| Summary: | Macrophage foam cells are prominent in atherosclerotic lesions. In late stage disease, much of the cholesterol accumulation within foam cells is found in large, swollen, lysosomes. Tissue culture models using human macrophages incubated with various modified LDLs indicate that cholesterol accumulation within lysosomes can disrupt lysosome function leading to foam cells with significant lysosomal free and esterified cholesterol, similar to cells found in atherosclerotic lesions. The cholesterol is trapped and not accessible for efflux, even in the presence of strong efflux promoters. In the artery wall, however, the foam cells are bathed not only in modified LDLs but other lipid particles as well, including triglyceride-rich particles (TRPs), such as VLDL. Little is known about how metabolism of TRPs might affect cholesterol metabolism and, specifically, the formation of cholesterol-rich macrophage foam cells. The studies presented in this dissertation explore the effect of TRPs on intracellular cholesterol metabolism. Results show that cellular and, specifically, lysosomal triglyceride (TG) enrichment reduces cholesteryl ester (CE) accumulation by over 50% in THP-1 macrophage foam cells. TG, delivered to the cell as a component of TRP, decreases the volume of lysosomes providing further evidence of increased lysosomal cholesterol clearance. Cholesterol accumulation in lysosomes inhibits acidification of lysosomes. In contrast, lysosomal TG enrichment reduced this inhibition and allowed lysosomes to remain active. Maintained lysosomal activity results in enhanced degradation and clearance of internalized CE and facilitates the movement of cholesterol out of the lysosome, to sites where it can be utilized for cholesterol efflux. In sum, our results show that introduction of TG into CE-laden foam cells influences CE metabolism and, potentially, atherogenesis.
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