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.
| Morton, R E; Steinbrunner, J V (1990) Concentration of neutral lipids in the phospholipid surface of substrate particles determines lipid transfer protein activity. J Lipid Res 31:1559-67 |
| Morton, R E (1988) Free cholesterol is a potent regulator of lipid transfer protein function. J Biol Chem 263:12235-41 |
| Morton, R E (1988) Interaction of plasma-derived lipid transfer protein with macrophages in culture. J Lipid Res 29:1367-77 |
