Dietary Fat and HDL Metabolism

描述（由申请人提供）：膳食脂肪和HDL代谢。 营养和心血管疾病（CVD）中一个悬而未决的问题是如何解释当膳食不饱和脂肪增加而碳水化合物或蛋白质减少时发生的HDL胆固醇浓度增加。不饱和脂肪的这种明显优势是一些专家与碳水化合物或蛋白质相比更喜欢高不饱和脂肪饮食的原因之一。其他专家并不那么有信心，认为提高HDL浓度的治疗干预一定能预防动脉粥样硬化。有一种不适感使用简单的改变高密度脂蛋白胆固醇的营养和健康政策。缺乏明确的基础生理干扰知情的意见。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对它们的影响。关键的问题是，膳食脂肪是否能改善HDL代谢中的步骤，这些步骤涉及胆固醇的逆向转运，从而防止动脉粥样硬化。 HDL无疑是胆固醇转运和体内平衡系统的必要组成部分，低HDL浓度是CVD高风险的最强预测因子之一。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和小HDL的优势来测量。这表明HDL从小胆固醇耗尽颗粒成熟为大胆固醇酯丰富颗粒的阻滞，以及胆固醇反向转运受损。我们不知道饮食中的不饱和脂肪是否能纠正HDL的代谢功能障碍。 我们提出了一个临床干预研究，在20人谁有低HDL胆固醇浓度的超重或肥胖的典型设置，和高血浆甘油三酯，以确定如何饮食不饱和脂肪增加他们的HDL浓度。我们将使用稳定的同位素示踪剂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”）到大的胆固醇加载的成熟颗粒（“α 1，2和3 HDL”）的代谢，并评估代表肝脏选择性去除胆固醇酯的逆过程的程度。我们将研究膳食脂肪是否减少载脂蛋白C-Ⅲ参与HDL代谢。具有apoC-III的HDL与CVD有不良关联，与不具有apoC-III的主要HDL类型相反。这一信息将被证明是非常宝贵的，在解释既定的HDL升高作用的膳食脂肪的保护，防止动脉粥样硬化。

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.