HDL Remodeling in Metabolic Syndrome

代谢综合征中的 HDL 重塑

• 批准号: 9278079
• 负责人: Nancy R Webb
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9278079
• 关键词: Affinity; Apolipoprotein A-I; Biological; Blood; Blood Circulation; Cardiovascular Diseases; Catabolism; Cells; Cholesterol; Cholesterol Ester Transfer Proteins; Chronic; Clinical Management; Complex; Data; Disease; Epidemic; Failure; Fibrates; Generations; Goals; Heart Diseases; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Hypertriglyceridemia; Incidence; Individual; Inflammation; Intervention; LIPG gene; Lipase; Lipids; Lipoproteins; Mediating; Metabolic Control; Metabolic syndrome; Metabolism; Outcome; Patients; Phospholipase; Phospholipase A2; Phospholipid Transfer Proteins; Plasma; Play; Population; Predisposition; Prevalence; Production; Public Health; Research; Risk; Risk Factors; SR-BI receptor; Stroke; Testing; Triglycerides; United States; Veterans; base; diabetes risk; hepatic lipase; high density lipoprotein receptor; inflammatory marker; insight; novel; particle; public health relevance; uptake

DESCRIPTION (provided by applicant): With a prevalence of 30-50% and clear association with increased cardiovascular disease (CVD), Metabolic Syndrome (MetS) is emerging as a major public health problem. MetS is characterized by elevated markers of inflammation, hypertriglyceridemia, and low levels of high density lipoprotein (HDL). This proposal aims to understand how HDL metabolism and function are altered in MetS. In MetS, increases in triglyceride-rich lipoproteins (TGRL) in combination with increased activity of cholesterol ester transfer protein (CETP) leads to TG enrichment of HDL. Although there is evidence that TG enrichment per se may destabilize the particle to promote release of apoA-I, it is likely that HDL remodeling factors in the circulation act on TG-enriched HDL to amplify apoA-I release and catabolism. Based on our preliminary data, we propose that circulating phospholipases (endothelial lipase, Group IIA secretory phospholipase A2) contribute significantly to HDL remodeling in MetS by liberating lipid-poor apoA-I from TG-enriched HDL. Once released from remodeled HDL, lipid-poor apoA-I has three potential fates: it may serve as an acceptor for cellular cholesterol efflux, associate with circulating HDL, or be cleared from the circulation due to a failure to undergo re-lipidation. Emerging evidence indicates that not all lipid-poor apoA-I species are capable of acquiring additional lipid and are thus susceptible to rapid catabolism. We propose that HDL lowering in MetS is due not only to enhanced HDL remodeling to amplify the release of lipid-poor apoA-I, but is also due to the increased production of "dysfunctional" lipid-poor species that are inherently susceptible to catabolism. The HDL receptor SR-BI plays a key role in HDL metabolism by mediating the selective uptake of CE from the core of HDL particles into cells. We have shown that SR-BI processing of HDL from healthy subjects generates at least 3 distinct lipid-depleted HDL "remnants" that differ in composition and subsequent metabolism. We propose that as SR-BI depletes the core of TG-enriched MetS HDL, the propensity of such particles to remodel leads to enhanced released of lipid-poor apoA-I. The central hypothesis of this proposal is that TG enrichment of HDL in MetS predisposes the particle to remodeling by intravascular factors and alters its processing by SR-BI, leading to the generation of lipid-poor species that are susceptible to catabolism. Specific Objective 1: Test the hypothesis that enhanced remodeling of HDL in hypertriglyceridemic MetS subjects leads to generation of lipid-poor apoA-I. The goal is to identify specific features of MetS HDL and/or MetS plasma that predict susceptibility to remodeling. We will also determine whether fibrate-induced TG lowering in MetS subjects leads to altered HDL remodeling. Specific Objective 2: Test the hypothesis that enhanced remodeling of TG-enriched HDL leads to alterations in subsequent HDL metabolism. Specific Objective 3: Test the hypothesis that TG enrichment alters SR-BI metabolism of HDL. Results from this project will provide new insights into mechanisms underlying reduced HDL in MetS, a prevalent condition in the Veteran population that significantly increases the risk of developing CVD. Findings from this project have the potential to define novel biological correlates of accelerated apoA-I catabolism in MetS and to identify MetS subjects most likely to benefit from TG lowering/HDL raising interventions.

描述（由申请人提供）： 代谢综合征（MetS）的患病率为30-50%，与心血管疾病（CVD）的增加有明显的相关性，正在成为一个主要的公共卫生问题。MetS的特征在于炎症、高脂血症和低水平的高密度脂蛋白（HDL）的升高的标志物。该提案旨在了解HDL代谢和功能如何在MetS中改变。在MetS中，富含甘油三酯的脂蛋白（TGRL）的增加与胆固醇酯转移蛋白（CETP）活性的增加相结合，导致HDL的TG富集。尽管有证据表明TG富集本身可能使颗粒不稳定以促进apoA-I的释放，但循环中的HDL重塑因子可能作用于TG富集的HDL以放大apoA-I的释放和catalysis。基于我们的初步数据，我们提出，循环磷脂酶（内皮脂肪酶，IIA组分泌型磷脂酶A2）有助于显着的HDL重塑代谢综合征的释放脂贫载脂蛋白A-I从TG-丰富的HDL。一旦从重塑的HDL中释放出来，脂质贫乏的apoA-I有三种潜在的命运：它可以作为细胞胆固醇流出的受体，与循环HDL相关，或者由于未能进行再脂化而从循环中清除。新出现的证据表明，并不是所有的脂质贫乏的apoA-I物种都能够获得额外的脂质，因此容易受到快速catalysis。我们认为代谢综合征中HDL的降低不仅是由于HDL重塑增强以放大脂质贫乏的apoA-I的释放，而且还由于“功能失调”的脂质贫乏物种的产生增加，这些物种固有地对catastrophic敏感。HDL受体SR-BI通过介导CE从HDL颗粒核心选择性摄取到细胞中而在HDL代谢中起关键作用。我们已经表明，来自健康受试者的HDL的SR-BI加工产生至少3种不同的脂质耗尽的HDL“残余物”，其在组成和随后的代谢方面不同。我们提出，由于SR-BI耗尽TG富集的MetS HDL的核心，这种颗粒重塑的倾向导致脂质贫乏的apoA-I的释放增强。该提议的中心假设是MetS中HDL的TG富集使颗粒易于通过血管内因子重塑，并通过SR-BI改变其加工，导致产生易受卡他汀影响的脂质贫乏物质。具体目标1：检验高脂血症MetS受试者中HDL重塑增强导致脂质缺乏apoA-I产生的假设。目的是鉴定MetS HDL和/或MetS血浆的预测重构易感性的特定特征。我们还将确定MetS受试者中纤维素诱导的TG降低是否会导致HDL重塑改变。具体目标2：检验以下假设：TG富集的HDL的增强重塑导致随后HDL代谢的改变。具体目标3：检验TG富集改变HDL的SR-BI代谢的假设。该项目的结果将为MetS中HDL降低的机制提供新的见解，MetS是退伍军人人群中的一种普遍疾病，显著增加了患CVD的风险。该项目的发现有可能定义MetS中加速apoA-I催化剂的新生物学相关性，并确定最有可能从TG降低/HDL升高干预中获益的MetS受试者。