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.
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