Dietary Fat and HDL Metabolism

膳食脂肪和高密度脂蛋白代谢

• 批准号: 8121581
• 负责人: FRANK M SACKS
• 金额: $ 76.48万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-09 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121581
• 关键词: Affect; Alpha Particles; Apolipoprotein A-I; Apolipoprotein E; Apolipoproteins C; Atherosclerosis; Blood; Blood Circulation; Body Weight decreased; Carbohydrates; Cardiovascular Diseases; Cholesterol; Cholesterol Ester Transfer Proteins; Cholesterol Esters; Cholesterol Nutrition; Clinical; Complex; Coronary heart disease; Data; Diet; Dietary Carbohydrates; Dietary Fats; Excision; Genetic Variation; Goals; Guidelines; Health Policy; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Hypertriglyceridemia; Insulin Resistance; Intervention; Intervention Studies; LDL Cholesterol Lipoproteins; Label; Lipids; Lipoprotein (a); Lipoproteins; Liver; Low Density Lipoprotein Receptor; Macronutrients Nutrition; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolic syndrome; Metabolism; Non-Insulin-Dependent Diabetes Mellitus; Nutrition Policy; Nutritional; Obesity; Overweight; Pathway interactions; Phenotype; Physiology; Plasma; Process; Production; Proteins; Risk; Study Section; System; Testing; Therapeutic Intervention; Tracer; Triglycerides; Unsaturated Fats; Very low density lipoprotein; apolipoprotein C-III; cardiovascular disorder risk; hepatic lipase; high density lipoprotein-1; high density lipoprotein-2; high density lipoprotein-3; high risk; improved; metabolic abnormality assessment; nutrition; particle; pre-beta high-density lipoprotein; public health relevance; receptor; response; reverse cholesterol transport; saturated fat; uptake

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.

描述（由申请人提供）：膳食脂肪和高密度脂蛋白代谢。在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而碳水化合物或蛋白质减少时高密度脂蛋白胆固醇浓度的增加。不饱和脂肪的这种明显优势是一些专家青睐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。另一些专家则对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不那么有信心。通过对高密度脂蛋白胆固醇的简单改变来制定营养和健康政策，会让人感到不舒服。缺乏对潜在生理学的清晰了解会干扰有根据的意见。有几种代谢途径可以维持高HDL浓度。目前还不清楚膳食脂肪是如何影响它们的。关键的问题是膳食脂肪是否能改善高密度脂蛋白代谢的步骤，而高密度脂蛋白代谢与胆固醇的逆向运输有关，从而防止动脉粥样硬化。HDL无疑是胆固醇运输和体内平衡系统的必要组成部分，低HDL浓度是心血管疾病高风险的最强预测因子之一。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很突出。这种低HDL浓度与血液循环中HDL颗粒的加速清除有关，通过它们的主要蛋白，载脂蛋白a - i和小HDL的优势来测量。这表明HDL从小的胆固醇耗尽颗粒到大的富含胆固醇酯颗粒的成熟受到阻碍，并损害了胆固醇的逆向运输。我们不知道饮食中的不饱和脂肪是否能纠正高密度脂蛋白代谢的失调。我们提出了一项临床干预研究，对20名典型超重或肥胖的低HDL胆固醇浓度和高血浆甘油三酯的人进行研究，以确定饮食不饱和脂肪如何增加他们的HDL浓度。我们将使用稳定的同位素示踪剂来标记内源性载脂蛋白A-I（高密度脂蛋白的定义蛋白），以追踪其从小的新生颗粒（“前- β - HDL”）到大的，装载胆固醇的成熟颗粒（“α 1,2和3 HDL”）的代谢，并评估肝脏选择性去除胆固醇酯的反向过程的程度。我们将研究膳食脂肪是否会减少载脂蛋白C-III在HDL代谢中的参与。与不含apoC-III的主要HDL类型相反，含有apoC-III的HDL与CVD有不良关联。这一信息对于解释膳食脂肪在预防动脉粥样硬化方面提高高密度脂蛋白的作用是非常宝贵的。