Population studies have demonstrated that the prevalence and incidence of coronary heart disease is inversely correlated with the plasma concentration of high density lipoprotein (HDL) cholesterol, suggesting that HDL may protect against atherosclerosis. This protection may be related to the ability of HDL to promote the """"""""clearance"""""""" of cholesterol from cells of the artery wall. In support of this proposal are results from recent studies suggesting that cultured extrahepatic, nonsteroidogenic cells possess specific high-affinity receptors on their cell surfaces that are induced when cells become loaded with cholesterol. More recent studies have identified a 75,000- to 80,000- molecular-weight protein in membranes from cholesterol-loaded cells that appears to be the HDL receptor. The objective of this research proposal is to characterize the physical and biochemical properties of this receptor and its attendant cellular pathway and to assess the role of this receptor in modulation of cellular cholesterol homeostasis in cells of the artery wall. Studies are proposed to isolate and purify the receptor protein and to characterize its properties. With the use of technology in areas of cell biology, molecular biology, and immunochemistry, the cellular pathway for synthesis, processing, and transporting of HDL receptors and its ligands will be studied. In addition, studies will be designed to identify and define possible genetic polymorphisms in the structure of HDL apoproteins and the HDL receptor that could lead to defective receptor-ligand interaction and abnormal cellular cholesterol metabolism. Results from these studies should increase our understanding of the role of HDL in modulation of cholesterol content of the artery and provide insights into possible biochemical and genetic defects that contribute to the pathogenesis of atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL031194-06
Application #
3342250
Study Section
Metabolism Study Section (MET)
Project Start
1983-12-01
Project End
1990-12-31
Budget Start
1989-04-01
Budget End
1990-12-31
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Mendez, A J; Oram, J F (1997) Limited proteolysis of high density lipoprotein abolishes its interaction with cell-surface binding sites that promote cholesterol efflux. Biochim Biophys Acta 1346:285-99
Oram, J F; Yokoyama, S (1996) Apolipoprotein-mediated removal of cellular cholesterol and phospholipids. J Lipid Res 37:2473-91
Francis, G A; Knopp, R H; Oram, J F (1995) Defective removal of cellular cholesterol and phospholipids by apolipoprotein A-I in Tangier Disease. J Clin Invest 96:78-87
Mendez, A J; Anantharamaiah, G M; Segrest, J P et al. (1994) Synthetic amphipathic helical peptides that mimic apolipoprotein A-I in clearing cellular cholesterol. J Clin Invest 94:1698-705
Xia, Y R; Klisak, I; Sparkes, R S et al. (1993) Localization of the gene for high-density lipoprotein binding protein (HDLBP) to human chromosome 2q37. Genomics 16:524-5
Hokland, B M; Slotte, J P; Bierman, E L et al. (1993) Cyclic AMP stimulates efflux of intracellular sterol from cholesterol-loaded cells. J Biol Chem 268:25343-9
McKnight, G L; Reasoner, J; Gilbert, T et al. (1992) Cloning and expression of a cellular high density lipoprotein-binding protein that is up-regulated by cholesterol loading of cells. J Biol Chem 267:12131-41
Hokland, B; Mendez, A J; Oram, J F (1992) Cellular localization and characterization of proteins that bind high density lipoprotein. J Lipid Res 33:1335-42
Zambon, S; Brazg, R; Aviram, M et al. (1992) The effect of probucol on HDL-mediated sterol translocation and efflux from cells. Atherosclerosis 94:51-60
Mendez, A J; Oram, J F; Bierman, E L (1991) Protein kinase C as a mediator of high density lipoprotein receptor-dependent efflux of intracellular cholesterol. J Biol Chem 266:10104-11

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