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J. Biol. Chem., Vol. 278, Issue 29, 27180-27189, July 18, 2003

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Distinct Endosomal Compartments in Early Trafficking of Low Density Lipoprotein-derived Cholesterol^*

Shigeki Sugii , Patrick C. Reid , Nobutaka Ohgami , Hong Du  and Ta-Yuan Chang   ¶

From the Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755 and the Division of Human Genetics, Children's Hospital Medical Center, Cincinnati, Ohio 45229

We previously studied the early trafficking of low density lipoprotein (LDL)-derived cholesterol in mutant Chinese hamster ovary cells defective in Niemann-Pick type C1 (NPC1) using cyclodextrin (CD) to monitor the arrival of cholesterol from the cell interior to the plasma membrane (PM) (Cruz, J. C., Sugii, S., Yu, C., and Chang, T.-Y. (2000) J. Biol. Chem. 275, 4013–4021). We found that newly hydrolyzed cholesterol derived from LDL first appears 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), in this study, we performed additional experiments, including the use of revised CD incubation protocols. We found that prolonged incubation with CD (>30 min) caused cholesterol in internal membrane compartment(s) to redistribute to the PM, where it became accessible to CD. In contrast, a short incubation with CD (5–10 min) did 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 and then moves to the NPC1-containing late endosome/lysosome before reaching the PM or the endoplasmic reticulum.

Received for publication, January 17, 2003 , and in revised form, April 10, 2003.

^* This work was supported by National Institutes of Health Grant HL 36709 (to T.-Y. C.). The Herbert C. Englert Cell Analysis Laboratory was established by equipment grants from the Fannie E. Rippel Foundation and the National Institutes of Health Shared Instrument Program, and its operation is supported in part by NCI Core Grant CA 23108 from the National Institutes of Health (to the Norris Cotton Cancer Center). The costs of publication of this article were defrayed in part by the payment of page charges. This 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 Biochemistry, Dartmouth Medical School, HB 7200, Hanover, NH 03755. Tel.: 603-650-1622; Fax: 603-650-1128; E-mail: Ta.Yuan.Chang{at}dartmouth.edu.

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