Abstract
In late-stage atherosclerosis, much of the cholesterol in macrophage foam cells resides within enlarged lysosomes. Similarly, human macrophages incubated in vitro with modified LDLs contain significant amounts of lysosomal free cholesterol and cholesteryl ester (CE), which disrupts lysosomal function similar to macrophages in atherosclerotic lesions. The lysosomal cholesterol cannot be removed, even in the presence of strong efflux promoters. Thus, efflux of sterol is prevented. In the artery wall, foam cells interact with triglyceride-rich particles (TRPs) in addition to modified LDLs. Little is known about how TRP metabolism affects macrophage cholesterol. Therefore, we explored the effect of TRP on intracellular CE metabolism. Triglyceride (TG), delivered to lysosomes in TRP, reduced CE accumulation by 50%. Increased TG levels within the cell, particularly within lysosomes, correlated with reductions in CE content. The volume of cholesterol-engorged lysosomes decreased after TRP treatment, indicating cholesterol was cleared. Lysosomal TG also reduced the cholesterol-induced inhibition of lysosomal acidification allowing lysosomes to remain active. Enhanced degradation and clearance of CE may be explained by movement of cholesterol out of the lysosome to sites where it is effluxed. Thus, our results show that introduction of TG into CE-laden foam cells influences CE metabolism and, potentially, atherogenesis.-Ullery-Ricewick, J. C., B. E. Cox, E. E. Griffin, and W. G. Jerome. Triglyceride alters lysosomal cholesterol ester metabolism in cholesteryl ester-laden macrophage foam cells.
Highlights
In late-stage atherosclerosis, much of the cholesterol in macrophage foam cells resides within enlarged lysosomes
triglyceride-rich particle (TRP) can flux through the atherosclerotic lesion, and our studies indicate that uptake of these particles by macrophage foam cells can influence the ability of foam cells to metabolize the extensive lysosomal cholesteryl ester (CE) stores found in late-stage lesions
To determine if TRPs affect the lysosomal metabolism of CE, cellular lipid levels were measured in THP-1 macrophages treated with VLDL and aggregated LDL (aggLDL) at the same time
Summary
In late-stage atherosclerosis, much of the cholesterol in macrophage foam cells resides within enlarged lysosomes. Foam cells interact with triglyceride-rich particles (TRPs) in addition to modified LDLs. Little is known about how TRP metabolism affects macrophage cholesterol. Triglyceride alters lysosomal cholesterol ester metabolism in cholesteryl ester-laden macrophage foam cells. An early event in atherosclerosis is the development of macrophage foam cells These are primarily formed through the uptake of modified lipoproteins by macrophages within the artery wall [1,2,3,4]. In late-stage atherosclerotic lesions, a large amount of both free cholesterol (FC) and cholesteryl ester (CE) accumulates in foam cell lysosomes. Factors that influence the removal of lysosomally sequestered sterol could have profound effects on foam cell biology and atherosclerotic lesion development.
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