to use that intravenous tracer, along with a different oral tracer, to partition fecal cholesterol into excreted endogenous cholesterol, unabsorbed dietary cholesterol and newly-synthesized cholesterol derived from the liver and intestine. Measurements will be made during consumption of a controlled diet provided by the metabolic kitchen. The pool size of the rapidly-mixing body cholesterol pool will be measured along with the fractional rate of cholesterol catabolism. These direct measures of reverse cholesterol transport will be correlated with plasma biomarkers and with metabolic covariates. The relation of reverse cholesterol transport to carotid intima-media thickness will be determined. The third specific aim will use similar methods to study the mechanism of action for the widely-used drug ezetimibe. Changes in fractional endogenous cholesterol excretion and related measures will be determined after ezetimibe or placebo treatment in a clinical trial. This work represents a new direction for cholesterol research with the potential to develop new and complementary methods of reducing CHD risk that can be added to diet and statin drug treatment.