METABOLISM OF HDL APOLIPOPROTEINS IN NORMAL & HYPOALPHALIPOPROTEINEMIC SUBJECTS

正常情况下 HDL 载脂蛋白的代谢

• 批准号: 3779541
• 负责人: D J RADER
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3779541
• 关键词: apolipoproteins; blood lipoprotein metabolism; cholesterol esters; coronary disorder; disease /disorder proneness /risk; enzyme activity; high density lipoproteins; human subject; hypolipoproteinemia; lecithin cholesterol acyltransferase deficiency; molecular pathology

Plasma HDL cholesterol and apoA-I are epidemiologically associated with risk of premature coronary heart disease, but are not always predictive in individual patients. One example are the genetic syndromes of LCAT deficiency. LCAT is a plasma enzyme which catalyzes the formation of HDL cholesteryl ester in plasma. Patients with classic (complete) LCAT deficiency and with a partial LCAT deficiency termed fish-eye disease (FED) have very low levels of HDL and apoA-I but do not have an increased risk of premature CHD. We investigated HDL apoA-I and apoA-II in a total of five patients with different types of LCAT deficiency using both endogenous labeling with stable isotopes and exogenously labeled radiotracers. We found that apoA-I and especially apoA-II were catabolized substantially faster than in control subjects, accounting for their low levels in plasma. The two major classes of HDL particles include those containing only apoA-I (LpA-I) and those containing both apoA-I and apoA-II (LpA-I:A-II). LpA-I, but not LpA-I:A-II, has been found to be specifically associated with risk of premature CHD. We have previously established that in normal subjects the catabolism of apoA-I on LpA-I is significantly faster than that of apoA-I on LpA-I:A-II, indicating that the metabolic regulation of these two HDL particles is fundamentally divergent. In the LCAT deficient patients, however, the catabolism of LpA-I:A-II was markedly faster than that of LpA-I, resulting in plasma levels of LpA-I:A-II that were proportionately much lower than those of LpA-I. This could be an explanation for the observation that these patients are not at increased risk for premature CHD despite their low levels of HDL. We have also investigated HDL metabolism in a series of five other patients who also have very low levels of HDL but no CHD. In these patients we also found rapid catabolism of apoA-I, apoA-II, and LpA-I:A-II accounting for the low plasma levels of these apolipoproteins. These studies demonstrate that not all syndromes of low HDL necessarily predispose to premature CHD, and that rapid catabolism of LpA-I:A-II may be one cause of low HDL not associated with increased risk of CHD.

血浆高密度脂蛋白胆固醇和载脂蛋白A-I在流行病学上与 早发冠心病的风险，但并不总是可以预测的 在个别病人身上。LCAT的遗传综合征就是一个例子 缺乏症。LCAT是一种催化高密度脂蛋白形成的血浆酶 血浆中的胆固醇酯。典型(完整)LCAT患者 LCAT缺乏和部分缺乏称为鱼眼病 (FED)高密度脂蛋白和载脂蛋白A-I水平非常低，但没有增加 患早产儿冠心病的风险。我们总共研究了高密度脂蛋白apoA-I和apoA-II 在五名患有不同类型LCAT缺乏症的患者中 稳定同位素内源标记和外源标记 放射性示踪剂。我们发现载脂蛋白A-I尤其是载脂蛋白A-II 分解速度大大快于对照组，占 他们血浆中的低水平。 高密度脂蛋白颗粒的两大类包括那些只含有 ApoA-I(LPA-I)和同时含有apoA-I和apoA-II的那些(LPA-I：A-II)。 LPA-I，而不是LPA-I：A-II被发现与LPA-I：A-II特别相关 有患早产冠心病的风险。我们之前已经确定，在正常情况下 受试者载脂蛋白A-I在LPA-I上的分解代谢明显快于 载脂蛋白A-I对LPA-I：A-II的影响，表明代谢调节 这两个高密度脂蛋白粒子从根本上是发散的。在LCAT中 然而，缺乏LPA-I：A-II的患者分解代谢明显 比LPA-I更快，导致血浆LPA-I：A-II水平 在比例上远低于LPA-I。这可能是一个 对观察到这些患者没有增加的解释 尽管他们的高密度脂蛋白水平较低，但仍有过早发生CHD的风险。我们还有 研究了一系列其他五名患者的高密度脂蛋白代谢 高密度脂蛋白水平很低，但没有冠心病。在这些患者中，我们还发现 载脂蛋白A-I、载脂蛋白A-II和脂蛋白A-I：A-II的快速分解代谢 这些载脂蛋白的血浆水平较低。这些研究表明 并不是所有的低高密度脂蛋白综合征都有早产倾向 CHD和LPA-I：A-II快速分解代谢可能是导致低密度脂蛋白的原因之一 与冠心病风险增加无关。