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Papers In Press, published online ahead of print December 30, 2005
Pathology-Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040
Corresponding Author: lyu{at}wfubmc.edu
While Niemann-Pick C1-Like 1 (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. In the steady state, the NPC1L1 protein was predominantly localized to the transferrin-positive endocytic recycling compartment where free cholesterol also accumulated as revealed by filipin staining. Interestingly, acute cholesterol depletion induced with methyl-
J. Biol. Chem, 10.1074/jbc.M511123200
Submitted on October 12, 2005
Revised on December 22, 2005
Accepted on December 30, 2005
Cholesterol-regulated translocation of Niemann-pick C1-like 1 to the cell surface facilitates free cholesterol uptake
-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.
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