REVERSE CHOLESTEROL TRANSPORT IN HUMANS

描述（由申请人提供）：本提案的中心假设是胆固醇逆向转运与冠心病（CHD）风险相关。它是补充的概念，减少胆固醇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，而不是静态水平的循环脂蛋白。虽然这是一个古老的想法，但由于缺乏合适的方法，它尚未在人类中进行充分的测试。在这项提案中，我们将应用创新的稳定同位素和质谱技术来研究人体胆固醇的逆向转运。第一个具体目标是改进静脉内氘代胆固醇示踪剂的制备，这是全身胆固醇代谢研究中的关键限制元素。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和来自肝脏和肠的新合成的胆固醇。将在消耗代谢厨房提供的受控饮食期间进行测量。将沿着测量快速混合体胆固醇样本池的样本池大小以及胆固醇催化剂的分数。这些胆固醇逆向转运的直接测量将与血浆生物标志物和代谢协变量相关。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依折麦布的作用机制。在临床试验中，将测定依折麦布或安慰剂治疗后内源性胆固醇排泄分数和相关指标的变化。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，可以添加到饮食和他汀类药物治疗中。 公共卫生相关性：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胆固醇。在这里，我们将研究全身胆固醇，包括最大的部分，这是血液外的组织胆固醇。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个应用程序的根本目的。这一知识将允许考虑新的治疗方法，可以与降低血液胆固醇一起降低心脏病风险。

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.