PLASMA LIPID TRANSFER PROTEIN

动脉粥样硬化的特点是局部积聚 动脉壁中的血浆衍生脂质；在早期病变期间 在发育过程中，脂肪堆积主要集中在细胞内。脂类 沉积与海平面上升相关，也可能是海平面上升的结果。 血浆胆固醇和异常脂蛋白的发生。 因此，对脂蛋白脂代谢的详细了解 血管内和血管外的隔室是 描述与发展有关的生化事件 动脉硬化。 目前的知识表明，甘油三酯和 脂转移促进脂蛋白间的胆固醇酯 蛋白质是脂蛋白代谢的重要组成部分。在现在 关于这项提议，已经采取了三种普遍的方法来更好地 描述血浆携带的脂转移蛋白(LTP)，其功能， 以及对活动的规范。首先，脂类的依赖性 考察了转移活性对脂蛋白组成的影响。在这些 重组高密度脂蛋白(r-HDL)的组成研究 将被系统地改变以产生r-高密度脂蛋白粒子 高脂血症个体的脂蛋白和动物体内的脂蛋白 喂食致动脉粥样硬化的饮食。脂蛋白组成对高脂血症的影响 胆固醇酯和甘油三酯的转移及其对物理状态的影响 通过荧光偏振测量的脂蛋白的含量将是 学习。在第二种方法中，研究将进一步评估 LTP-脂蛋白结合在转移反应中的重要性。这个 LTP与分离的天然和体外修饰的LTP结合动力学 将对不同组成的脂蛋白和r-高密度脂蛋白进行研究。 重点将放在生理和心理方面 脂蛋白衣层脂质成分的病理生理变化 影响结合动力学和脂质转移活性。测量的结果 LTP在全血清脂蛋白组间的结合分布 试图为这些体外观察提供体内相关性。LTP 将通过免疫电测法进行定量。最后，除了 脂蛋白-脂蛋白脂转移，这些拟议的研究将 探讨LTP促进脂质转移的机制 变成)完整的巨噬细胞。此外，LTP促进 细胞内脂质包涵体的形成和/或消退将是 学习。 对这项建议的研究是主要工作的组成部分 研究人员对脂蛋白脂代谢的长期兴趣，在 对这一复杂过程的调节，以及这些事件之间的关系 致动脉粥样硬化。本提案涉及这些利益。 因为它们与脂转移蛋白有关。

Atherosclerosis is characterized by the focal accumulation of plasma-derived lipids in the arterial wall; during early lesion development, lipid accumulation is predominantly intracellular. Lipid deposition correlates with and may be the consequence of, an elevation in plasma cholesterol and the occurrence in plasma of abnormal lipoproteins. Hence, a detailed understanding of lipoprotein lipid metabolism in both the intravascular and extravascular compartments is an essential component in describing the biochemical events associated with the development of atherosclerosis. Current knowledge indicates that the transfer of triglyceride and cholesteryl ester between lipoproteins as promoted by the lipid transfer protein is an integral component of lipoprotein metabolism. In the present proposal, three general approaches have been undertaken to better characterize the plasma-borne lipid transfer protein (LTP), its function, and the regulation of the activity. In the first, the dependence of lipid transfer activity on lipoprotein composition is investigated. In these studies, the composition of reconstituted high density lipoproteins (r-HDL) will be systematically altered to produce r-HDL particles that model the lipoproteins of hyperlipemic individuals and those which occur in animals fed atherogenic diets. The effect of lipoprotein composition on the transfer of cholesteryl ester and triglyceride, and on the physical state of lipoproteins, as measured by fluorescence polarization, will be studied. In the second approach, studies will evaluate further the importance of LTP-lipoprotein binding in the transfer reaction. The kinetics of LTP binding to isolated native and in vitro-modified lipoproteins and to r-HDL of different composition will be studied. Emphasis will be placed on the ways in which physiological and pathophysiological changes in the lipid composition of the lipoprotein coat affect binding kinetics and lipid transfer activity. Measurements of the binding distribution of LTP among lipoprotein classes in whole plasma will attempt to provide in vivo relevance to these in vitro observations. LTP will be quantitated by an electroimmunoassay. Finally, in addition to lipoprotein-lipoprotein lipid transfers, these proposed studies will investigate the mechanism of LTP-facilitated lipid transfer from (and/or into) intact macrophages. Additionally, the capacity of LTP to promote the formation and/or regression of intracellular lipid inclusions will be studied. The studies of this proposal are an integral part of the Principal Investigator's long-term interest in lipoprotein lipid metabolism, in the regulation of this complex process, and in the relationship of these events to atherosclerosis. These interests are addressed in the present proposal as they relate to the lipid transfer protein.