REVERSE CHOLESTEROL TRANSPORT IN HUMANS

人体中的胆固醇反向转运

• 批准号: 8238613
• 负责人: RICHARD E. OSTLUND
• 金额: $ 55.49万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8238613
• 关键词: Address; Affect; Animals; Bile Acids; Biochemical; Biological Assay; Biological Markers; Blood; Blood Circulation; Catabolism; Cholesterol; Cholesterol Homeostasis; Clinical Trials; Complex; Consumption; Coronary heart disease; Data; Diet; Dietary Cholesterol; Disease Outcome; Double-Blind Method; Drug effect disorder; Drug usage; Epidemiology; Excretory function; Fat emulsion; Filtration; Future; Heart Diseases; Human; In Vitro; Indium; Individual; Institutional Review Boards; Intestines; Intravenous; Ions; Kinetics; Knowledge; Label; Laboratories; Lead; Lipoproteins; Liver; Low-Density Lipoproteins; Mass Spectrum Analysis; Measurement; Measures; Metabolic; Methods; Missouri; Oral; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Pharmacy facility; Phytosterols; Placebo Control; Placebos; Plasma; Preparation; Public Health; Publishing; Randomized; Regulation; Reporting; Research; Steroids; Sterols; Technology; Testing; Therapeutic; Thick; Tissues; Tracer; Translating; Work; cholesterol absorption; cholesterol biosynthesis; clinically relevant; ezetimibe; heart disease risk; human subject; improved; innovation; innovative technologies; intima media; novel; prevent; reverse cholesterol transport; stable isotope; tool

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.

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。这与他汀类药物减少胆固醇生物合成预防冠心病的概念是互补的，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。虽然这是一个古老的想法，但由于缺乏合适的方法，它尚未在人体中进行充分的测试。在本提案中，我们将应用创新的稳定同位素和质谱技术来研究人类受试者的逆向胆固醇转运。第一个具体目的是改进静脉内氘化胆固醇示踪剂的制备，这是研究全身胆固醇代谢的关键限制因素。第二个目标是使用静脉示踪剂和另一种口服示踪剂，将粪便胆固醇分解为排出的内源性胆固醇、未吸收的膳食胆固醇和来自肝脏和肠道的新合成胆固醇。测量将在代谢厨房提供的控制饮食中进行。快速混合体胆固醇池的池大小将与胆固醇分解代谢的分数率一起测量。这些反向胆固醇运输的直接测量将与血浆生物标志物和代谢协变量相关。将确定逆向胆固醇转运与颈动脉内膜-中膜厚度的关系。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。依折替米贝或安慰剂治疗后，内源性胆固醇排泄量的变化及相关措施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，有可能开发出新的和补充的方法来降低冠心病的风险，这些方法可以添加到饮食和他汀类药物治疗中。