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Papers In Press, published online ahead of print July 7, 2006
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Nutrition, Hôpital Ste-Justine, Montréal, Québec H3T 1C5
Corresponding Author: 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 facilitate cholesterol transport in mice and rats. The current investigation was undertaken to explore the localization and function of NPC1L1 in human epithelial cells of the small intestine. Cell fractionation experiments revealed the association of NPC1L1 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 the high resolution protein A-gold immunocytochemical approach. In order to define the role of NPC1L1 in intestinal cholesterol absorption, we knocked down its expression in Caco-2 cells. RNA interference-mediated NPC1L1 cutback manifestly caused declined ability of Caco-2 cells to capture micellar free [14C]-cholesterol without alterations in cell viability and differentiation. Furthermore, this NPC1L1 suppression resulted in increased and decreased mRNA levels and activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting step in cholesterol synthesis, and of acylcoenzyme A:cholesterol acyltransferase, 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 fall in the levels of scavenger receptor class B type I with no changes in ATP Binding Cassette Transporter (ABC) A1, ABCG5, and Custer Determinant 36 in NPC1L1-deficient Caco-2 cells. Taken together, our data suggest that NPC1L1 contributes to intestinal cholesterol homeostasis and possibly cooperates with SR-BI to mediate cholesterol absorption in humans.
Revised on July 5, 2006
Accepted on July 7, 2006
Localization and role of NPC1L1 in cholesterol absorption in human intestine
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