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Journal of Lipid Research, Vol. 46, 2052-2060, October 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Aggregated LDL and lipid dispersions induce lysosomal cholesteryl ester accumulation in macrophage foam cells

Evelyn E. Griffin^*, Jody C. Ullery^*, Brian E. Cox^* and W. Gray Jerome^1,*,

^* Departments of Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232
Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232

Published, JLR Papers in Press, July 16, 2005. DOI 10.1194/jlr.M500059-JLR200

¹ To whom correspondence should be addressed. e-mail: jay.jerome{at}vanderbilt.edu

Macrophage foam cells in atherosclerotic lesions accumulate substantial cholesterol stores within large, swollen lysosomes. Previous studies with mildly oxidized low density lipoprotein (OxLDL)-treated THP-1 macrophages suggest an initial buildup of free cholesterol (FC), followed by an inhibition of lysosomal cholesteryl ester (CE) hydrolysis and a subsequent lysosomal accumulation of unhydrolyzed lipoprotein CE. We examined whether other potential sources of cholesterol found within atherosclerotic lesions could also induce similar lysosomal accumulation. Biochemical analysis combined with microscopic analysis showed that treatment of THP-1 macrophages with aggregated low density lipoprotein (AggLDL) or CE-rich lipid dispersions (DISP) produced a similar lysosomal accumulation of both FC and CE. Cotreatment with an ACAT inhibitor, CP113,818, confirmed that the CE accumulation was primarily the result of the inhibition of lysosomal CE hydrolysis. The rate of unhydrolyzed CE buildup was more rapid with DISP than with AggLDL. However, with both treatments, FC appeared to accumulate in lysosomes before the inhibition in hydrolysis and CE accumulation, a sequence shared with mildly OxLDL.

Thus, lysosomal accumulation of FC and CE can be attributable to more general mechanisms than just the inhibition of hydrolysis by oxidized lipids.

Abbreviations: AcLDL, acetylated low density lipoprotein; AggLDL, aggregated low density lipoprotein; CE, cholesteryl ester; DISP, lipid dispersions; EEA-1, early endosomal antigen-1; EM, electron microscopy; FC, free cholesterol; HMM, human monocyte-derived macrophages; LAMP-1, lysosomal-associated membrane protein-1; OxLDL, oxidized low density lipoprotein; TBARS, thiobarbituric acid-reactive substances; TPA, phorbol ester

Supplementary key words atherosclerosis • lysosome • microscopy • low density lipoprotein

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