Dietary Fat and HDL Metabolism

描述(申请人提供)：膳食脂肪和高密度脂蛋白代谢。营养学和心血管疾病(CVD)中一个悬而未决的问题是如何解释当饮食中不饱和脂肪增加，碳水化合物或蛋白质减少时，高密度脂蛋白浓度的增加。不饱和脂肪的这一明显优势是一些专家喜欢高不饱和脂肪饮食而不是碳水化合物或蛋白质饮食的原因之一。其他专家则不那么有信心，认为提高高密度脂蛋白浓度的治疗干预一定能预防动脉粥样硬化。在营养和健康政策中使用简单的高密度脂蛋白胆固醇变化会让人感到不适。缺乏对潜在生理学的清楚认识干扰了知情的观点。有几种代谢途径可以维持高密度脂蛋白的浓度。目前还不清楚膳食脂肪是如何影响他们的。关键问题是，饮食脂肪是否改善了高密度脂蛋白代谢的步骤，这些步骤涉及防止动脉粥样硬化的胆固醇反向运输。毋庸置疑，高密度脂蛋白是胆固醇运输和体内平衡系统的必要组成部分，低密度脂蛋白浓度是心血管疾病高风险的最强预测因素之一。低高密度脂蛋白胆固醇在超重和肥胖、胰岛素抵抗、2型糖尿病和代谢综合征中尤为突出。这种低的高密度脂蛋白浓度与高密度脂蛋白颗粒从血液循环中加速清除有关，以其主要蛋白质载脂蛋白A-I和小高密度脂蛋白的优势来衡量。这表明，高密度脂蛋白的成熟受阻，从小的胆固醇耗尽颗粒到大的富含胆固醇酯的颗粒，并损害了胆固醇的反向运输。我们不知道饮食中的不饱和脂肪是否能纠正这种高密度脂蛋白代谢紊乱。我们提出了一项临床干预研究，对象是20名在超重或肥胖的典型情况下高密度脂蛋白胆固醇浓度，而血浆甘油三酯高的人，以确定饮食不饱和脂肪如何增加他们的高密度脂蛋白浓度。我们将使用稳定的同位素示踪剂在内源性标记载脂蛋白A-I，这是高密度脂蛋白的定义蛋白，以追踪其从小的新生颗粒(“前β-高密度脂蛋白”)到大的、含胆固醇的成熟颗粒(“α1，2和3高密度脂蛋白”)的代谢，并评估代表肝脏选择性清除胆固醇酯的反向过程的程度。我们将研究饮食脂肪是否减少载脂蛋白C-III在高密度脂蛋白代谢中的作用。有载脂蛋白C-III的高密度脂蛋白与心血管疾病有不良关联，而不含载脂蛋白C-III的主要高密度脂蛋白类型则相反。这一信息将被证明是非常有价值的，可以用来解释饮食脂肪在预防动脉粥样硬化方面已确立的提高高密度脂蛋白的作用。 公共卫生相关性：膳食脂肪和高密度脂蛋白代谢这项建议的目标是确定饮食中的不饱和脂肪增加血液中高密度脂蛋白(高密度脂蛋白)浓度的机制，高密度脂蛋白是一种保护性脂蛋白，可从动脉粥样硬化中清除胆固醇，并降低心血管疾病的风险。该项目是一项对照饮食研究，比较了高不饱和脂肪饮食和高碳水化合物饮食。在每种饮食结束时，将进行人类对高密度脂蛋白的直接代谢研究，以跟踪其代谢。其目标是开发一张关于不饱和脂肪如何提高高密度脂蛋白和预防心血管疾病的详细图片。

DESCRIPTION (provided by applicant): Dietary Fat and HDL Metabolism. A great unanswered question in nutrition and cardiovascular disease (CVD) is how to interpret the increase in HDL cholesterol concentration that occurs when dietary unsaturated fat is increased and carbohydrate or protein is reduced. This apparent advantage of unsaturated fat is one reason why some experts favor high unsaturated fat diets compared to those with carbohydrate or protein. Other experts are not so confident that that a therapeutic intervention that raises HDL concentration invariably protects against atherosclerosis. There is a sense of discomfort using simple changes in HDL cholesterol for nutrition and health policy. Lack of clarity of the underlying physiology interferes with informed opinion. There are several metabolic pathways that can sustain a high HDL concentration. It is unclear how dietary fat affects them. The critical issue is whether dietary fat improves the steps in HDL metabolism that are involved in reverse cholesterol transport that protects against atherosclerosis. HDL is indisputably a necessary component of the cholesterol transport and homeostatic system, and a low HDL concentration is one of the strongest predictors of high risk of CVD. Low HDL cholesterol is prominent in overweight and obesity, insulin resistance, type 2 diabetes, and metabolic syndrome. This low HDL concentration is associated with accelerated clearance from the blood circulation of HDL particles, measured by their principal protein, apolipoprotein A-I, and a preponderance of small HDL. This suggests a block in the maturation of HDL from small cholesterol-depleted to large cholesterol ester-rich particles, and impaired reverse cholesterol transport. We do not know whether dietary unsaturated fat corrects this dysfunctional metabolism of HDL. We propose a clinical intervention study in 20 people who have low HDL cholesterol concentrations in the typical setting of overweight or obesity, and high plasma triglycerides to determine how dietary unsaturated fat increases their HDL concentration. We will use stable isotopic tracers to label endogenously apolipoprotein A-I, the defining protein of HDL, to trace its metabolism from small nascent particles ("pre-beta HDL") to large, cholesterol-loaded mature particles ("alpha 1,2, and 3 HDL"), and evaluate the extent of the reverse process representing selective removal of cholesterol ester by the liver. We will study whether dietary fat reduces the involvement of apolipoprotein C-III in HDL metabolism. HDL that has apoC-III has an adverse association with CVD, opposite to the major HDL type that does not have apoC-III. This information will prove invaluable in interpreting the established HDL-raising effect of dietary fat in terms of protection against atherosclerosis. PUBLIC HEALTH RELEVANCE: Dietary fat and HDL metabolism The goal of this proposal is to determine the mechanisms by which unsaturated fat in the diet increases blood concentrations of high density lipoprotein (HDL), a protective lipoprotein that removes cholesterol from atherosclerosis, and reduces risk of cardiovascular disease. The project is a controlled diet study comparing a high unsaturated fat diet with a high carbohydrate diet. Direct metabolic studies of HDL in humans that trace its metabolism will be conducted at the end of each diet. The goal is to develop a detailed picture of how unsaturated fat raises HDL and protects against cardiovascular disease.