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Papers In Press, published online ahead of print April 28, 2003
Biochemistry Dept., Dartmouth Medical School, Hanover, NH 03755
Corresponding Author: Ta.Yuan.Chang{at}Dartmouth.Edu
We had previously studied the early trafficking of LDL-derived cholesterol in mutant CHO cells defective in Niemann-Pick Type C1 (NPC1) by using cyclodextrin (CD) to monitor the arrival of cholesterol from the cell interior to the plasma membrane (PM). It was found that newly-hydrolyzed cholesterol derived from LDL first appeared in certain CD-accessible pool(s), which we assumed to be the PM, before accumulating in the late endosome/lysosome where NPC1 resides. To determine the identity of the early, CD-accessible pool(s), we now perform additional experiments, including the use of revised CD incubation protocols. We find that prolonged incubation of CD (> 30 min) causes cholesterol in internal membrane compartment(s) to redistribute to the PM where it becomes accessible to CD. In contrast, short incubation of CD (5 to 10 min) does not cause such an effect. We also show that one of the early compartments contains acid lipase (AL), the enzyme required for liberating cholesterol from cholesteryl ester in LDL. Biochemical and microscopic evidence indicates that most of the AL is present in endocytic compartment(s) distinct from the late endosome/lysosome. Our results suggest that cholesterol is liberated from LDL cholesteryl ester in the hydrolytic compartment containing AL, then moves to the NPC1-containing late endosome/lysosome before reaching the PM or the ER.
J. Biol. Chem, 10.1074/jbc.M300542200
Submitted on January 17, 2003
Revised on April 10, 2003
Accepted on April 28, 2003
Distinct endosomal compartments in early trafficking of low density lipoprotein-derived cholesterol
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