HDL Remodeling in Metabolic Syndrome

代谢综合征中的 HDL 重塑

• 批准号: 8633785
• 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/8633785
• 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; Health; Heart Diseases; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Hypertriglyceridemia; Incidence; Individual; Inflammation; Intervention; Lipase; Lipids; Lipoproteins; Mediating; Metabolic syndrome; Metabolism; Outcome; Patients; Phospholipase; Phospholipase A2; Phospholipid Transfer Proteins; Plasma; Play; Population; Predisposition; Prevalence; Process; Production; Public Health; Research; Risk; Risk Factors; Stroke; Testing; Triglycerides; United States; Veterans; base; diabetes risk; hepatic lipase; high density lipoprotein receptor; inflammatory marker; insight; novel; particle; uptake

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.

由于患病率为30-50%，并且与心血管疾病（CVD）增加明显相关， 综合征（MetS）正在成为一个主要的公共卫生问题。MetS的特征在于升高的 炎症、高脂血症和低水平的高密度脂蛋白（HDL）。这项建议旨在 了解HDL代谢和功能如何在MetS中改变。在代谢综合征中， 脂蛋白（TGRL）与胆固醇酯转移蛋白（CETP）活性增加的组合导致 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， 促进apoA-I的释放，很可能是循环中的HDL重塑因子作用于富含TG的HDL， 增强apoA-I的释放和催化。根据我们的初步数据，我们建议， 磷脂酶（内皮脂肪酶，IIA型分泌型磷脂酶A2）对HDL的合成有重要作用。 通过从富含TG的HDL中释放脂质贫乏的apoA-I来重塑MetS。一旦从重塑的HDL中释放出来， 贫脂apoA-I有三种可能的命运：它可能作为细胞胆固醇流出的受体， 与循环HDL，或从循环中清除，由于未能进行再脂化。新兴 有证据表明，并非所有的贫脂质apoA-I种类都能够获得额外的脂质， 易受快速catalytic。我们认为代谢综合征中HDL的降低不仅是由于HDL的增强 重塑以放大脂质贫乏的apoA-I的释放，但也是由于 “功能失调”的低血脂物种，天生容易受到catastrophic。高密度脂蛋白受体SR-BI起着 通过介导CE从HDL颗粒核心选择性摄取到细胞中，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。 HDL“残余物”的组成和随后的代谢不同。我们建议，随着SR-BI耗尽， 在富含TG的MetS HDL的核心中，这种颗粒重塑的倾向导致增强的 低脂的apoA-I。该建议的中心假设是，代谢综合征中HDL的TG富集倾向于 颗粒通过血管内因素重塑，并通过SR-BI改变其加工，导致产生 低脂物种容易感染卡那霉素。具体目标1：检验以下假设： 高脂血症MetS受试者中HDL的增强的重塑导致脂质贫乏的apoA-I的产生。 目标是鉴定MetS HDL和/或MetS血浆的特异性特征，其预测对以下疾病的易感性： 重塑我们还将确定MetS受试者中纤维素诱导的TG降低是否会导致HDL改变 重塑具体目标2：检验增强的富含TG的HDL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。该项目的结果将提供有关潜在机制的新见解 MetS中HDL降低，这是退伍军人人群中的一种普遍疾病， 发展CVD。该项目的发现有可能定义新的生物学相关性， MetS中apoA-I的加速催化作用，并鉴定最有可能从TG中获益的MetS受试者 降低/升高HDL干预。