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J Biol Chem, Vol. 273, Issue 30, 18915-18922, July 24, 1998
,, and
From the The cholesterol in the lysosomes of cultured
human fibroblasts was determined to constitute ~6% of the cell
total. This pool was enlarged by as much as 10-fold in Niemann-Pick
type C cells. Certain amphiphiles (e.g. U18666A,
progesterone, and imipramine) caused lysosomal cholesterol to increase
to similarly high levels at a rate of ~0.8% of cell cholesterol/h.
Lysosomal cholesterol accumulated even in the absence of exogenous
lipoproteins. Furthermore, nearly all of the lysosomal cholesterol in
both of the two perturbed systems was shown to be derived from the
plasma membrane. Oxysterols known to alter cholesterol movement and
homeostasis blocked lysosomal cholesterol accretion in
amphiphile-treated cells, suggesting that this process is regulated
physiologically.
Treating cells with amphiphiles slightly reduced the efflux of
cholesterol from lysosomes and slightly increased the influx from the
plasma membrane, causing the lysosomal cholesterol compartment to
double in size in ~15 h. After more prolonged amphiphile treatments, a population of buoyant lysosomes appeared that exchanged cholesterol with the plasma membrane completely but slowly. Niemann-Pick type C
lysosomes were similarly buoyant and sluggish.
We conclude that cholesterol circulates bidirectionally between the
plasma membrane and lysosomes. The massive accumulation of lysosomal
cholesterol in the perturbed cells does not appear to reflect disabled
lysosomal transport but rather the formation of lysosomes modified for
lipid storage, i.e. lamellar bodies.
Departments of Pathology and Biochemistry,
Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612 and the ¶ Department of Biochemistry and Molecular Biology,
University of Chicago, Chicago, Illinois 60637
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