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Journal of Lipid Research, Vol. 47, 2112-2120, October 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology
* Department of Nutrition, CHU-Sainte-Justine, and University of Montreal, Montreal, Quebec H3T 1C5, Canada
Department of Pediatrics, CHU-Sainte-Justine, and University of Montreal, Montreal, Quebec H3T 1C5, Canada
Department of Biochemistry, CHU-Sainte-Justine, and University of Montreal, Montreal, Quebec H3T 1C5, Canada
** Department of Pathology and Cell Biology, CHU-Sainte-Justine, and University of Montreal, Montreal, Quebec H3T 1C5, Canada
Group on the Functional Development and Physiopathology of the Digestive Tract, Canadian Institute of Health Research, and Department of Cellular Biology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada
Published, JLR Papers in Press, July 7, 2006.
1 To whom correspondence should be addressed. e-mail: emile.levy{at}recherche-ste-justine.qc.ca
Recent studies have documented the presence of Niemann-Pick C1-Like 1 (NPC1L1) in the small intestine and its capacity to transport cholesterol in mice and rats. The current investigation was undertaken to explore the localization and function of NPC1L1 in human enterocytes. Cell fractionation experiments revealed an NPC1L1 association with apical membrane of the enterocyte in human jejunum. Signal was also detected in lysosomes, endosomes, and mitochondria. Confirmation of cellular NPC1L1 distribution was obtained by immunocytochemistry. Knockdown of NPC1L1 caused a decline in the ability of Caco-2 cells to capture micellar [14C]free cholesterol. Furthermore, this NPC1L1 suppression resulted in increased and decreased mRNA levels and activity of HMG-CoA reductase, the rate-limiting step in cholesterol synthesis, and of ACAT, the key enzyme in cholesterol esterification, respectively. An increase was also noted in the transcriptional factor sterol-regulatory element binding protein that modulates cholesterol homeostasis. Efforts were devoted to define the impact of NPC1L1 knockdown on other mediators of cholesterol uptake. RT-PCR evidence is presented to show the significant decrease in the levels of scavenger receptor class B type I (SR-BI) with no changes in ABCA1, ABCG5, and cluster determinant 36 in NPC1L1-deficient Caco-2 cells. Together, our data suggest that NPC1L1 contributes to intestinal cholesterol homeostasis and possibly cooperates with SR-BI to mediate cholesterol absorption in humans.
Supplementary key words enterocyte • 3-hydroxy-3-methylglutaryl-coenzyme A reductase • acyl-coenzyme A:cholesterol acyltransferase • scavenger receptor class B type I • sterol-regulatory element binding protein • cluster determinant 36 • ATP binding cassette transporter A1 • ATP binding cassette transporter G5 • Niemann-Pick C1-Like 1
Abbreviations: CD36, cluster determinant 36; CE, cholesteryl ester; FC, free cholesterol; GFP, green fluorescent protein; NPC1L1, Niemann-Pick C1-Like 1; RNAi, RNA interference; siRNA, small interfering RNA; SR-BI, scavenger receptor class B type I; SREBP, sterol-regulatory element binding protein
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