REVERSE CHOLESTEROL TRANSPORT IN HUMANS

描述(由申请人提供)：这项建议的中心假设是胆固醇的反向运输与冠心病(CHD)的风险有关。它补充了他汀类药物减少胆固醇生物合成预防冠心病的概念，但它侧重于全身胆固醇代谢和动态胆固醇运输，而不是循环脂蛋白的静态水平。尽管这是一个古老的想法，但由于缺乏合适的方法，它还没有在人体上进行充分的测试。在这项提案中，我们将应用创新的稳定同位素和质谱学技术来研究人体内胆固醇的反向运输。第一个特别的目标是改进静脉注射氚胆固醇示踪剂的制备方法，该示踪剂是研究全身胆固醇代谢的关键限制因素。第二个目的是使用静脉示踪剂和不同的口服示踪剂，将粪便胆固醇划分为排泄的内源性胆固醇、未被吸收的饮食胆固醇和来自肝脏和肠道的新合成的胆固醇。测量将在新陈代谢厨房提供的受控饮食期间进行。快速混合的体内胆固醇池的大小将与胆固醇分解代谢的分数一起测量。这些反向胆固醇转运的直接测量将与血浆生物标记物和代谢协变量相关。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广泛使用的药物依折麦布的作用机制。Ezetimibe或安慰剂治疗后，内源性胆固醇排泄分数和相关措施的变化将在临床试验中确定。这项工作代表了胆固醇研究的新方向，有可能开发新的和补充的方法来降低CHD风险，这些方法可以添加到饮食和他汀类药物治疗中。 与公共健康相关：胆固醇是心脏病的重要原因。大多数与胆固醇相关的项目只关注循环血液中的胆固醇。在这里，我们将研究全身胆固醇，包括最大的部分，也就是血液之外的组织胆固醇。了解个人拥有多少胆固醇以及他们排泄胆固醇的效率是这项应用的根本目的。这一知识将使人们能够考虑新的治疗方法，在降低血液胆固醇的同时降低心脏病风险。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Cholesterol is an important cause of heart disease. Most cholesterol-related projects focus only on circulating blood cholesterol. Here we will study whole body cholesterol, including the largest portion, which is tissue cholesterol outside the bloodstream. Understanding how much cholesterol individuals possess and how efficiently they excrete it is the underlying purpose of this application. This knowledge will allow consideration of new treatments that can work alongside reduction of blood cholesterol to lower heart disease risk.