REVERSE CHOLESTEROL TRANSPORT IN HUMANS

人体中的胆固醇反向转运

基本信息

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
项目类别：
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

项目摘要

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）：该提案的中心假设是反向胆固醇转运与冠心病（CHD）风险有关。这是补充的概念，即用他汀类药物降低胆固醇生物合成可以预防冠心病，但它的重点是全身胆固醇代谢和动力学胆固醇的转运，而不是静态的脂蛋白水平。尽管这是一个古老的想法，但由于缺乏合适的方法，它在人类中没有得到充分的测试。在此提案中，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反向胆固醇运输。第一个具体目的是改善静脉内氘化胆固醇示踪剂的制备，这是整个身体胆固醇代谢研究的关键限制元素。第二个目的是将静脉示踪剂与不同的口服示踪剂一起将粪便胆固醇分配为排泄的内源性胆固醇，未吸收的饮食胆固醇和新近共同的胆固醇，这些胆固醇是从肝脏和肠道中衍生而来的。在食用代谢厨房提供的控制饮食期间将进行测量。快速混合体胆固醇池的池尺寸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志物和代谢协变量相关。将确定反向胆固醇转运到颈动脉内膜厚度的关系。第三个特定目的将使用类似的方法研究广泛使用的药物的作用机理。在一项临床试验中，将确定内源性胆固醇排泄和相关措施的变化。这项工作代表了胆固醇研究的一个新方向，有可能开发新的和互补的方法来降低CHD风险，从而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仅着重于循环血液胆固醇。在这里，我们将研究全身胆固醇，包括最大的部分，即血液外的组织胆固醇。了解胆固醇个体拥有多少，以及他们排泄的效率，这是本应用的基本目的。这些知识将允许考虑可以在降低血液胆固醇以降低心脏病风险的同时起作用的新疗法。