Abnormal Lysosomal Processing of Internalized Cholesteryl Esters In Macrophages





W.G. Jerome

Vanderbilt University School of Medicine, Department of Pathology, 1161 21st Ave, South, Nashville, TN 37232-2561, USA



Progressive lysosomal dysfunction has been associated with aging. One cause of this dysfunction is build up of indigestible material within lysosomes and a resultant inhibition of lysosome function. In the case of lysosomal storage diseases with well characterized genetic defects, the link between defect and dysfunction is clear and usually occurs early in life. It is generally associated with mutations in particular enzymes responsible for lysosomal digestion of internalized or autophagic material. Since specific precursors cannot be degraded for removal, they accumulate within the lysosome. Another well characterize cause of storage disorders is illustrated by black lung disease, where indigestible material is taken up by cells and delivered to lysosomes and can remain their for decades.

Less well understood are situations where normally digestible material becomes indigestible. Disorders of this category usually are manifested later in life. Given the diversity of such states, there are undoubtedly a variety of etiologies explaining these occurrences. One such situation is the lysosomal cholesterol accumulation that accompanies atherosclerosis. THP-1 and human monocyte-derived macrophages mimic this lysosomal cholesterol accumulation when incubated with mildly oxidized LDL (ox-LDL), aggregates of LDL (agg-LDL) or cholesteryl ester (CE)-rich lipid dispersions (DISP). The cholesterol accumulation seen under these conditions can be divided into an initial free cholesterol (FC) stage and a subsequent CE stage. In the initial stage, lysosomal hydrolysis of exogenous CE is normal but the resulting FC is not efficiently transported out of lysosomes. In the second phase, cholesteryl ester hydrolysis is inhibited leading to an accumulation of exogenously derived CE. Studies with the pH-sensitive dye Lysosensor Yellow/Blue (Molecular Probes) indicate that in the CE stage lysosomes loose their ability to maintain an acidic environment. Loss of acidity of course would be expected to impair lysosome function. Our studies suggest the inability to maintain an acid environment is, in part, related to the initial accumulation of FC within lysosomes. One line of evidence for this is that CE internalized as part of acetylated LDL (ac-LDL) is efficiently hydrolyzed and the resultant FC transported out of lysosomes. However, incubation of cells with ac-LDL in the presence of progesterone leads to a lysosomal accumulation of FC and loss of acidity. If sufficient unesterified cholesterol accumulates in lysosomes, the inhibition of CE hydrolysis continues even if the progesterone block is removed. Predictably, the increase in lysosome pH also inhibits proteolytic degradation of apolipoprotein B, a component of ox- and agg-LDL.

Our data leads us to suggest that if lysosomal FC levels reach a critical concentration they produce a long-lived, acquired defect that impairs most, if not all, lysosome function. Since some lysosomal products can act as signal molecules within cells, these defects can impair cell function and possibly cell survival.




Key words: lysosome cholesterol atherosclerosis pH







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