REVERSE CHOLESTEROL TRANSPORT IN HUMANS

人体中的胆固醇反向转运

基本信息

批准号：
8403769
负责人：
RICHARD E. OSTLUND
金额：
$ 48.98万
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/8403769
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

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.

项目概要该提案的中心假设是胆固醇反向转运与冠心病有关（冠心病）风险。它补充了用他汀类药物减少胆固醇生物合成的概念预防冠心病，但它更注重全身胆固醇代谢和动态胆固醇转运高于循环脂蛋白的静态水平。虽然这是一个老想法，但还没有经过充分的测试由于缺乏合适的方法而发生在人类身上。在本提案中，我们将应用创新的稳定同位素和质谱技术用于研究人类受试者中胆固醇的反向转运。第一个具体目标是为了改进静脉用氘代胆固醇示踪剂的制备，该示踪剂是该研究中的一个关键限制元素全身胆固醇代谢。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胆固醇、未吸收的膳食胆固醇以及来自肝脏和肠道的新合成的胆固醇。测量将在消耗代谢厨房提供的受控饮食。快速混合体的池大小胆固醇池将与胆固醇分解代谢的分数速率一起测量。这些直接反向胆固醇转运的测量将与血浆生物标志物和代谢相关协变量。将确定反向胆固醇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的作用机制依折麦布。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使用依折麦布或安慰剂治疗后。这项工作代表了胆固醇的新方向研究有可能开发出新的、补充性的降低冠心病风险的方法添加到饮食和他汀类药物治疗中。