Dietary Fat and HDL Metabolism

膳食脂肪和高密度脂蛋白代谢

• 批准号: 8314034
• 负责人: FRANK M SACKS
• 金额: $ 73.75万
• 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/8314034
• 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）：饮食脂肪和HDL代谢。 营养和心血管疾病（CVD）的一个很大的未解决问题是如何解释当饮食中不饱和脂肪增加并降低碳水化合物或蛋白质时发生的HDL胆固醇浓度的增加。这种不饱和脂肪的明显优势是一些专家比碳水化合物或蛋白质相比高度不饱和脂肪饮食的原因之一。其他专家不太信心，即提高HDL浓度的治疗干预总是可以防止动脉粥样硬化。 HDL胆固醇的营养和健康政策中的简单变化有一种不适感。基本生理学缺乏明确性会干扰知情的意见。有几种代谢途径可以维持高HDL浓度。目前尚不清楚饮食脂肪如何影响它们。关键的问题是，饮食脂肪是否改善了抗胆固醇转运的HDL代谢的步骤，可防止动脉粥样硬化。 HDL无疑是胆固醇运输和稳态系统的必要组成部分，低HDL浓度是CVD高风险的最强预测指标之一。低HDL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HDL颗粒的血液循环的加速清除相关，该颗粒的血液循环是由其主要蛋白质载脂蛋白A-I和大量的小型HDL测量的。这表明HDL从耗尽大胆固醇到富含胆固醇酯的富含胆固醇的颗粒和反向胆固醇转运受损的HDL成熟。我们不知道饮食中的不饱和脂肪是否纠正了HDL的这种功能失调的代谢。 我们建议在典型的超重或肥胖症环境中对20人进行临床干预研究，并提出高血浆甘油三酸酯，以确定饮食中的不饱和脂肪如何增加其HDL浓度。我们将使用稳定的同位素示踪剂来将HDL定义的蛋白质内源性蛋白质A-I标记，以将其代谢从小小的新生颗粒（“ pre-Beta hdl”）标记为大型胆固醇的成熟颗粒（“ Alpha 1,2 HDL”和3 HDL的范围，并评估了范围的范围，并逐步改进了范围，并将其用于远程处理。肝脏。我们将研究饮食脂肪是否会减少载脂蛋白C-III参与HDL代谢。具有APOC-III的HDL与CVD具有不良关联，与没有APOC-III的主要HDL类型相反。在解释饮食脂肪对动脉粥样硬化的保护方面，该信息将证明是无价的。 公共卫生相关性：饮食脂肪和HDL代谢，该提案的目的是确定饮食中未饱和脂肪增加高密度脂蛋白（HDL）的血液浓度的机制，高密度脂蛋白（HDL）是一种保护性脂蛋白，该保护性脂蛋白是一种将胆固醇从动脉粥样硬化中去除的，并降低了心血管疾病的风险。该项目是一项受控饮食研究，将高不饱和脂肪饮食与高碳水化合物饮食进行比较。 HDL在人类中的直接代谢研究将在每种饮食结束时进行。目的是制定详细的图片，说明不饱和脂肪如何提高HDL并防止心血管疾病。