Interaction of cholesterol with sphingosine

Abstract

Molecular associations between sphingomyelin and cholesterol provide a molecular basis for the colocalization of these lipids in plasma membrane microdomains (lipid rafts) and for the inhibitory effect of sphingomyelin on the intestinal absorption of cholesterol. Using surface pressure measurements at the air-water interface, we showed that sphingosine, the common sphingoid backbone of most sphingolipids, formed condensed lipid complexes with cholesterol. Structure-activity relationship studies with long-chain analogs of sphingosine, together with molecular mechanics simulations, were consistent with a specific interaction between sphingosine and the α face of cholesterol. The uptake of micellar cholesterol and the effect of sphingosine on cholesterol absorption were studied with two human model intestinal epithelial cell lines, Caco-2 and HT-29-D4. Real-time PCR quantifications of the putative cholesterol transporter Niemann-Pick C1 like 1 (NPC1L1) mRNA revealed that, in these cell lines, the activity of cholesterol transport correlated with the level of NPC1L1 expression. In both cell lines, sphingosine induced a dose-dependent decrease of cholesterol absorption. Yet the effect of sphingosine was more dramatic in Caco-2 cells, which also displayed the highest expression of NPC1L1 mRNA.Altogether, these data suggested that sphingosine interacts specifically with cholesterol and inhibits the intestinal NPC1L1-dependent transport of micellar cholesterol. Molecular associations between sphingomyelin and cholesterol provide a molecular basis for the colocalization of these lipids in plasma membrane microdomains (lipid rafts) and for the inhibitory effect of sphingomyelin on the intestinal absorption of cholesterol. Using surface pressure measurements at the air-water interface, we showed that sphingosine, the common sphingoid backbone of most sphingolipids, formed condensed lipid complexes with cholesterol. Structure-activity relationship studies with long-chain analogs of sphingosine, together with molecular mechanics simulations, were consistent with a specific interaction between sphingosine and the α face of cholesterol. The uptake of micellar cholesterol and the effect of sphingosine on cholesterol absorption were studied with two human model intestinal epithelial cell lines, Caco-2 and HT-29-D4. Real-time PCR quantifications of the putative cholesterol transporter Niemann-Pick C1 like 1 (NPC1L1) mRNA revealed that, in these cell lines, the activity of cholesterol transport correlated with the level of NPC1L1 expression. In both cell lines, sphingosine induced a dose-dependent decrease of cholesterol absorption. Yet the effect of sphingosine was more dramatic in Caco-2 cells, which also displayed the highest expression of NPC1L1 mRNA. Altogether, these data suggested that sphingosine interacts specifically with cholesterol and inhibits the intestinal NPC1L1-dependent transport of micellar cholesterol. It has been known for several years that cholesterol interacts with sphingomyelin (1Demel R.A. Jansen J.W. van Dijck P.W. van Deenen L.L. The preferential interaction of cholesterol with different classes of phospholipids.Biochim. Biophys. Acta. 1977; 465: 1-10Crossref PubMed Scopus (304) Google Scholar, 2Smaby J.M. Brockman H.L. Brown R.E. Cholesterol's interfacial interactions with sphingomyelins and phosphatidylcholines: hydrocarbon chain structure determines the magnitude of condensation.Biochemistry. 1994; 33: 9135-9142Crossref PubMed Scopus (172) Google Scholar, 3Slotte J.P. Sphingomyelin-cholesterol interactions in biological and model membranes.Chem. Phys. Lipids. 1999; 102: 13-27Crossref PubMed Scopus (179) Google Scholar) and that this interaction is of high biological significance for two main reasons. i) The formation of ordered lipid domains in the plasma membrane of eukaryotic cells is, at least in part, driven by lipid-lipid interactions (4Simons K. Ikonen E. Functions of lipid rafts in biological membranes.Nature. 1997; 387: 569-572Crossref PubMed Scopus (8188) Google Scholar, 5Rietveld A. Simons K. The differential miscibility of lipids as the basis for the formation of functional membrane rafts.Biochim. Biophys. Acta. 1998; 1376: 467-479Crossref PubMed Scopus (454) Google Scholar). Among them, the molecular association between sphingomyelin and cholesterol is an important parameter that controls the segregation of both lipids into cholesterol-enriched microdomains usually referred to as lipid rafts (6van Duyl B.Y. Ganchev D. Chupin V. Kruijff B. de Killian J.A. Sphingomyelin is much more effective than saturated phosphatidylcholine in excluding unsaturated phosphatidylcholine from domains formed with cholesterol.FEBS Lett. 2003; 547: 101-106Crossref PubMed Scopus (91) Google Scholar). These microdomains of the plasma membrane are involved in key cellular functions, such as the control of signal transduction pathways, and they are used as landing platforms and ports of entry by many pathogens or toxins (7Pike L.J. Lipid rafts: bringing order to chaos.J. Lipid Res. 2003; 44: 655-667Abstract Full Text Full Text PDF PubMed Scopus (966) Google Scholar, 8Edidin M. The state of lipid rafts: from model membranes to cells.Annu. Rev. Biophys. Biomol. Struct. 2003; 32: 257-283Crossref PubMed Scopus (1140) Google Scholar, 9Taïeb N. Yahi N. Fantini J. Rafts and related glycosphingolipid-enriched microdomains in the intestinal epithelium: bacterial targets linked to nutrient absorption.Adv. Drug Deliv. Rev. 2004; 56: 779-794Crossref PubMed Scopus (49) Google Scholar). ii) On the other hand, the formation of cholesterol-sphingomyelin molecular complexes in the intestinal lumen explains the mutual inhibitory effects of cholesterol and sphingomyelin on their intestinal absorption (10Nyberg L. Duan R. Nilsson A. A mutual inhibitory effect on absorption of sphingomyelin and cholesterol.J. Nutr. Biochem. 2000; 11: 244-249Crossref PubMed Scopus (100) Google Scholar). Indeed, it was recently demonstrated that sphingomyelin decreased the absorption of cholesterol by affecting the thermodynamic activity (i.e., the active concentration) of cholesterol monomers in the small intestine (11Eckhardt E.R. Wang D.Q. Donovan J.M. Carey M.C. Dietary sphingomyelin suppresses intestinal cholesterol absorption by decreasing thermodynamic activity of cholesterol monomers.Gastroenterology. 2002; 122: 948-956Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). The process of intestinal sphingomyelin absorption is complex. A part of sphingomyelin can be directly absorbed by the intestinal epithelium, but this phosphorylated sphingolipid is also cleaved by intestinal sphingomyelinases, giving rise to ceramide and phosphorylcholine (12Vesper H. Schmelz E-V. Nikolova-Karakashian M.N. Dillehay D.L. Lynch D.V. Merrill Jr, A.H. Sphingolipids in food and the emerging importance of sphingolipids to nutrition.J. Nutr. 1999; 129: 1239-1250Crossref PubMed Scopus (373) Google Scholar, 13Nilsson A. Duan R.D. Alkaline sphingomyelinases and ceramidases of the gastrointestinal tract.Chem. Phys. Lipids. 1999; 102: 97-105Crossref PubMed Scopus (60) Google Scholar). Ceramide is poorly absorbed and is further hydrolyzed into fatty acid and sphingosine by intestinal ceramidases (13Nilsson A. Duan R.D. Alkaline sphingomyelinases and ceramidases of the gastrointestinal tract.Chem. Phys. Lipids. 1999; 102: 97-105Crossref PubMed Scopus (60) Google Scholar, 14Nilsson A. Metabolism of sphingomyelin in the intestinal tract of the rat.Biochim. Biophys. Acta. 1968; 164: PubMed Scopus Google Scholar, Dillehay D.L. Merrill Jr, A.H. and of sphingolipids in intestinal of Nutr. 1994; PubMed Scopus Google Scholar). These are more absorbed than The of sphingosine cellular as suggested by Schmelz Dillehay D.L. Merrill Jr, A.H. and of sphingolipids in intestinal of Nutr. 1994; PubMed Scopus Google Scholar). these studies on the intestinal absorption and of sphingolipids, we sphingosine, like can with cholesterol. sphingosine the common backbone of of sphingolipid J. R. N. Yahi N. Lipid rafts: and in and Rev. 2002; Scopus Google this is for molecular of the a part of sphingomyelin is cleaved by intestinal is it that the sphingosine a inhibitory effect on cholesterol these we studied the interaction of sphingosine and cholesterol at the air-water interface, a molecular model of the by molecular and the intestinal absorption of micellar cholesterol in the or of transport studies were with Caco-2 and human intestinal cell J. N. of epithelial cell by 1 human is with cell surface expression of a PubMed Scopus Google Scholar). used as in for the intestinal epithelium, such cell in their transport M. R. A. Fantini J. The A intestinal and absorption but has effect on PubMed Scopus Google which specific membrane J. N. of epithelial cell by 1 human is with cell surface expression of a PubMed Scopus Google Scholar). this we studied the expression of mRNA for two intestinal the transporter Fantini J. The of transport of an intestinal epithelial cell is by Full Text Full Text PDF PubMed Scopus Google Scholar) and the intestinal and cholesterol transporter Niemann-Pick C1 like 1 (NPC1L1) L.J. M. J. Niemann-Pick C1 like 1 (NPC1L1) is the intestinal and cholesterol transporter and a key of cholesterol 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). NPC1L1 was recently as the main intestinal cholesterol transporter an L.J. M. A. M. Wang L. N. Niemann-Pick C1 like 1 is for intestinal cholesterol 2004; PubMed Scopus Google Scholar). The a and is on the membrane of in the NPC1L1 in their to cholesterol. Altogether, these data suggested that NPC1L1 is for intestinal cholesterol absorption the cholesterol transporter 2004; PubMed Scopus Google Scholar). is the for such as which is on both the and membranes of and an in cholesterol the cholesterol transporter 2004; PubMed Scopus Google Scholar). Indeed, to absorption of cholesterol M. L. The of intestinal by expression and in cholesterol Biophys. Acta. 2002; PubMed Scopus Google Scholar). this we the on the expression of NPC1L1 mRNA. sphingosine, and of the highest were from and were from was from and were from which was from The surface pressure was with a The the of and the of interaction of a with the a of were in a at of the lipids were on of from as R. M. Fantini J. A of the the cholesterol for high Lipid Res. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, R. M. M. A. A. Fantini J. interaction of with and molecular studies at the air-water 2002; PubMed Scopus Google Scholar). of the was for the interaction of sphingosine long-chain with cholesterol the was in the with a and pressure were for the The data were with the The of the was for surface were with the The lipids were from a in on a of The were at a of of in lipid was by molecular J.M. Brockman H.L. Brown R.E. Cholesterol's interfacial interactions with sphingomyelins and phosphatidylcholines: hydrocarbon chain structure determines the magnitude of condensation.Biochemistry. 1994; 33: 9135-9142Crossref PubMed Scopus (172) Google Scholar, J.M. Brockman H.L. Brown R.E. Cholesterol's interfacial interactions with 1994; 33: PubMed Scopus (60) Google Scholar). The molecular of at a surface pressure was the is the of and and are the molecular of 1 and at surface between the of the and the by the molecular of the by in the the of lipid from and Caco-2 and cells J. N. of epithelial cell by 1 human is with cell surface expression of a PubMed Scopus Google Scholar) were in in with cells were in with and for as Fantini J. The of transport of an intestinal epithelial cell is by Full Text Full Text PDF PubMed Scopus Google Scholar). 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Full Text PDF PubMed Google Scholar). of and sphingosine were and the was and was that the were cholesterol phosphatidylcholine and sphingosine The micellar was and for several on were with and with cholesterol in the or of the of the the was and the cells were with The cells were with and 1 and the was in a as Fantini J. The of transport of an intestinal epithelial cell is by Full Text Full Text PDF PubMed Scopus Google Scholar). Molecular mechanics studies were with the and sphingosine were in a with Molecular mechanics was with the as were in and the are as and the were with were A of cholesterol was at the air-water at an surface pressure of of sphingosine were in the and the surface pressure was the was and the surface pressure induced by sphingosine was as the of sphingosine The data showed a dose-dependent interaction between sphingosine and the cholesterol The effect was with and the surface pressure was with the level of of sphingosine the cholesterol decreased specifically as the surface pressure with a pressure of of The of the pressure of for is of the between the and the lipid R. M. Fantini J. 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Brockman H.L. Brown R.E. Cholesterol's interfacial interactions with sphingomyelins and phosphatidylcholines: hydrocarbon chain structure determines the magnitude of condensation.Biochemistry. 1994; 33: 9135-9142Crossref PubMed Scopus (172) Google Scholar, J.M. Brockman H.L. Brown R.E. Cholesterol's interfacial interactions with 1994; 33: PubMed Scopus (60) Google Scholar). The data at different surface and are in from at of these surface that the was to the surface In the effect from at was at of cholesterol between and These data that sphingosine and cholesterol condensed A molecular model of the by molecular mechanics simulations, is in the sphingosine chain the cholesterol and the chain of the The of sphingosine is at a of from the of cholesterol. the of a between these also between the and the of The to which face of cholesterol interacts with the hydrocarbon chain of to the for by A for of PubMed Google this is the α the of cholesterol with the interaction of the with the hydrocarbon chain of The of sphingosine is on the of sphingosine that with cholesterol. as the of is than the of sphingosine is to in biological In this the of a is consistent with the that the interaction of sphingosine with cholesterol at high (i.e., between and data In the part of this we used human epithelial intestinal cell and as to the intestinal absorption of cholesterol. The absorption of on the membrane surface that a of and on the level of expression of specific nutrient the of the it was important to the expression of cholesterol in and Caco-2 this PCR was used to the of mRNA for which was recently as the most intestinal transporter for cholesterol L.J. M. J. Niemann-Pick C1 like 1 (NPC1L1) is the intestinal and cholesterol transporter and a key of cholesterol 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, L.J. M. A. M. Wang L. N. Niemann-Pick C1 like 1 is for intestinal cholesterol 2004; PubMed Scopus Google Scholar). the of we also studied the expression of the intestinal transporter B. K. J. van Fantini J. J. of an in a human epithelial cell PubMed Scopus Google Scholar). The data are as the in expression to an and to an the Caco-2 cell this that 1 The data that NPC1L1 mRNA expression was more in Caco-2 cells with cells, were for mRNA expression NPC1L1 mRNA was and more in Caco-2 cells than in and cells, In expression of mRNA was and in Caco-2 cells than in and cells, The process of cells, induced by the with a Fantini J. 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J. of an in a human epithelial cell PubMed Scopus Google Scholar) and the expression of this in Caco-2 cells M. R. A. Fantini J. The A intestinal and absorption but has effect on PubMed Scopus Google Scholar, intestinal transporter of surface expression and transport with of transport and Full Text Full Text PDF PubMed Scopus Google Scholar, D. R. of epithelial is with J. 1997; PubMed Google Scholar). as the of NPC1L1 in intestinal cholesterol absorption is a L.J. M. A. M. Wang L. N. Niemann-Pick C1 like 1 is for intestinal cholesterol 2004; PubMed Scopus Google it is known the level of cholesterol absorption is with NPC1L1 expression in intestinal cell In the in micellar cholesterol 1 was with cells or Caco-2 cells for the The data showed that the uptake of cholesterol was in cells with Caco-2 The of cholesterol uptake was and for and Caco-2 cells, the transport was saturated for cells, with a uptake of In the uptake of micellar cholesterol was more in Caco-2 cells uptake of these data were in with the PCR of NPC1L1 expression. we studied the effect of sphingosine on micellar cholesterol cholesterol 1 was for with or Caco-2 cells the or of sphingosine In both sphingosine induced a of cholesterol with to the cell In Caco-2 cells, the inhibitory effect was with a effect for a of sphingosine, to a of sphingosine cholesterol. The inhibitory effect of was with In the of cells, a of sphingosine of effect on cholesterol sphingosine, the uptake of micellar cholesterol was decreased by of these the effect was at sphingosine, to a of sphingosine cholesterol. The main of this were to sphingosine, which from the of sphingomyelin in the intestinal the of sphingomyelin to a condensed lipid with cholesterol. sphingosine with the intestinal absorption of like sphingomyelin Using a on the we demonstrated a specific interaction between sphingosine and to the formation of condensed lipid sphingosine like interfacial interactions with cholesterol been studied with an to J.M. Brockman H.L. Brown R.E. Cholesterol's interfacial interactions with sphingomyelins and phosphatidylcholines: hydrocarbon chain structure determines the magnitude of condensation.Biochemistry. 1994; 33: 9135-9142Crossref PubMed Scopus (172) Google Scholar). Indeed, the effect of cholesterol on sphingomyelin has been demonstrated by the from the by J.M. Brockman H.L. Brown R.E. Cholesterol's interfacial interactions with sphingomyelins and phosphatidylcholines: hydrocarbon chain structure determines the magnitude of condensation.Biochemistry. 1994; 33: 9135-9142Crossref PubMed Scopus (172) Google Scholar, J.M. Brockman H.L. Brown R.E. Cholesterol's interfacial interactions with 1994; 33: PubMed Scopus (60) Google Scholar). to this the that the molecular by a (i.e., sphingomyelin is than it be it to was of of cholesterol and sphingosine were at the air-water these studies demonstrated the molecular association of cholesterol and sphingosine in the The of this interaction was further by the interaction of a of long-chain with cholesterol The of activity of suggested that interactions from a of the of a at the of the hydrocarbon of an and cholesterol sphingosine such as and with both and at the of the to sphingosine and cholesterol with high These data demonstrated that the interaction of with cholesterol a a or but the the The of the interaction at suggested that the or the has to be for an interaction with cholesterol. Molecular mechanics suggested a of the with the α face of with sphingoid the of sphingosine is involved in the a that with data with sphingomyelin L. R. J.P. of cholesterol with sphingomyelin PubMed Scopus Google Scholar) and with the long-chain analogs used in the these are consistent with the studies at the air-water In the lipids in the condensed the (i.e., part than the that the can be formed at the The model is also consistent with the formation of a in a the interaction of the of the lipids is an data suggested that sphingosine decrease the thermodynamic activity (i.e., the active concentration) of cholesterol consistent with the data with cholesterol and sphingomyelin J.M. Brockman H.L. Brown R.E. Cholesterol's interfacial interactions with sphingomyelins and phosphatidylcholines: hydrocarbon chain structure determines the magnitude of condensation.Biochemistry. 1994; 33: 9135-9142Crossref PubMed Scopus (172) Google Scholar, E.R. Wang D.Q. Donovan J.M. Carey M.C. Dietary sphingomyelin suppresses intestinal cholesterol absorption by decreasing thermodynamic activity of cholesterol monomers.Gastroenterology. 2002; 122: 948-956Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). of this was to the of sphingosine on the intestinal transport of cholesterol the plasma membrane of human epithelial intestinal cell used for intestinal transport functions, M. R. A. Fantini J. The A intestinal and absorption but has effect on PubMed Scopus Google Scholar, Fantini J. The of transport of an intestinal epithelial cell is by Full Text Full Text PDF PubMed Scopus Google Scholar, B. K. J. van Fantini J. J. of an in a human epithelial cell PubMed Scopus Google Scholar) and Caco-2 E. of cholesterol by micellar cholesterol in Caco-2 Lipid Res. Full Text PDF PubMed Google Scholar, A human cell with as a model to and of the Caco-2 Rev. Drug 1997; PubMed Google were used in this These cell were with to the expression of cholesterol which is for intestinal uptake of both cholesterol and and a in cholesterol L.J. M. J. Niemann-Pick C1 like 1 (NPC1L1) is the intestinal and cholesterol transporter and a key of cholesterol 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, L.J. M. A. M. Wang L. N. Niemann-Pick C1 like 1 is for intestinal cholesterol 2004; PubMed Scopus Google Scholar). Indeed, absorption of cholesterol was in which was the for such as M. L. The of intestinal by expression and in cholesterol Biophys. Acta. 2002; PubMed Scopus Google Scholar, V. L. M. M. B. M. A. cholesterol and acid and intestinal cholesterol absorption in Lipid Res. Full Text Full Text PDF PubMed Google Scholar). On the other hand, the and are to into the intestinal lumen than cholesterol absorption H. L. J. B. R. of cholesterol in by in 2000; PubMed Scopus Google Scholar). NPC1L1 be cholesterol as recently by and the cholesterol transporter 2004; PubMed Scopus Google Scholar). NPC1L1 a and is in the and at the it was important to the level of expression of NPC1L1 in model intestinal cell Using the PCR we that NPC1L1 mRNA was more in Caco-2 cells than in this for two i) the PCR data been with an which displayed the PCR for cell ii) were for the level of and this with the high activity of in cells with Caco-2 cells M. R. A. Fantini J. The A intestinal and absorption but has effect on PubMed Scopus Google Scholar, B. K. J. van Fantini J. J. of an in a human epithelial cell PubMed Scopus Google Scholar, intestinal transporter of surface expression and transport with of transport and Full Text Full Text PDF PubMed Scopus Google Scholar). the activity of cholesterol transport was high in Caco-2 cells and in cells, as by the data of as for the PCR data correlated with the functional activity of the cholesterol These data are important they the of NPC1L1 in intestinal cholesterol absorption. In the of two human intestinal model cell in their expression of NPC1L1 studies of NPC1L1 important of the is that sphingosine micellar cholesterol uptake in both cell but was more active in cells that the level of NPC1L1 mRNA (i.e., Caco-2 These data are consistent with the that sphingosine the transport of cholesterol in a decrease of cholesterol absorption. the formation of complexes decrease the thermodynamic activity of the lipid monomers (i.e., cholesterol and decreasing the of monomers to the intestinal is also consistent with the of and in intestinal A. Metabolism of sphingomyelin in the intestinal tract of the rat.Biochim. Biophys. Acta. 1968; 164: PubMed Scopus Google Scholar). sphingosine be from the of sphingomyelin and ceramide in the A of was recently to the of cholesterol absorption by sphingomyelin (11Eckhardt E.R. Wang D.Q. Donovan J.M. Carey M.C. Dietary sphingomyelin suppresses intestinal cholesterol absorption by decreasing thermodynamic activity of cholesterol monomers.Gastroenterology. 2002; 122: 948-956Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). this model that the condensed complexes and NPC1L1 to the cells, of their with lipid It can also be from data that the of the is that the of NPC1L1 for the in the of cholesterol to to Yet it to be a in the sphingosine effect between Caco-2 and In the data in the absorption of cholesterol for both cell has been as a of cholesterol the inhibitory effects were the effect of sphingosine been for both cell Indeed, the of cholesterol is the of sphingosine to cholesterol in the the of of cholesterol uptake be of cell surface expression of data that to the inhibitory effect of sphingosine, in cells with of NPC1L1 expression. the of cholesterol by cells in the of sphingosine, we that a small of complexes be the cell of these complexes be the but of the The of microdomains in intestinal membranes N. Yahi N. Fantini J. Rafts and related glycosphingolipid-enriched microdomains in the intestinal epithelium: bacterial targets linked to nutrient absorption.Adv. Drug Deliv. Rev. 2004; 56: 779-794Crossref PubMed Scopus (49) Google Scholar, J. R. N. Yahi N. Lipid rafts: and in and Rev. 2002; Scopus Google Scholar) the interaction of these complexes with the plasma of sphingosine the cell the of the inhibitory effect of sphingosine was for high of sphingosine in the of the of putative cholesterol from NPC1L1 and a to it be to such cholesterol from for of data are consistent with a effect of sphingosine on cholesterol as a of the of this is the that sphingosine with intestinal cholesterol absorption. two biological i) of the inhibitory effect of sphingomyelin can be to sphingosine sphingosine of the common backbone of sphingolipids, it can be that most sphingolipids be to decrease cholesterol absorption. ii) sphingolipids from of they of a backbone (i.e., sphingosine with an between and M.C. Lynch D.V. Merrill A.H. J. of and by 2000; PubMed Scopus (100) Google Scholar). The molecular model in that also with that this sphingosine is to inhibitory effects on intestinal cholesterol absorption. both sphingomyelins Dillehay D.L. Merrill Jr, A.H. of by sphingomyelins with saturated or unsaturated sphingoid 1997; PubMed Scopus Google Scholar) and sphingolipids H. Schmelz Dillehay D.L. Merrill Jr, A.H. Dietary sphingolipids and expression in and Nutr. 2004; PubMed Scopus Google Scholar) been to and sphingolipids and also to intestinal cholesterol absorption. from and de is