The Structure and Atherogenicity of LDL

低密度脂蛋白的结构和致动脉粥样硬化性

• 批准号: 6438121
• 负责人: HENDRICUS G VAN ANTWERPEN
• 金额: $ 25.49万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6438121
• 关键词: apolipoprotein B; atherosclerosis; blood tests; calorimetry; chemical structure function; cholesterol esters; computer data analysis; cryoelectron microscopy; digital imaging; human subject; hydropathy; immunoaffinity chromatography; intermolecular interaction; lipid structure; liquid crystal; low density lipoprotein; low density lipoprotein receptor; molecular shape; mucopolysaccharides; physical property; physical state; radiotracer; receptor mediated endocytosis; statistics /biometry; structural biology; temperature; apolipoprotein B; atherosclerosis; blood tests; calorimetry; chemical structure function; cholesterol esters; computer data analysis; cryoelectron microscopy; digital imaging; human subject; hydropathy; immunoaffinity chromatography; intermolecular interaction; lipid structure; liquid crystal; low density lipoprotein; low density lipoprotein receptor; molecular shape; mucopolysaccharides; physical property; physical state; radiotracer; receptor mediated endocytosis; statistics /biometry; structural biology; temperature

The human low-density lipoprotein (LDL) has a hydrophobic core that contains mainly cholesteryl esters. These cholesteryl esters are normally in a disordered, liquid state at physiological temperature, in a more ordered, liquid-crystalline state at room temperature. However, non- human primate studies have shown that diets with a high content of cholesterol and saturated fat can generate LDL particles that have a liquid-crystalline core in vivo. It has been suggested that these abnormal LDL particles with a liquid core. The long-term goal of this study is to determine how the structure and atherogenicity of LDL are affected by the physical state of the lipoprotein core. Preliminary cryo-electron microscopic studies suggest that human LDL has a spherical shape when its cholesteryl ester core is in the liquid state, and an oblate ellipsoid, or "discoid" shape when its core is in the liquid crystalline state. It is further suggested that apo B in discoid LDL has an altered conformation. These observations indicate that the alleged increase in the atherogenicity of LDL particles with a liquid-crystalline core may result from dramatic changes in the shape and substructure of the lipoprotein complex. The specific aims of this study are: [1] To determine if changes in the physical state of the LDL core indeed to predictable changes in the shape and substructure of the lipoprotein particle. [2] To determine if LDL particles with a liquid-crystalline core differ from LDL particles with a liquid core in their affinity for the LDL receptor, in their affinity for glycosaminoglycans, or in their affinity for the macrophage scavenger receptor. It is anticipated that this study will correlate diet- inducible aberrations in the structure of LDL with significant increases in the atherogenic potential of the lipoprotein complex. The results of this project may, therefore, provide a new framework for future studies on the role of LDL particles with a liquid-crystalline core as a risk factor in coronary heart disease and stroke.

人类低密度脂蛋白（LDL）具有主要含有胆固醇酯的疏水核。这些胆固醇酯通常处于生理温度下的无序液态状态，在室温下更有序的液晶状态。然而，非人类灵长类动物研究表明，胆固醇和饱和脂肪含量较高的饮食可以产生在体内具有液晶核心的LDL颗粒。有人提出，这些具有液体的异常LDL颗粒。这项研究的长期目标是确定LDL的结构和动脉粥样硬化如何受脂蛋白核心的物理状态的影响。初步的冷冻电子显微镜研究表明，当人LDL的胆固醇酯芯处于液态状态时，人LDL具有球形形状，而当其核心处于液体结晶状态时，则具有块状椭圆形或“盘状”形状。进一步提出，盘状LDL中的apo b具有改变构象的改变。这些观察结果表明，据称使用液晶核心的LDL颗粒的动脉粥样硬化性增加可能是由于脂蛋白复合物的形状和亚结构的巨大变化而引起的。这项研究的具体目的是：[1]确定LDL核心物理状态的变化是否确实是脂蛋白颗粒的形状和亚结构的可预测变化。 [2]确定具有液晶芯的LDL颗粒是否与LDL颗粒具有与LDL受体相关的LDL颗粒，其对糖胺聚糖的亲和力或对巨噬细胞可寻求的受体的亲和力。可以预料，这项研究将与LDL结构中的饮食诱导畸变相关，并显着增加脂蛋白复合物的动脉粥样硬化潜力。因此，该项目的结果可能为将来的研究提供了一个新的框架，以研究具有液体结晶核作为冠心病和中风的危险因素的LDL颗粒的作用。