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胆固醇反向转运与冠心病（CHD）风险相关。它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，但它关注的是全身胆固醇代谢和动态胆固醇转运，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，它尚未在人体中得到充分的测试。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中的反向胆固醇转运。第一个具体目标是改进静脉氘化胆固醇示踪剂的制备，该示踪剂是全身胆固醇代谢研究中的关键限制元素。第二个目标是使用静脉注射示踪剂以及不同的口服示踪剂，将粪便胆固醇分为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道的新合成的胆固醇。测量将在食用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速率一起测量。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。内源性胆固醇排泄分数的变化和相关措施将在临床试验中在依折麦布或安慰剂治疗后确定。这项工作代表了胆固醇研究的新方向，有可能开发出新的补充方法来降低冠心病风险，这些方法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，即血液外的组织胆固醇。了解个体拥有多少胆固醇以及他们排泄胆固醇的效率是该应用程序的根本目的。这些知识将使我们能够考虑新的治疗方法，这些治疗方法可以与降低血液胆固醇一起发挥作用，从而降低心脏病风险。