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J. Biol. Chem., Vol. 278, Issue 17, 14850-14856, April 25, 2003
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From the Department of Physiology, Tufts University School of
Medicine, Boston, Massachusetts 02111
Niemann-Pick disease type C (NPC) is
characterized by lysosomal storage of cholesterol and gangliosides,
which results from defects in intracellular lipid trafficking. Most
studies of NPC1 have focused on its role in intracellular cholesterol
movement. Our hypothesis is that NPC1 facilitates the egress of
cholesterol from late endosomes, which are where active NPC1 is
located. When NPC1 is defective, cholesterol does not exit late
endosomes; instead, it is carried along to lysosomal storage bodies,
where it accumulates. In this study, we addressed whether
cholesterol is transported from endosomes to the plasma membrane before
reaching NPC1-containing late endosomes. Our study was conducted in
Chinese hamster ovary cell lines that display the classical NPC
biochemical phenotype and belong to the NPC1 complementation group. We
used three approaches to test whether low density lipoprotein
(LDL)-derived cholesterol en route to NPC1-containing organelles
passes through the plasma membrane. First, we used cyclodextrins to
measure the arrival of LDL cholesterol at the plasma membrane and found
that the arrival of LDL cholesterol in a cyclodextrin-accessible pool
was significantly delayed in NPC1 cells. Second, the movement of LDL
cholesterol to NPC1-containing late endosomes was assessed and found to
be normal in Chinese hamster ovary mutant 3-6, which exhibits
defective movement of plasma membrane cholesterol to intracellular
membranes. Third, we examined the movement of plasma membrane
cholesterol to the endoplasmic reticulum and found that this pathway is
intact in NPC1 cells, i.e. it does not pass through
NPC1-containing late endosomes. Our data suggest that in NPC1 cells LDL
cholesterol traffics directly through endosomes to lysosomes, bypassing
the plasma membrane, and is trapped there because of dysfunctional NPC1.
The Transport of Low Density Lipoprotein-derived Cholesterol to
the Plasma Membrane Is Defective in NPC1 Cells*
*
This work was supported by National Institutes of Health
Grant DK49564, National Institutes of Health Training Grant DK07704, and by the Center for Gastroenterology Research on Absorptive and
Secretory Processes, Molecular Biology and Image Analysis Core
(NIDDK P30 DK34928).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Physiology,
Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA
02111. Tel.: 617-636-6945; Fax: 617-636-0445; E-mail: Laura.Liscum@Tufts.Edu.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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