PLASMA LIPID TRANSFER PROTEIN

动脉粥样硬化的特点是局灶性积聚 动脉壁中的血浆衍生脂质;在早期病变期间 在发育过程中，脂质积累主要是细胞内的。 脂质 沉积与海拔高度相关，也可能是海拔高度升高的结果。 血浆胆固醇和血浆中异常脂蛋白的出现。 因此，详细了解脂蛋白脂质代谢在这两个 血管内和血管外隔室是 描述与发展相关的生物化学事件， 动脉粥样硬化 目前的知识表明，甘油三酯和 胆固醇酯脂蛋白之间的促进脂质转移 蛋白质是脂蛋白代谢的组成部分。 本 建议，采取了三种一般方法，以更好地 表征血浆载脂转运蛋白（LTP），其功能， 和活动的调节。 第一，脂质的依赖性 研究了对脂蛋白组成的转移活性。 在这些 研究，重组高密度脂蛋白（r-HDL）的组成 将被系统地改变，以产生r-HDL颗粒， 高脂血症个体的脂蛋白和动物中的脂蛋白 喂食致动脉粥样硬化的食物。 脂蛋白成分对脂蛋白合成的影响 胆固醇酯和甘油三酯的转移，并对身体状态 通过荧光偏振测量， 研究了 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。 的 LTP与分离的天然和体外修饰的 脂蛋白和不同组成的r-HDL进行研究。 重点将放在如何在生理和 脂蛋白外壳脂质组成的病理生理学变化 影响结合动力学和脂质转移活性。 测量 LTP在整个血浆中脂蛋白类别之间的结合分布将 尝试提供与这些体外观察结果的体内相关性。 LTP 将通过电免疫测定法进行定量。 最后，除了 脂蛋白-脂蛋白脂质转移，这些拟议的研究将 研究LTP促进脂质从（和/或） 进入）完整的巨噬细胞。 此外，LTP促进 细胞内脂质内含物的形成和/或消退将是 研究了 对这一建议的研究是校长的一个组成部分， 研究者对脂蛋白脂质代谢的长期兴趣， 调节这一复杂的过程，并在这些事件的关系， 动脉粥样硬化 本提案涉及这些利益 因为它们与脂质转移蛋白有关。

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.