Atherosclerosis is characterized by the focal accumulation of plasma-derived lipids in the arterial wall. 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 metabolism is an essential component in describing the biochemical events associated with the development of atherosclerosis. Current knowledge suggests that the transfer of triglyceride and cholesteryl ester between lipoproteins as promoted by the lipid transfer protein is an integral component of lipoprotein metabolism, although the details of its metabolic role have not been elucidated. In the present proposal, two general approaches have been taken to better characterize the plasma-borne lipid transfer protein (LTP) and its function. 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 which occur in animals fed atherogenic diets. In the second, three specific aims seek to evaluate the biological role of LTP. These are: 1) to define the role of LTP in the catabolism of very low density lipoproteins and in the regulation of lecithin:cholesterol acyltransferase activity, 2) to evaluate the capacity of LTP to promote lipid transfer between lipoproteins and cells, and 3) to measure LTP in the plasma of normal and hyperlipemic subjects as a correlate to lipoprotein metabolism studies. In the first of these studies, the ability of LTP to facilitate lipoprotein metabolism will be evaluated in assays that reconstitute isolated plasma enzymes and lipoproteins. The effect of native and in vitro-modified lipoproteins on these metabolic events will also be studied. In Study #2, the protein-mediated transfer of triglyceride and cholesteryl ester to (and from) confluent bovine endothelial cells in culture will be studied. And in the last aim, the level of LTP and its inhibitor will be quantitated after their separation by ion exchange or affinity chromatography. The studies of this proposal are an integral part of the Principal Investigator's long-term interests in lipoprotein metabolism, in the regulation of this complex process, and in the relationship of the events to atherosclerosis. These interests are addressed in the present proposal as they relate to the lipid transfer protein.
| Greenberg, S S; Diecke, F P; Cantor, E et al. (1990) Inhibition of sympathetic neurotransmitter release by modulators of cyclic GMP in canine vascular smooth muscle. Eur J Pharmacol 187:409-23 |
| 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 |
| Morton, R E (1986) Specificity of lipid transfer protein for molecular species of cholesteryl ester. J Lipid Res 27:523-9 |
| Morton, R E (1985) Binding of plasma-derived lipid transfer protein to lipoprotein substrates. The role of binding in the lipid transfer process. J Biol Chem 260:12593-9 |
