FFA Production From Triglyceride-Rich Lipoproteins

描述（由申请人提供）：拟进行的研究将继续我们在燃料代谢调节领域的工作。脂质能量以多种形式在血液中运输，包括乳糜微粒和游离脂肪酸（FFA）。乳糜微粒是膳食脂肪吸收和储存的关键因素，也通过产生残余颗粒在动脉粥样硬化的发病机制中发挥作用，但其作为直接燃料来源的作用尚未被探索。FFA是体内主要的脂质燃料，其浓度的增加已被证明会导致胰岛素抵抗、内皮功能障碍和极低密度脂蛋白的产生增加。FFA通过激素敏感脂肪酶对脂肪细胞中储存的甘油三酯的作用释放到血液中。乳糜微粒在FFA代谢中的作用知之甚少，但乳糜微粒对FFA的潜在贡献是相当大的，特别是在食用高脂肪饮食的人群中。最初的研究表明，除了乳糜微粒在脂肪储存中的作用外，一部分乳糜微粒脂肪酸在一个称为“溢出”的过程中以FFA的形式释放。这些研究表明，乳糜微粒对FFA的贡献在2型糖尿病中增加。一项关于内脏床溢出的研究发现，超重和肥胖的高甘油三酯血症患者的内脏溢出率非常高。研究者已经开发了非常准确和精确的方法来测量血浆中游离脂肪酸和乳糜微粒甘油三酯脂肪酸的浓度和比活性。此外，还开发了一种准确测定乳糜微粒动力学的示踪方法。在拟议的研究中，示踪技术将用于系统地研究乳糜微粒对总FFA有效性的贡献。该技术将适用于正常受试者在休息和运动后，以及2型糖尿病和高甘油三酯血症受试者。具体来说，这些研究将：1)确定2型糖尿病患者体重减轻是否会减少乳糜微粒的溢出效应；2)确定胰岛素输注急性降低FFA是否能减少非糖尿病合并血脂异常个体的溢出；3)确定非胰岛素介导的FFA降低是否会减少糖尿病合并血脂异常患者的外溢；4)确定肥胖、胰岛素抵抗个体是否会增加内脏床的外溢。公共卫生相关性：

DESCRIPTION (provided by applicant): The proposed research will continue our work in the area of the regulation of fuel metabolism. Lipid energy is transported in the blood in several forms, including chylomicrons and free fatty acids (FFA). Chylomicrons are key elements in the absorption and storage of dietary fat, and also play a role in the pathogenesis of atherosclerosis via the production of remnant particles, but their role as a direct fuel source has not been explored. FFA are the major lipid fuel in the body, and increases in their concentration have been shown to cause insulin resistance, endothelial dysfunction and increases in the production of very low density lipoproteins. FFA are released into the blood through the action of hormone sensitive lipase on triglyceride stores in fat cells. Very little is known about the role of chylomicrons in FFA metabolism, but the potential contribution of chylomicrons to FFA is considerable, especially in people who consume high fat diets. Initial studies indicate that in addition to the role of chylomicrons in fat storage, a portion of chylomicron fatty acids are released as FFA in a process called "spillover". These studies indicate that the contribution of chylomicrons to FFA is increased in type 2 diabetes. A study of spillover in the splanchnic bed found very high rates of splanchnic spillover in overweight and obese individuals with hypertriglyceridemia. Extremely accurate and precise methods have been developed by the investigator for the measurement of the concentration and specific activity of FFA and chylomicron triglyceride fatty acids in plasma. In addition, a tracer method for accurately determining the kinetics of chylomicrons has been developed. In the proposed studies, the tracer technique will be used to systematically investigate the contribution of chylomicrons to total FFA availability. The technique will be applied to normal subjects at rest and after exercise, as well as subjects with type 2 diabetes mellitus and hypertriglyceridemia. Specifically, these studies will: 1) determine whether weight loss in people with type 2 diabetes reduces spillover from chylomicrons; 2) determine whether acute lowering of FFA with insulin infusion reduces spillover in nondiabetic individuals with dyslipidemia; 3) determine whether noninsulin-mediated lowering of FFA reduces spillover in diabetic individuals with dyslipidemia, and 4) determine whether obese, insulin-resistant individuals have increased spillover in the splanchnic bed. PUBLIC HEALTH RELEVANCE: Elevated free fatty acids levels (FFAs) in blood are a recognized cause of insulin resistance and may contribute to the development of diabetes, high blood pressure and cardiovascular disease. Dietary fat may contribute to FFAs by a process known as "spillover", which occurs during fat storage. This work is a comprehensive evaluation of the importance of spillover as a contributor to FFAs.