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Papers In Press, published online ahead of print March 1, 2003
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Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03755
Corresponding Author: Ta.Yuan.Chang{at}Dartmouth.edu
Niemann-Pick type C1 disease (NPC1) is an inherited neurovisceral lipid storage disorder, hallmarked by the intracellular accumulation of unesterified cholesterol and glycolipids in endocytic organelles. Cells acquire cholesterol through exogenous uptake and endogenous biosynthesis. NPC1 participates in the trafficking of low density lipoprotein (LDL)-derived cholesterol; however, its role in the trafficking of cholesterol endogenously synthesized has received much less attention. Previously, using mutant CHO cells, we showed that endogenously synthesized cholesterol (endoCHOL) moves from the ER to the PM independent of NPC1; after arriving at the PM, it moves between the PM and internal compartments. The movement of endoCHOL from internal membranes back to the PM and to the ER for esterification was shown to be defective in NPC1 cells. To test the generality of these findings, we have examined the trafficking of endoCHOL in four different physiologically relevant cell types, isolated from wild-type, heterozygous, and homozygous BALB/c NPC1NIH mice. The results show that all NPC1 homozygous cell types (embryonic fibroblasts, peritoneal macrophages, hepatocytes, and cerebellar glial cells) exhibit partial trafficking defects, with macrophages and glial cells most prominently affected. Our findings suggest that endoCHOL may contribute significantly to the overall cholesterol accumulation observed in selective tissues affected by the NPC disease.
Revised on February 25, 2003
Accepted on February 25, 2003
Trafficking defects in endogenously synthesized cholesterol (endoCHOL) in fibroblasts, macrophages, hepatocytes, and glial cells from the niemann-pick type C1 mice
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