J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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A more recent version of this article appeared on May 1, 2007

Papers In Press, published online ahead of print February 16, 2007
J. Lipid Res., doi:10.1194/jlr.M600390-JLR200
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Submitted on August 31, 2006
Revised on February 12, 2007
Accepted on February 16, 2007

Effects of cellular cholesterol loading on macrophage foam cell lysosome acidification

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

Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232-2561

Corresponding Author: jay.jerome{at}vanderbilt.edu

Macrophages incubated with mildly oxidized-LDL, aggregated-LDL or cholesteryl ester- rich lipid dispersions accumulate cholesterol in lysosomes followed by an inhibition of lysosomal cholesteryl ester hydrolysis. The variety of cholesterol-containing particles producing inhibition of hydrolysis suggests inhibition may relate to general changes in lysosomes. Lysosome pH is a key mediator of activity and is thus a potential mechanism for lipid-induced inhibition. We investigated the effects of cholesterol accumulation on THP-1 macrophage lysosome pH. Treatment with oxidized-LDL, aggregated-LDL, and dispersions resulted in inhibition of the lysosome’s ability to maintain an active pH and concomitant decreases in cholesteryl ester hydrolysis. Consistent with an overall disruption of lysosome function, exposure to oxidized-LDL or aggregated-LDL reduced lysosomal apo B degradation. The lysosomal cholesterol sequestration and inactivation is not observed in cholesterol equivalent cells loaded using acetylated-LDL. However, acetylated-LDL-derived cholesterol in the presence of progesterone (to block cholesterol egression from lysosomes) inhibited lysosome acidification. Lysosome inhibition was not due to a decrease in the overall levels of the vacuolar-ATPase. However, augmentation of membrane cholesterol in isolated lysosomes inhibited vacuolar-ATPase-dependent pumping of H+-ions into lysosomes. These data indicate that lysosomal cholesterol accumulation alters lysosomes in ways that could exacerbate foam cell formation and influence atherosclerotic lesion development.


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