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J. Biol. Chem., Vol. 281, Issue 10, 6616-6624, March 10, 2006

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Cholesterol-regulated Translocation of NPC1L1 to the Cell Surface Facilitates Free Cholesterol Uptake^*

Liqing Yu¹, Shantaram Bharadwaj, J. Mark Brown, Yinyan Ma, Wei Du, Matthew A. Davis, Peter Michaely, Pingsheng Liu, Mark C. Willingham, and Lawrence L. Rudel

From the Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1040 and the Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Although NPC1L1 is required for intestinal cholesterol absorption, data demonstrating mechanisms by which this protein facilitates the process are few. In this study, a hepatoma cell line stably expressing human NPC1L1 was established, and cholesterol uptake was studied. A relationship between NPC1L1 intracellular trafficking and cholesterol uptake was apparent. At steady state, NPC1L1 proteins localized predominantly to the transferrin-positive endocytic recycling compartment, where free cholesterol also accumulated as revealed by filipin staining. Interestingly, acute cholesterol depletion induced with methyl--cyclodextrin stimulated relocation of NPC1L1 to the plasma membrane, preferentially to a newly formed "apical-like" subdomain. This translocation was associated with a remarkable increase in cellular cholesterol uptake, which in turn was dose-dependently inhibited by ezetimibe, a novel cholesterol absorption inhibitor that specifically binds to NPC1L1. These findings define a cholesterol-regulated endocytic recycling of NPC1L1 as a novel mechanism regulating cellular cholesterol uptake.

Received for publication, October 12, 2005 , and in revised form, December 22, 2005.

^* This work was supported by intramural grants from the Department of Pathology, Wake Forest University Health Sciences, and by an Atorvastatin research award from Pfizer (to L. Y.), National Institutes of Health Grant HL-49373, and a Merck medical school grant. 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.

¹ To whom correspondence should be addressed: Dept. of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1040. Tel.: 336-716-0920; Fax: 336-716-6279; E-mail: lyu{at}wfubmc.edu.

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