HDL Remodeling in Metabolic Syndrome

患病率为30%-50%，并与心血管疾病(CVD)增加明显相关，代谢 综合症(METS)正在成为一个主要的公共卫生问题。METS的特征是标志物升高 炎症、高甘油三酯血症和低水平的高密度脂蛋白(HDL)。这项建议旨在 了解高密度脂蛋白代谢和功能在蛋氨酸中是如何改变的。在蛋氨酸中，富含甘油三酯的增加 脂蛋白(TGRL)与胆固醇酯转移蛋白(CETP)活性增加共同导致 高密度脂蛋白的TG浓缩。尽管有证据表明，TG浓缩本身可能会破坏颗粒的稳定性 促进apoA-I的释放，很可能是循环中的高密度脂蛋白重塑因子作用于富含甘油三酯的高密度脂蛋白，从而 放大载脂蛋白A-I的释放和分解代谢。根据我们的初步数据，我们建议循环 磷脂酶(内皮脂酶，IIA分泌型磷脂酶A2)对高密度脂蛋白有重要作用 通过从富含甘油三酯的高密度脂蛋白中释放低脂载脂蛋白A-I来重塑蛋氨酸。一旦从改装的高密度脂蛋白中释放出来， 缺乏脂质的apoA-I有三种潜在的命运：它可能是细胞胆固醇外流的受体 与循环中的高密度脂蛋白一起，或由于未能进行再脂化而从循环中清除。新兴 证据表明，并不是所有缺乏脂质的apoA-I物种都能够获得额外的脂肪，因此 易受快速分解代谢的影响。我们认为，蛋氨酸中高密度脂蛋白的降低不仅仅是由于高密度脂蛋白的增加 重塑能放大低脂载脂蛋白A-I的释放，也是由于 “功能失调”的低脂物种，天生就容易分解代谢。高密度脂蛋白受体SR-BI发挥作用 在高密度脂蛋白新陈代谢中的关键作用，通过介导从高密度脂蛋白颗粒核心选择性地摄取CE进入细胞。 我们已经证明，来自健康受试者的高密度脂蛋白的SR-BI处理至少产生3种不同的脂质耗竭 高密度脂蛋白“残留物”在组成和随后的新陈代谢上有所不同。我们认为，随着SR-BI耗尽 富含甘油三酯的蛋氨酸高密度脂蛋白的核心，这些粒子的重塑倾向导致增强释放 低脂载脂蛋白A-I。这一建议的中心假设是，蛋氨酸中高密度脂蛋白的TG富集会使 血管内因子使颗粒重塑，并通过SR-BI改变其加工过程，导致生成 容易分解新陈代谢的贫脂物种。具体目标1：检验假设 高甘油三酯血症患者高密度脂蛋白重塑增强导致低脂载脂蛋白A-I的产生。 我们的目标是确定甲硫氨酸高密度脂蛋白和/或蛋氨酸血浆的特定特征，这些特征可以预测易感性 改建。我们还将确定甲硫氨酸受试者贝特诱导的甘油三酯降低是否导致高密度脂蛋白改变 改建。具体目标2：验证富含甘油三酯的高密度脂蛋白重塑增强导致 随后的高密度脂蛋白代谢的改变。具体目标3：测试TG富集会改变这一假设 高密度脂蛋白的SR-BI代谢。该项目的结果将提供对潜在机制的新见解 蛋氨酸高密度脂蛋白降低，这是退伍军人人群中的一种普遍情况，显著增加了患上 发展中的心血管疾病。该项目的发现有可能定义新的生物相关性 蛋氨酸受试者加速apoA-I分解代谢及最有可能受益于甘油三酯的研究 降低/升高高密度脂蛋白干预。

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.