Dietary Fat and HDL Metabolism

膳食脂肪和高密度脂蛋白代谢

• 批准号: 8496098
• 负责人: FRANK M SACKS
• 金额: $ 70万
• 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/8496098
• 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.

描述（由申请人提供）：膳食脂肪和高密度脂蛋白代谢。 营养和心血管疾病 (CVD) 领域一个尚未解答的重要问题是，如何解释当膳食不饱和脂肪增加、碳水化合物或蛋白质减少时，HDL 胆固醇浓度增加。与碳水化合物或蛋白质相比，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的原因之一。其他专家并不相信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。将高密度脂蛋白胆固醇的简单变化用于营养和健康政策会产生一种不适感。基础生理学缺乏清晰度会影响知情意见。有多种代谢途径可以维持高 HDL 浓度。目前尚不清楚膳食脂肪如何影响它们。关键问题是膳食脂肪是否可以改善高密度脂蛋白代谢的步骤，这些步骤涉及逆转胆固醇转运，从而防止动脉粥样硬化。 HDL 无疑是胆固醇转运和稳态系统的必要组成部分，低 HDL 浓度是 CVD 高风险的最强预测因素之一。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表现突出。这种低 HDL 浓度与 HDL 颗粒从血液循环中的加速清除有关，通过其主要蛋白质载脂蛋白 A-I 和大量小 HDL 来测量。这表明高密度脂蛋白从不含胆固醇的小颗粒转变为富含胆固醇酯的大颗粒的成熟过程受到阻碍，并且胆固醇反向转运受损。我们不知道膳食不饱和脂肪是否可以纠正这种高密度脂蛋白代谢失调。 我们建议对 20 名在超重或肥胖的典型情况下 HDL 胆固醇浓度较低且血浆甘油三酯较高的人进行临床干预研究，以确定膳食不饱和脂肪如何增加他们的 HDL 浓度。我们将使用稳定同位素示踪剂来标记内源性载脂蛋白 A-I（HDL 的定义蛋白），以追踪其从小的新生颗粒（“前 β HDL”）到大的、负载胆固醇的成熟颗粒（“α 1,2 和 3 HDL”）的代谢，并评估代表选择性去除胆固醇酯的逆过程的程度 肝脏。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。具有 apoC-III 的 HDL 与 CVD 存在不利关联，这与不具有 apoC-III 的主要 HDL 类型相反。这一信息对于解释膳食脂肪在预防动脉粥样硬化方面已确立的升高 HDL 的作用将具有无价的价值。