At specific important stages of atherosclerosis, foam cells accumulate cholesterol within large swollen lysosomes. Numerous studies have suggested the importance of this phenomenon in the pathogenesis of the disease, but the cause of this lysosomal accumulation is unknown. The long term goal of our research is to understand both the mechanism and importance of lysosomal lipid engorgement in atherogenesis. The experiments proposed in this application will explore the mechanism by which lysosomal lipid accumulation occurs. For these studies, two lipoproteins will be used to load cholesterol into cells. One (ox-LDL) promotes significant lysosomal accumulation of cholesterol (ox-LDL) while cholesterol from the other (ac-LDL) appears to be efficiently cleared from lysosomes and accumulates within cytoplasmic inclusion. We will compare metabolism of cholesterol from these two lipoproteins in order to correlate differences with alterations in their storage patterns. This involves relating quantitative ultrastructural data on lipid accumulation within lysosomes and cytoplasmic inclusions to biochemical measures of cholesterol metabolism and accumulation. Specifically, we will determine to what extent cellular transport, lysosomal hydrolysis, cytoplasmic reesterification, cytoplasmic hydrolysis, and cellular cholesterol efflux play a role in lysosomal accumulation. As an early occurrence in atherogenesis, lysosomal lipid accumulation is potentially very important in disease progression. The integrated use of ultrastructural quantitation and lipid biochemistry will provide a detailed understanding of the mechanism of this early event and, in turn, will help better define the mechanism of this early event and, in turn, will help better define the process of atherosclerotic lesion progression. In addition, the research could provide important clues as to possible early treatment modalities.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL049148-01A2
Application #
2225259
Study Section
Pathology A Study Section (PTHA)
Project Start
1995-05-01
Project End
1998-04-30
Budget Start
1995-05-01
Budget End
1996-04-30
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Pathology
Type
Schools of Medicine
DUNS #
041418799
City
Winston-Salem
State
NC
Country
United States
Zip Code
27106
Chen, Bin; Ren, Xuefeng; Neville, Tracey et al. (2009) Apolipoprotein AI tertiary structures determine stability and phospholipid-binding activity of discoidal high-density lipoprotein particles of different sizes. Protein Sci 18:921-35
Ullery-Ricewick, Jody C; Cox, Brian E; Griffin, Evelyn E et al. (2009) Triglyceride alters lysosomal cholesterol ester metabolism in cholesteryl ester-laden macrophage foam cells. J Lipid Res 50:2014-26
Jerome, W Gray; Cox, Brian E; Griffin, Evelyn E et al. (2008) Lysosomal cholesterol accumulation inhibits subsequent hydrolysis of lipoprotein cholesteryl ester. Microsc Microanal 14:138-49
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Jerome, W Gray (2006) Advanced atherosclerotic foam cell formation has features of an acquired lysosomal storage disorder. Rejuvenation Res 9:245-55
Ren, Xuefeng; Zhao, Lei; Sivashanmugam, Arun et al. (2005) Engineering mouse apolipoprotein A-I into a monomeric, active protein useful for structural determination. Biochemistry 44:14907-19
Griffin, Evelyn E; Ullery, Jody C; Cox, Brian E et al. (2005) Aggregated LDL and lipid dispersions induce lysosomal cholesteryl ester accumulation in macrophage foam cells. J Lipid Res 46:2052-60
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Jerome, W Gray; Handt, Stefan; Hantgan, Roy R (2005) Endothelial cells organize fibrin clots into structures that are more resistant to lysis. Microsc Microanal 11:268-77

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