GENETIC DETERMINANTS OF PLASMA LIPOPROTEINS

肝脂肪酶是一种由476个氨基酸组成的糖蛋白，在循环脂蛋白中催化磷脂和甘油三酯水解。肝脂肪酶活性在个体之间差异很大，这种差异与高密度脂蛋白（HDL）的血浆浓度，特别是HDL2亚组分，低密度脂蛋白（LDL）的合成和分解代谢率以及LDL的大小分布的个体间差异有关。我们实验室的初步数据表明，肝脂肪酶活性的种族差异也可能是众所周知的非裔美国人和白人美国人血浆高密度脂蛋白浓度差异的原因。然而，由于这些研究是基于表型之间的相关性，因此它们容易受到肥胖和血浆甘油三酯浓度等次要因素的干扰，这些因素可能对肝脂肪酶活性和脂蛋白代谢有独立的影响。因此，很难从这些研究中推断出肝脂肪酶活性与血浆脂蛋白浓度之间是否存在因果关系。因此，这些研究仍未解决的一个关键问题是“肝脏脂肪酶活性的原发性变异是否会导致人类血浆脂蛋白代谢的变异？”第二个尚未解决的问题是，是什么原因导致在其他健康个体中观察到肝脂肪酶活性的广泛变化？这两个问题提供了这个竞争延续的焦点。在前两个特定目标中，我们将比较具有遗传定义的肝脂肪酶活性的个体，以确定：i)肝脂肪酶活性的遗传变异是否解释了非裔美国人和白人男性之间众所周知的血浆HDL-C浓度差异，ii)肝脂肪酶活性的主要差异是否导致血浆脂蛋白的差异。在第三个特定目标中，我们将确定肝脂肪酶的遗传多态性是否导致白人男性中常见的非常高的肝脂肪酶活性。这些研究将有助于确定肝脂肪酶活性变化在确定血浆HDL浓度和LDL大小分布中的作用，这是冠状动脉疾病的两个重要危险因素。

Hepatic lipase is a 476 amino acid glycoprotein that catalyzes phospholipid and triglyceride hydrolysis in circulating lipoproteins. Hepatic lipase activity varies widely among individuals, and this variation has been associated with inter-individual differences in the plasma concentrations of high density lipoproteins (HDL), particularly the HDL2 subfraction, the rates of low density lipoprotein (LDL) synthesis and catabolism, and in the size distribution of LDL. Preliminary data from our laboratory suggest that ethnic differences in hepatic lipase activity may also be responsible for the well known differences in plasma HDL concentrations between African American and white American men. Since these studies are based on correlations between phenotypes, however, they are subject to confounding by secondary factors such as obesity and plasma triglyceride concentrations that may have independent effects on hepatic lipase activity and lipoprotein metabolism. Therefore it is difficult to infer from these studies whether or not the relationship between hepatic lipase activity and plasma lipoprotein concentrations is causal. Thus a key question that remains unanswered by these studies is "does primary variation in hepatic lipase activity cause variation in plasma lipoprotein metabolism in humans?" A second question that remains unanswered is what causes the wide variation in hepatic lipase activity observed in otherwise healthy individuals? These two questions provide the focus of this competing continuation. In the first two Specific Aims, we will compare individuals with genetically defined hepatic lipase activities to determine: i) whether genetic variation in hepatic lipase activity accounts for the well known differences in plasma HDL-C concentrations between African American and white men, and ii) whether primary differences in hepatic lipase activity cause differences in plasma lipoproteins. In the third Specific Aim, we will determine whether genetic polymoprhism in hepatic lipase contributes to the very high hepatic lipase activities commonly seen in white Men. These studies will help to determine the role of variation in hepatic lipase activity in determining plasma HDL concentrations, and LDL size distribution, two important risk factors for coronary artery disease.