REVERSE CHOLESTEROL TRANSPORT IN HUMANS

项目摘要 这一提议的中心假设是，胆固醇的反向运输与冠心病有关 (CHD)风险。这是对他汀类药物减少胆固醇生物合成这一概念的补充 预防CHD，但它侧重于全身胆固醇代谢和动态胆固醇转运 而不是循环脂蛋白的静态水平。尽管这是一个古老的想法，但它还没有得到充分的检验 在人类身上，因为缺乏合适的方法。在这项提案中，我们将应用创新的稳定同位素和 研究人体胆固醇反向转运的质谱学技术。第一个具体目标 是为了改进静脉注射氚胆固醇示踪剂的制备，这是研究中的一个关键限制因素 全身的胆固醇新陈代谢。第二个目标是使用静脉示踪剂，以及不同的 口服示踪剂，将粪便胆固醇分解为排泄的内源性胆固醇，未吸收的饮食胆固醇 以及来自肝脏和肠道的新合成的胆固醇。测量将在以下时间进行 新陈代谢厨房提供的控制饮食的消费。快速混合体的水池大小 胆固醇池将与胆固醇分解代谢的分数一起测量。这些直接 胆固醇反向转运的措施将与血浆生物标记物和代谢相关 协变量。胆固醇的反向转运与颈动脉内膜-中层厚度的关系将被确定。 第三个具体目标将使用类似的方法来研究这种广泛使用的药物的作用机制。 依泽替米布。将确定内源性胆固醇排泄分数的变化和相关措施 在临床试验中接受依折麦布或安慰剂治疗后。这项工作代表了胆固醇研究的新方向 有潜力开发降低冠心病风险的新的补充方法的研究 加上饮食和他汀类药物治疗。

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.