Localization and role of NPC1L1 in cholesterol absorption in human intestine

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. 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. Abbreviations CD36cluster determinant 36CEcholesteryl esterFCfree cholesterolGFPgreen fluorescent proteinNPC1L1Niemann-Pick C1-Like 1RNAiRNA interferencesiRNAsmall interfering RNASR-BIscavenger receptor class B type ISREBPsterol-regulatory element binding protein cluster determinant 36 cholesteryl ester free cholesterol green fluorescent protein Niemann-Pick C1-Like 1 RNA interference small interfering RNA scavenger receptor class B type I sterol-regulatory element binding protein Coronary heart disease is the most important clinical manifestation of atherosclerosis and remains the main cause of death in developed societies. Hypercholesterolemia is beyond doubt the most prominent risk factor for the development of atherosclerosis, which is caused by derangements in cholesterol homeostasis (i.e., intestinal uptake, endogenous synthesis and metabolism, transport in lipoprotein particles, and biliary excretion). At present, there are increasing efforts to understand the physiology of intestinal fat transport in view of the positive relationship between cholesterol absorption, plasma cholesterol levels, and coronary heart disease (1Huff M.W. Dietary cholesterol, cholesterol absorption, postprandial lipemia and atherosclerosis..Can. J. Clin. Pharmacol. 2003; 10 (Suppl. A): 26-32PubMed Google Scholar, 2McMurry M.P. Connor W.E. Lin D.S. Cerqueira M.T. Connor S.L. The absorption of cholesterol and the sterol balance in the Tarahumara Indians of Mexico fed cholesterol-free and high cholesterol diets..Am. J. Clin. Nutr. 1985; 41: 1289-1298Crossref PubMed Scopus (48) Google Scholar, 3Steiner G. The need for a different cholesterol lowering drug..Can. J. Clin. Pharmacol. 2003; 10 (Suppl. A): 4-6PubMed Google Scholar, 4Turley S.D. Daggy B.P. Dietschy J.M. Psyllium augments the cholesterol-lowering action of cholestyramine in hamsters by enhancing sterol loss from the liver..Gastroenterology. 1994; 107: 444-452Abstract Full Text PDF PubMed Scopus (88) Google Scholar). Additionally, augmented dietary fat and cholesterol intake have been tightly linked to the increased incidence of other diseases, such as cancer, diabetes, and obesity (5Hannah J.S. Howard B.V. Dietary fats, insulin resistance, and diabetes..J. Cardiovasc. Risk. 1994; 1: 31-37Crossref PubMed Google Scholar, 6Vessby B. Nutrition, lipids and diabetes mellitus..Curr. Opin. Lipidol. 1995; 6: 3-7Crossref PubMed Scopus (24) Google Scholar, 7Mehta N. Hordines J. Volpe C. Doerr R. Cohen S.A. Cellular effects of hypercholesterolemia in modulation of cancer growth and metastasis: a review of the evidence..Surg. Oncol. 1997; 6: 179-185Crossref PubMed Scopus (18) Google Scholar). In stark contrast to previous tenets suggesting that cholesterol uptake occurs as a passive diffusion down a concentration gradient, more and more investigators now support protein-mediated cholesterol absorption. Curiously, protein transporters intervening in intestinal cholesterol movement have not yet been ascertained. A few recent studies have proposed scavenger receptor class B type I (SR-BI) as a candidate protein involved in dietary cholesterol transport (8Cai S.F. Kirby R.J. Howles P.N. Hui D.Y. Differentiation-dependent expression and localization of the class B type I scavenger receptor in intestine..J. Lipid Res. 2001; 42: 902-909Abstract Full Text Full Text PDF PubMed Google Scholar, 9Hauser H. Dyer J.H. Nandy A. Vega M.A. Werder M. Bieliauskaite E. Weber F.E. Compassi S. Gemperli A. Boffelli D. et al.Identification of a receptor mediating absorption of dietary cholesterol in the intestine..Biochemistry. 1998; 37: 17843-17850Crossref PubMed Scopus (223) Google Scholar, 10Altmann S.W. Davis Jr., H.R. Yao X. Laverty M. Compton D.S. Zhu L.J. Crona J.H. Caplen M.A. Hoos L.M. Tetzloff G. et al.The identification of intestinal scavenger receptor class B, type I (SR-BI) by expression cloning and its role in cholesterol absorption..Biochim. Biophys. Acta. 2002; 1580: 77-93Crossref PubMed Scopus (140) Google Scholar, 11Levy E. Menard D. Suc I. Delvin E. Marcil V. Brissette L. Thibault L. Bendayan M. Ontogeny, immunolocalisation, distribution and function of SR-BI in the human intestine..J. Cell Sci. 2004; 117: 327-337Crossref PubMed Scopus (45) Google Scholar). On the other hand, the involvement of SR-BI in cholesterol uptake has been questioned because intestinal cholesterol absorption was shown to be unaffected by deletion of the SR-BI gene in mice (10Altmann S.W. Davis Jr., H.R. Yao X. Laverty M. Compton D.S. Zhu L.J. Crona J.H. Caplen M.A. Hoos L.M. Tetzloff G. et al.The identification of intestinal scavenger receptor class B, type I (SR-BI) by expression cloning and its role in cholesterol absorption..Biochim. Biophys. Acta. 2002; 1580: 77-93Crossref PubMed Scopus (140) Google Scholar, 12Mardones P. Quinones V. Amigo L. Moreno M. Miquel J.F. Schwarz M. Miettinen H.E. Trigatti B. Krieger M. VanPatten S. et al.Hepatic cholesterol and bile acid metabolism and intestinal cholesterol absorption in scavenger receptor class B type I-deficient mice..J. Lipid Res. 2001; 42: 170-180Abstract Full Text Full Text PDF PubMed Google Scholar). Other laboratories suggested that cluster determinant 36 (CD36) may provide a conduit for the movement of cholesterol from the brush-border membrane into the intestinal mucosa (13Werder M. Han C.H. Wehrli E. Bimmler D. Schulthess G. Hauser H. Role of scavenger receptors SR-BI and CD36 in selective sterol uptake in the small intestine..Biochemistry. 2001; 40: 11643-11650Crossref PubMed Scopus (83) Google Scholar), but such assumptions have not been confirmed by in vitro and in vivo studies. Using a genetic approach, Niemann-Pick C1-Like 1 (NPC1L1) has been identified as a critical mediator of cholesterol absorption (14Altmann S.W. Davis Jr., H.R. Zhu L.J. Yao X. Hoos L.M. Tetzloff G. Iyer S.P. Maguire M. Golovko A. Zeng M. et al.Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption..Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1421) Google Scholar). Indeed, NPC1L1 has been found abundantly expressed in animal intestine, and mice deficient in NPC1L1 displayed marked reductions in sterol absorption (14Altmann S.W. Davis Jr., H.R. Zhu L.J. Yao X. Hoos L.M. Tetzloff G. Iyer S.P. Maguire M. Golovko A. Zeng M. et al.Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption..Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1421) Google Scholar). Furthermore, genetic variation in NPC1L1 appeared to contribute to variability in cholesterol uptake and plasma levels of low density lipoproteins (15Cohen J.C. Pertsemlidis A. Fahmi S. Esmail S. Vega G.L. Grundy S.M. Hobbs H.H. Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels..Proc. Natl. Acad. Sci. USA. 2006; 103: 1810-1815Crossref PubMed Scopus (328) Google Scholar). However, there were only limited biochemical and immunocytochemical analyses revealing NPC1L1 in the gut. To our knowledge, studies have mostly been carried out in and more to intestinal is to the role of NPC1L1 in sterol homeostasis in humans. To into the localization of NPC1L1 in human intestine, an was undertaken protein to To support to fractionation was carried out to NPC1L1 protein were also in the Caco-2 a human intestinal for metabolism and lipoprotein E. M. E. Caco-2 cells as a for intestinal lipoprotein synthesis and J. 1995; PubMed Scopus Google Scholar, lipoprotein synthesis and Lipid Res. 1995; PubMed Scopus Google Scholar), to the of NPC1L1 in intestinal cholesterol transport and studies were to the relationship between ABCA1, ABCG5, and sterol-regulatory element binding protein a factor that to and cholesterol homeostasis A that the cholesterol of and Natl. Acad. Sci. USA. PubMed Scopus Google Scholar). human small intestine was obtained from with the of C. and were The was by the of the of The small intestine was into and The were with and intestine were obtained from with disease of different of the found to the was in as by from the were to were by the for the of the and by the of were by in and for and in to our M. a for the localization of 1: Scopus Google Scholar). were by to of the different were on with and for immunocytochemistry. immunocytochemical were to the presence of NPC1L1 in intestinal as E. S. Delvin E. Menard D. C. C. I. E. G. Bendayan M. of protein in the role in the of 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, M. immunocytochemical the protein PubMed Scopus Google Scholar, M. 1995; PubMed Scopus Google Scholar). the were in for on a of and to a of the the were with to were to the and on a of protein for The were with with and were with and with a NPC1L1 were a of in with protein which were 10 to our E. S. Delvin E. Menard D. C. C. I. E. G. Bendayan M. of protein in the role in the of 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). experiments were to the of the was on with the protein were also with the protein the step to for of the protein to Caco-2 cells were with in and and with Caco-2 cells were in were cells were a density of 1 on with in with The were and for which Caco-2 cells are and for metabolism V. Delvin E. E. L. M. C. E. of synthesis, and lipoprotein by J. 2002; PubMed Scopus Google Scholar, Suc I. C. M. E. E. the of Caco-2 cells to and J. PubMed Google Scholar). Caco-2 cells were on as and for were with small interfering RNA NPC1L1 and to the were in and cells were The of and were green fluorescent protein Caco-2 cells were with as cells were to and in B be were to and to cells were and only the of NPC1L1 was with and and to the expression the were and were and into the cells were with the on and were and was and with and to the presence of the The was with a the and the NPC1L1 Caco-2 cells with were as experiments for ACAT, HMG-CoA reductase, ABCA1, and as as a were the of were for for and for were on to to the of the from human Caco-2 cells To the presence of intestinal Caco-2 cells were and for as E. D. Thibault L. Delvin E. Menard D. modulation of and in human gene expression and mRNA are not PubMed Scopus Google Scholar). were in and on a and binding of the were by the of the of this not the protein of the no was noted on this knockdown of the of our The of was detected with were and the of NPC1L1 was a with a and were carried out to SR-BI and obtained from To cholesterol uptake, a micellar was 10 of 1 cholesterol, and Caco-2 cells were in the micellar for 1 activity was as Suc I. C. M. E. E. the of Caco-2 cells to and J. PubMed Google Scholar, E. N. Thibault L. D. Delvin E. Menard D. Lipid and lipoprotein synthesis by the human J. Google Scholar). The of cellular and of of the was by the of for The was into by the of 10 by and an to for The activity of was by of activity to the of cellular protein to the in a of cholesterol, and 1 for 10 the was by by free cholesterol and cholesteryl ester as The and were by and from human was The brush-border membrane from Caco-2 cells and mucosa was as I. Bendayan M. C. Delvin E. M. E. of protein in intestinal brush-border Cell Res. 2004; PubMed Scopus Google Scholar). was in and 10 and as The was by for 10 and was to a concentration of 10 on the was for 10 to and the was for 1 to a of from the experiments were are expressed as was were to the distribution of NPC1L1 the human small intestine and in Caco-2 cells. with of protein were by and of the NPC1L1 on the that the a NPC1L1 protein the and Caco-2 cells were with a NPC1L1 data suggested a role for NPC1L1 in intestinal cells. Confirmation was obtained by RT-PCR the NPC1L1 mRNA in the To the expression of was carried out in the human small the presence and localization of NPC1L1 in cells. was mostly in the brush-border In an to understand the cellular localization of protein immunocytochemical were on with to NPC1L1 in human intestinal immunocytochemical studies revealed significant the associated with the plasma membrane and the and was also detected the and of the the was associated with the few were found the the was reduced its not the protein immunocytochemical was on Caco-2 were To cells from human analyses of the its expression in the (i.e., lysosomes, and Furthermore, of brush-border from human mucosa more the presence of NPC1L1 in which is with the Additionally, of gene expression the presence of NPC1L1 in Caco-2 cells and human with SR-BI and brush-border (i.e., and studies on revealed the of NPC1L1 with SR-BI as as with brush-border (i.e., and with in in our our suggest apical and of NPC1L1 in Caco-2 cells and human small intestine with in the brush-border a for and protein expression of NPC1L1 in Caco-2 cells and human jejunum. was to mRNA of NPC1L1 and SR-BI as as of the brush-border membrane (i.e., and with were carried out to the of NPC1L1 with brush-border To the of the the of were The of the enzyme was as for activity in brush-border for in for acid in and for in The of experiments NPC1L1 as a cholesterol in human cells. To this the effects of RNA interference NPC1L1 knockdown on Caco-2 cells. The resulted in a significant in NPC1L1 gene expression in Caco-2 cells by RT-PCR were by with the with the was a decrease in NPC1L1 protein expression by also confirmed the in NPC1L1 protein expression with protein which revealed in Caco-2 cells not The not and as in 1 NPC1L1 expression not between cells and Caco-2 cells of and in and NPC1L1 Niemann-Pick C1-Like To the of effects by the of interfering RNA was by the of and Cell was by the of and are for in a expression of NPC1L1 in and Caco-2 and cells. The of the on NPC1L1 was in Caco-2 cells to and to NPC1L1 gene expression was in Caco-2 cells as as in Caco-2 cells by RT-PCR Niemann-Pick C1-Like To the of effects by the of interfering RNA was by the of and Cell was by the of and are for uptake was in cells and intestinal cells. NPC1L1 gene knockdown caused decreased ability of Caco-2 cells to capture micellar and to to its the levels of were also decreased in the experiments the important role of NPC1L1 in intestinal cholesterol transport and the impact of NPC1L1 on the sterol HMG-CoA the rate-limiting step in cholesterol synthesis, and an protein in the that the of from and NPC1L1 gene knockdown in Caco-2 cells to an increase in the activity and mRNA of HMG-CoA On the other hand, the activity and mRNA of were decreased in cells deficient of the NPC1L1 gene expression and Cell were for as in and Additionally, the of mRNA was are for the gene expression of a critical factor homeostasis. The suppression of NPC1L1 in Caco-2 cells mRNA Other have been to the brush-border membrane of the cells and have been shown to be involved in the uptake of dietary cholesterol (8Cai S.F. Kirby R.J. Howles P.N. Hui D.Y. Differentiation-dependent expression and localization of the class B type I scavenger receptor in intestine..J. Lipid Res. 2001; 42: 902-909Abstract Full Text Full Text PDF PubMed Google Scholar, 9Hauser H. Dyer J.H. Nandy A. Vega M.A. Werder M. Bieliauskaite E. Weber F.E. Compassi S. Gemperli A. Boffelli D. et al.Identification of a receptor mediating absorption of dietary cholesterol in the intestine..Biochemistry. 1998; 37: 17843-17850Crossref PubMed Scopus (223) Google Scholar, 10Altmann S.W. Davis Jr., H.R. Yao X. Laverty M. Compton D.S. Zhu L.J. Crona J.H. Caplen M.A. Hoos L.M. Tetzloff G. et al.The identification of intestinal scavenger receptor class B, type I (SR-BI) by expression cloning and its role in cholesterol absorption..Biochim. Biophys. Acta. 2002; 1580: 77-93Crossref PubMed Scopus (140) Google Scholar, 11Levy E. Menard D. Suc I. Delvin E. Marcil V. Brissette L. Thibault L. Bendayan M. Ontogeny, immunolocalisation, distribution and function of SR-BI in the human intestine..J. Cell Sci. 2004; 117: 327-337Crossref PubMed Scopus (45) Google Scholar, M. Han C.H. Wehrli E. Bimmler D. Schulthess G. Hauser H. Role of scavenger receptors SR-BI and CD36 in selective sterol uptake in the small intestine..Biochemistry. 2001; 40: 11643-11650Crossref PubMed Scopus (83) Google Scholar, S.A. 1 is a of and intestinal cholesterol Natl. Acad. Sci. USA. 2004; PubMed Scopus Google Scholar). to the of NPC1L1 the of cholesterol ABCA1, ABCG5, and of the NPC1L1 gene in Caco-2 cells SR-BI mRNA and resulted in ABCA1, ABCG5, and CD36 mRNA levels significant the of dietary cholesterol uptake from the intestinal et (14Altmann S.W. Davis Jr., H.R. Zhu L.J. Yao X. Hoos L.M. Tetzloff G. Iyer S.P. Maguire M. Golovko A. Zeng M. et al.Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption..Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1421) Google suggested that a identified of is for intestinal cholesterol absorption. of important experiments were carried out in To a of the localization and function of NPC1L1 in human intestinal cellular and studies in Caco-2 cells. data revealed its in the the small intestine and the NPC1L1 in Caco-2 cells with different of human were to NPC1L1 the brush-border membrane with the of fractionation and NPC1L1 also in of the human the and mitochondria. to NPC1L1 as a cholesterol in human enterocytes. of NPC1L1 to of cholesterol in key sterol and and high gene expression of suggesting the role of NPC1L1 in cholesterol homeostasis. efforts documented that NPC1L1 knockdown reduced the of a protein in the apical which is suggested to a role in cholesterol uptake. of the of NPC1L1 is important because to the function of this NPC1L1 with and of the brush-border Using the was and of the enterocyte and was obtained by NPC1L1 is to the apical is its role in intestinal involved in cholesterol absorption in cholesterol To Caco-2 knockdown cells of which to be and not in and NPC1L1 in human Caco-2 cells decreased cholesterol uptake, a transport from that for NPC1L1-deficient mice (14Altmann S.W. Davis Jr., H.R. Zhu L.J. Yao X. Hoos L.M. Tetzloff G. Iyer S.P. Maguire M. Golovko A. Zeng M. et al.Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption..Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1421) Google Scholar). was to NPC1L1 suppression other cholesterol transporters on the brush-border Indeed, of evidence support the that are involved in cholesterol uptake by the enterocyte D. and sterol recent J. Full Text Full Text PDF PubMed Scopus Google Scholar, into the genetic of intestinal cholesterol Full Text Full Text PDF PubMed Scopus Google Scholar, D.Y. Howles P.N. of cholesterol absorption and transport in the Cell PubMed Scopus Google Scholar). SR-BI and CD36 have been proposed by laboratories to mediate intestinal cholesterol absorption (8Cai S.F. Kirby R.J. Howles P.N. Hui D.Y. Differentiation-dependent expression and localization of the class B type I scavenger receptor in intestine..J. Lipid Res. 2001; 42: 902-909Abstract Full Text Full Text PDF PubMed Google Scholar, 9Hauser H. Dyer J.H. Nandy A. Vega M.A. Werder M. Bieliauskaite E. Weber F.E. Compassi S. Gemperli A. Boffelli D. et al.Identification of a receptor mediating absorption of dietary cholesterol in the intestine..Biochemistry. 1998; 37: 17843-17850Crossref PubMed Scopus (223) Google Scholar, 10Altmann S.W. Davis Jr., H.R. Yao X. Laverty M. Compton D.S. Zhu L.J. Crona J.H. Caplen M.A. Hoos L.M. Tetzloff G. et al.The identification of intestinal scavenger receptor class B, type I (SR-BI) by expression cloning and its role in cholesterol absorption..Biochim. Biophys. Acta. 2002; 1580: 77-93Crossref PubMed Scopus (140) Google Scholar, 11Levy E. Menard D. Suc I. Delvin E. Marcil V. Brissette L. Thibault L. Bendayan M. Ontogeny, immunolocalisation, distribution and function of SR-BI in the human intestine..J. Cell Sci. 2004; 117: 327-337Crossref PubMed Scopus (45) Google Scholar, S.A. 1 is a of and intestinal cholesterol Natl. Acad. Sci. USA. 2004; PubMed Scopus Google Scholar). no was noted in ABCA1, ABCG5, and CD36 of NPC1L1 to a of SR-BI CD36 gene in NPC1L1 with for cholesterol absorption. The between NPC1L1 on the and SR-BI on the other is not to cholesterol transport activity in cells by of NPC1L1 have been that are to an cholesterol (14Altmann S.W. Davis Jr., H.R. Zhu L.J. Yao X. Hoos L.M. Tetzloff G. Iyer S.P. Maguire M. Golovko A. Zeng M. et al.Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption..Science. 2004; 303: 1201-1204Crossref PubMed Scopus (1421) Google Scholar). studies are to the between NPC1L1 and other cholesterol uptake, the is in the by the action of ACAT, an enzyme in the that the of from cholesterol and The is into and from the membrane of the enterocyte into the from which the The of activity are not may be of the of activity J. M.A. D. and of in cells as with 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, cholesterol M. In in The Scholar). cholesterol to increased the activity of intestinal of cholesterol in intestinal mucosa from of on the enzyme J. PubMed Scopus Google Scholar, of intestinal in vivo and in Full Text PDF PubMed Scopus Google Scholar, of dietary fat cholesterol and cholestyramine on activity in intestinal Biophys. Acta. PubMed Scopus (48) Google Scholar). The increase in activity is to from an of the cholesterol for cholesterol by NPC1L1 is to this is that NPC1L1 knockdown to reduced on the data in this out to be of NPC1L1 activity and low cholesterol levels HMG-CoA activity and which that cells cholesterol caused by NPC1L1 of the NPC1L1 identified the presence of in cholesterol of gene expression by of sterol element and its binding Natl. Acad. Sci. USA. 1998; PubMed Scopus Google Scholar, J. S.M. element binding protein to a element in the of the Natl. Acad. Sci. USA. PubMed Scopus Google Scholar, of transcriptional of in Full Text PDF PubMed Google Scholar, of for activity of sterol element in low density lipoprotein receptor Full Text PDF PubMed Google Scholar), which is in the sterol of gene expression J.M. of for low density lipoprotein receptor gene by sterol protein and is by the 1 Full Text Full Text PDF PubMed Scopus Google Scholar, The of cholesterol metabolism by of a 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). are that the synthesis and uptake of cholesterol and The of cholesterol metabolism by of a 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). have found that mRNA was increased in Caco-2 cells of levels may the positive of HMG-CoA NPC1L1 was associated with the apical membrane of with of the NPC1L1 The NPC1L1 to and endosomes, as by have also been found in cells C. A. of NPC1L1 transport and Full Text Full Text PDF PubMed Scopus Google Scholar). are with a in which NPC1L1 may be from to the plasma membrane in the may the and of evidence in cells that NPC1L1 protein between the plasma membrane and the by cellular cholesterol L. S. J.M. Davis M.A. P. P. of NPC1L1 to the free cholesterol 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). et L. S. J.M. Davis M.A. P. P. of NPC1L1 to the free cholesterol 2006; Full Text Full Text PDF PubMed Scopus Google have shown that cholesterol NPC1L1 to the to a in an increased uptake of which be by a cholesterol absorption studies are to this in intestinal In significant suppression of NPC1L1 in Caco-2 cells cholesterol uptake, key sterol and gene suggest the important role of NPC1L1 in intestinal cholesterol homeostasis. However, is to the between NPC1L1 and was by from the of and The for

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