Abstract

Human monocytes and murine/rat macrophages metabolize modified lipoproteins, such as acetylated LDL, through a specific cell surface receptor. Metabolism of modified lipoproteins produces massive cholesteryl ester deposition as cytoplasmic droplets, giving the cells the appearance of arterial foam cells.
Specific aims of the proposal are: (a) to isolate a receptor for abnormal lipoproteins from murine macrophages in quantities sufficient for amino acid and partial sequence analysis (b) to develop polyclonal and monoclonal reagents specific for the murine and human receptor; (c) to isolate cell mutants defective in synthesis and/or function of the receptor. The information and reagents obtained will permit development of probes specific for different regions of the receptor, allow definition of regions of the receptor important for its function, allow identification of the receptor in different cell types and species, allow localization of the receptor in the arterial lesion, and provide information on the synthesis and regulation of the receptor. Foam cell formation is a key event in the development of atheromatous lesions. A receptor for modified lipoproteins may play a role in this foam cell formation in vivo. Combined biochemical and immunochemical data will facilitate evaluation of the receptor's role in atherogenesis and provide information useful in developing reagents to modulate the function of the receptor. In addition to a role in atherogenesis, the receptor may be of importance in regulating macrophage functions such as protease secretion. Biochemical and immunochemical data on the receptor will thus be of importance in further understanding control of macrophage physiology.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL034111-02
Application #
3346702
Study Section
Metabolism Study Section (MET)
Project Start
1985-04-01
Project End
1988-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Mims, M P; Darnule, A T; Tovar, R W et al. (1994) A nonexchangeable apolipoprotein E peptide that mediates binding to the low density lipoprotein receptor. J Biol Chem 269:20539-47
Orekhov, A N; Tertov, V V; Sobenin, I A et al. (1992) Sialic acid content of human low density lipoproteins affects their interaction with cell receptors and intracellular lipid accumulation. J Lipid Res 33:805-17
Ottnad, E; Via, D P; Frubis, J et al. (1992) Differentiation of binding sites on reconstituted hepatic scavenger receptors using oxidized low-density lipoprotein. Biochem J 281 ( Pt 3):745-51
Via, D P; Kempner, E S; Pons, L et al. (1992) Mouse macrophage receptor for acetylated low density lipoprotein: demonstration of a fully functional subunit in the membrane and with purified receptor. Proc Natl Acad Sci U S A 89:6780-4
Lenz, M L; Hughes, H; Mitchell, J R et al. (1990) Lipid hydroperoxy and hydroxy derivatives in copper-catalyzed oxidation of low density lipoprotein. J Lipid Res 31:1043-50
Via, D P; Pons, L; Dennison, D K et al. (1989) Induction of acetyl-LDL receptor activity by phorbol ester in human monocyte cell line THP-1. J Lipid Res 30:1515-24
Kudo, K; Emmons, G T; Casserly, E W et al. (1989) Inhibitors of sterol synthesis. Chromatography of acetate derivatives of oxygenated sterols. J Lipid Res 30:1097-111
Bernini, F; Via, D P; Bocan, T M et al. (1988) Lactosaminated Fab fragments specific for low density lipoproteins/hepatocyte targeting and hypolipoproteinemic activity. Arteriosclerosis 8:825-31
Ottnad, E; Via, D P; Sinn, H et al. (1988) Evidence in liver for a disulphide-linked scavenger receptor containing a binding site for acetylated low-density lipoprotein and maleylated bovine serum albumin. Biochem J 253:835-8
Dresel, H A; Friedrich, E; Via, D P et al. (1987) Binding of acetylated low density lipoprotein and maleylated bovine serum albumin to the rat liver: one or two receptors? EMBO J 6:319-26

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