Cellular Cholesterol Efflux Mediated by Cyclodextrins

Abstract

In this study, we compared cholesterol efflux mediated by either high density lipoproteins (HDL3) or β-cyclodextrins, cyclic oligosaccharides that are able to dissolve lipids in their hydrophobic core. β-Cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and methyl-β-cyclodextrin at 10 mM induced the release of 50-90% of L-cell [3H]cholesterol after 8 h of incubation, with a major portion of this cholesterol being released in the first 1-2 h of incubation. The cholesterol efflux kinetics are different if cells are incubated with HDL3, which induces a relatively constant rate of release of cholesterol throughout an 8-h incubation. Cholesterol efflux to cyclodextrins was much greater than phospholipid release. To test the hypothesis that maximal efflux rate constants for a particular cell are independent of the type of acceptor, we estimated the maximal rate constants for efflux (Vmax) of cellular cholesterol from L-cells, Fu5AH cells, and GM3468A fibroblasts. The rate constant for HDL3-mediated efflux varied among cell lines in the order Fu5AH > L-cells > fibroblasts. However, these differences were not evident when cyclodextrins were used as cholesterol acceptors. The estimated Vmax values for cyclodextrin-mediated efflux were 3.5-70-fold greater than for HDL3 for the three cell lines. The very high efficiency of cyclodextrins in stimulating cell cholesterol efflux suggests that these compounds can be used in two general ways for studies of atherosclerosis: 1) as research tools to probe mechanisms of cholesterol transport and aspects of membrane structure or 2) as potential pharmacological agents that could modify in vivo cholesterol metabolism and influence the development of the atherosclerotic plaque. In this study, we compared cholesterol efflux mediated by either high density lipoproteins (HDL3) or β-cyclodextrins, cyclic oligosaccharides that are able to dissolve lipids in their hydrophobic core. β-Cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, and methyl-β-cyclodextrin at 10 mM induced the release of 50-90% of L-cell [3H]cholesterol after 8 h of incubation, with a major portion of this cholesterol being released in the first 1-2 h of incubation. The cholesterol efflux kinetics are different if cells are incubated with HDL3, which induces a relatively constant rate of release of cholesterol throughout an 8-h incubation. Cholesterol efflux to cyclodextrins was much greater than phospholipid release. To test the hypothesis that maximal efflux rate constants for a particular cell are independent of the type of acceptor, we estimated the maximal rate constants for efflux (Vmax) of cellular cholesterol from L-cells, Fu5AH cells, and GM3468A fibroblasts. The rate constant for HDL3-mediated efflux varied among cell lines in the order Fu5AH > L-cells > fibroblasts. However, these differences were not evident when cyclodextrins were used as cholesterol acceptors. The estimated Vmax values for cyclodextrin-mediated efflux were 3.5-70-fold greater than for HDL3 for the three cell lines. The very high efficiency of cyclodextrins in stimulating cell cholesterol efflux suggests that these compounds can be used in two general ways for studies of atherosclerosis: 1) as research tools to probe mechanisms of cholesterol transport and aspects of membrane structure or 2) as potential pharmacological agents that could modify in vivo cholesterol metabolism and influence the development of the atherosclerotic plaque. The first step in reverse cholesterol transport is the efflux of cellular cholesterol to a suitable acceptor, and this process is thought to be mediated by HDL1 1The abbreviations used are: HDLhigh density lipoproteinDMEMDulbecco's modified Eagle's mediumMEMEagle's minimum essential mediumFBSfetal bovine serumβCDβ-cyclodextrinMβCDmethyl-β-cyclodextrin2OHpβCD2-hydroxypropyl-β-cyclodextrin. or specific HDL subclasses(1Glomset J.A. J. Lipid Res. 1968; 9: 155-167Abstract Full Text PDF PubMed Google Scholar, 2Johnson W.J. Mahlberg F.H. Rothblat G.H. Phillips M.C. Biochim. Biophys. Acta. 1991; 1085: 273-298Crossref PubMed Scopus (389) Google Scholar, 3Fielding C.J. Fielding P.E. J. Lipid Res. 1995; 36: 211-228Abstract Full Text PDF PubMed Google Scholar). Although extensively investigated, the exact mechanism underlying the movement of cholesterol molecules from the plasma membrane to extracellular acceptors remains controversial. Although the generally accepted mechanism is now thought to involve the movement of cholesterol molecules from the cell membrane through the aqueous phase to the acceptor particle (i.e. aqueous diffusion mechanism)(2Johnson W.J. Mahlberg F.H. Rothblat G.H. Phillips M.C. Biochim. Biophys. Acta. 1991; 1085: 273-298Crossref PubMed Scopus (389) Google Scholar), other mechanisms have been proposed, including collision (4Steck T.L. Kezdy F.J. Lange Y. J. Biol. Chem. 1988; 263: 13023-13031Abstract Full Text PDF PubMed Google Scholar) or receptor-mediated mechanisms(5Oram J.F. Arteriosclerosis. 1983; 3: 420-432Crossref PubMed Google Scholar). high density lipoprotein Dulbecco's modified Eagle's medium Eagle's minimum essential medium fetal bovine serum β-cyclodextrin methyl-β-cyclodextrin 2-hydroxypropyl-β-cyclodextrin. β-Cyclodextrins, cyclic oligosaccharides consisting of 7 β(1-4)-glucopyranose units, are water-soluble compounds with a hydrophobic cavity capable of dissolving hydrophobic compounds and thus enhancing their solubility in aqueous solutions(6Pitha J. Irie T. Sklar P.B. Nye J.S. Life Sci. 1988; 43: 493-502Crossref PubMed Scopus (228) Google Scholar, 7Duchene D. Minutes of the 5th International Symposium on Cyclodextrins. Editions de Sante, Paris, France1990Google Scholar). Cyclodextrins have been used extensively as drug delivery vehicles(6Pitha J. Irie T. Sklar P.B. Nye J.S. Life Sci. 1988; 43: 493-502Crossref PubMed Scopus (228) Google Scholar, 8Stern W.C. Drug News Perspect. 1989; 2: 410Google Scholar), and derivatives of β-cyclodextrins have been made by chemical modifications of the hydroxyl groups which greatly improve their solubility and their ability to dissolve hydrophobic compounds, as well as reducing their toxicity(9DeCaprio J. Yun J. Javitt N.B. J. Lipid Res. 1992; 33: 441-443Abstract Full Text PDF PubMed Google Scholar, 10Frijlink H.W. Eissens A.C. Hefting N.R. Poelstra K. Lerk C.F. Meijer K.F. Pharm. Res. (NY). 1991; 8: 9-16Crossref PubMed Scopus (129) Google Scholar, 11Irie T. Fukunaga K. Pitha J. J. Pharm. Sci. 1992; 81: 521-523Abstract Full Text PDF PubMed Scopus (124) Google Scholar). In vitro, β-cyclodextrins have a high affinity for sterols as compared to other lipids(11Irie T. Fukunaga K. Pitha J. J. Pharm. Sci. 1992; 81: 521-523Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 12Ohtani Y. Irie T. Uekama K. Fukunaga K. Pitha J. Eur. J. Biochem. 1989; 186: 17-22Crossref PubMed Scopus (548) Google Scholar), and, because of the relatively high specificity of β-cyclodextrins for cholesterol, it has been suggested that these compounds might be effective in modifying cholesterol metabolism in vivo(11Irie T. Fukunaga K. Pitha J. J. Pharm. Sci. 1992; 81: 521-523Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 13Riottot M. Olivier P. Huet A. Caboche J.J. Parquet M. Khallou J. Lutton C. Lipids. 1993; 28: 181-188Crossref PubMed Scopus (68) Google Scholar). It can be proposed that cyclodextrins can be used in two general ways for studies of atherosclerosis: 1) as research tools to probe mechanisms of cholesterol transport and aspects of membrane structure or 2) as potential pharmacological agents that could modify in vivo cholesterol metabolism and influence the development of the atherosclerotic plaque. Although there is extensive literature on cyclodextrins, relatively little has been published on their ability to influence cholesterol metabolism, either in vitro or in vivo. It has been demonstrated by Frijlink et al.(10Frijlink H.W. Eissens A.C. Hefting N.R. Poelstra K. Lerk C.F. Meijer K.F. Pharm. Res. (NY). 1991; 8: 9-16Crossref PubMed Scopus (129) Google Scholar) that injection of either β-cyclodextrin or 2OHpβCD (200 mg/kg dose) resulted in transient decreases in both serum-unesterified and total cholesterol. It has been proposed that the cholesterol-lowering effect of the cyclodextrins was due to their ability to efficiently cross the capillary wall and to function as cholesterol carriers that redistribute cholesterol from the interstitial space to the plasma compartment(10Frijlink H.W. Eissens A.C. Hefting N.R. Poelstra K. Lerk C.F. Meijer K.F. Pharm. Res. (NY). 1991; 8: 9-16Crossref PubMed Scopus (129) Google Scholar), after which it was rapidly cleared in the urine. It is believed that the cyclodextrin-cholesterol complexes are processed within the kidneys. Within the kidneys, the dissociation of cholesterol from the carrier cyclodextrin can result in the deposition of cholesterol and the associated nephrotoxicity sometimes associated with cyclodextrins(10Frijlink H.W. Eissens A.C. Hefting N.R. Poelstra K. Lerk C.F. Meijer K.F. Pharm. Res. (NY). 1991; 8: 9-16Crossref PubMed Scopus (129) Google Scholar). In vitro studies have demonstrated that exposure of fibroblasts to cyclodextrins can produce cell toxicity, and that the extent of this toxicity is reduced by the presence of serum(6Pitha J. Irie T. Sklar P.B. Nye J.S. Life Sci. 1988; 43: 493-502Crossref PubMed Scopus (228) Google Scholar). Exposure of erythrocytes to cyclodextrins results in hemolysis in the order of β > α > γ(14Irie T. Otagiri M. Sunada M. Uekama K. Ohtani Y. Y. Y. J. PubMed Scopus Google Scholar). hemolysis be to the of membrane cholesterol. release of cholesterol can be of the cells with the T. Fukunaga K. Pitha J. J. Pharm. Sci. 1992; 81: 521-523Abstract Full Text PDF PubMed Scopus (124) Google Scholar). is the of cyclodextrins with erythrocytes is the of the movement of cholesterol from the cells to the with of than T. Fukunaga K. Pitha J. J. Pharm. Sci. 1992; 81: 521-523Abstract Full Text PDF PubMed Scopus (124) Google Scholar). is in to that for the or of cholesterol from erythrocytes to serum or which is in the of h a M.C. W.J. Rothblat G.H. Biochim. Biophys. Acta. PubMed Scopus Google It was this very rate that to the of the of cholesterol movement cells in and and were from fetal bovine serum and were from were with and cells were in a at with were with and of L-cell fibroblasts and GM3468A fibroblasts were in with and Fu5AH cells were in with were in or to 7 to efflux cells well for and well for were when the cells were for GM3468A which were used to after were for h with medium or of and was from and for by to F.H. A. Rothblat G.H. Full Text PDF PubMed Scopus Google Scholar). cells were incubated with medium bovine serum for h to for of the in the cellular cholesterol was both and was a from and cells were three with medium with and were to medium cholesterol acceptors. medium was with mM of were incubated for 10 to 8 h in a at and were for the at Cholesterol acceptors used in these studies were of either HDL3, β-cyclodextrin or methyl-β-cyclodextrin HDL3 was by of plasma to and Lipid Res. 1968; PubMed Google Scholar). and after the with were three with and lipids were with Rothblat G.H. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). was to the to and cholesterol was by a W.J. Phillips M.C. Rothblat G.H. J. Biol. Chem. Full Text PDF PubMed Google Scholar). of cells was at the of the efflux to cellular [3H]cholesterol and cholesterol was on the a of the of et Biochem. PubMed Scopus Google Scholar). was in a of and and were for was from the of [3H]cholesterol in the cells at these were to a as W.J. P.E. Phillips M.C. Rothblat G.H. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The used was in which is the of cell [3H]cholesterol in the cells and is the in The rate constant for efflux of cellular cholesterol, is the of the efflux and can be and the values are the of of maximal efflux rate constants were from the in with a used to maximal for In this the with the is the maximal and the at which of the maximal rate constant for efflux is the is the of the The test was used to L-cells were at cells well in of and of and to for cells were three with and incubated with bovine serum for The cells were and efflux was by the cells with of medium well for h at were used to cell and cell phospholipid were as a HDL3 or of or cyclodextrins or at or the of the incubation, were and was used for phospholipid both the cellular and the medium at were to et W.J. Rothblat G.H. J. Lipid Res. 1992; 33: Full Text PDF PubMed Google Scholar) to efflux was as the release of cell to the medium after h of incubation. cell phospholipid was used to the specific of the to the released phospholipid of released cell cholesterol and phospholipid were on the from L-cells to 10 mM 2OHpβCD for h at was a of the cyclodextrin to with lipids if the were and the presence of cyclodextrins the To this the 2OHpβCD was with of by with of and the the cholesterol was as W.J. Rothblat G.H. J. Lipid Res. 36: Full Text PDF Google Scholar). was by the by and Rothblat Rothblat G.H. Biol. PubMed Scopus Google Scholar) and was to at of of cholesterol and phospholipid were to the to to The of cholesterol was the of phospholipid from the was The release of cellular as by et 1992; Full Text PDF PubMed Scopus Google Scholar), was used to membrane To the of L-cells, cells were the as for efflux and, in of was to the efflux medium was the were extensively with to The release of cellular was by medium through and The of cellular was by dissolving the cells in of The total cell of to L-cells was by with mM 2OHpβCD and for h at The cells were and cell were in were used for and The high of three of β-cyclodextrin for stimulating the efflux of L-cell [3H]cholesterol is in and methyl-β-cyclodextrin induced a release of cellular cholesterol. was than the two other of cellular [3H]cholesterol was released after 8 h of with 10 mM the of L-cells after 8 h of with 2OHpβCD and L-cells G.H. PubMed Scopus Google Scholar), the release of cholesterol is to the of cellular cholesterol and a release of cellular than the other in a of the of cellular [3H]cholesterol efflux mediated by HDL3 or by of 2OHpβCD is in was efflux of [3H]cholesterol when cells were incubated with medium cholesterol HDL3 induced efflux of cholesterol at a relatively constant rate the 8-h However, 2OHpβCD induced a rate of cholesterol release than HDL3, when at the of The rate of [3H]cholesterol release after to an was the cholesterol in the medium and in the the kinetics for the efflux of cellular cholesterol are very different when cyclodextrin is compared to The kinetics of the cholesterol efflux studies 2) suggested that of L-cells with cyclodextrin resulted in the of cholesterol cells and the estimated of cell cholesterol to cyclodextrin in the medium after 8 h exposure of L-cells to the cholesterol acceptors. The was for and for were at both mM and mM of the results that cholesterol the cells and the cyclodextrin molecules in the and that the is on the affinity of cholesterol for the type of cyclodextrin that is in a The cyclodextrin-mediated release of a major portion of cell cholesterol as in might be to plasma membrane cholesterol and result in cell To test for the presence of cell toxicity, cells were with the release of which as a of cell membrane 1992; Full Text PDF PubMed Scopus Google Scholar, Biochem. PubMed Scopus Google Scholar). The release of cellular after an 8-h of L-cells with or of cyclodextrins was with the cell total The the of cyclodextrins the greater the of cell and the greater the of was than with greater ability to cholesterol The results in were from studies in which cells were extensively of cell cholesterol by with a for the release of was acceptors. the results for of and 8 The for the release of after 8 h of was to that release of was not evident after a exposure of cell to the acceptors at the of β-cyclodextrins and that toxicity after with cyclodextrins, not the first phase of of L-cell after or 8 h of with acceptors. L-cells were incubated with either HDL3 of or cyclodextrins at the The of cellular released to the medium was by and medium after and 8 h of Although β-cyclodextrins are to have a relatively high specificity for sterols compared to T. Fukunaga K. Pitha J. J. Pharm. Sci. 1992; 81: 521-523Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 12Ohtani Y. Irie T. Uekama K. Fukunaga K. Pitha J. Eur. J. Biochem. 1989; 186: 17-22Crossref PubMed Scopus (548) Google Scholar, K. Drug 3: Google Scholar), it is to the of cyclodextrin-mediated release of cellular in order to on the mechanism by which cyclodextrins cellular cholesterol To the release of cell L-cells were in as and to and the major in cell plasma in medium with cyclodextrins or HDL3 an of the release of from the cells The release of cellular was of cellular were released after h of with mM is to that with high of HDL3 and than that for cholesterol was made to the of phospholipid in the medium after a of L-cells with 10 mM from to of the cell of of cholesterol, was phospholipid was in the of of from 8 of it has been that the rate of cholesterol release from cells on the cell G.H. M. Phillips M.C. PubMed Scopus Google Scholar, Phillips M.C. C. Rothblat G.H. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). The differences in the of cholesterol release among cells is with acceptor including and and G.H. M. Phillips M.C. PubMed Scopus Google Scholar, F.H. Rothblat G.H. J. Biol. Chem. 1991; Full Text PDF PubMed Google Scholar, M. P. Rothblat G.H. PubMed Google Scholar, W.J. Rothblat Phillips M.C. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). To if efflux values when the very and cyclodextrins as cholesterol a of were L-cell Fu5AH cells, and GM3468A fibroblasts. HDL3, and as acceptors. of 10 were used for the cyclodextrins and for the HDL3 in order to the of cell cholesterol release. the for the three cell on three different acceptors. It is from the in that with HDL as the acceptor the differences in among cell was as L-cell > G.H. M. Phillips M.C. PubMed Scopus Google Scholar). However, in to the HDL the cell in of cholesterol was not when either 2OHpβCD or as acceptors. the cyclodextrins, cholesterol efflux from the fibroblasts and Fu5AH cells was and greater than that for The in can be used to of the rate of cellular cholesterol release for cell of Vmax for cholesterol efflux is from is the release of cholesterol h and is the of acceptor, in with a used to maximal for Scholar). Vmax values for the cell are in 7 and that in to the results with HDL as an acceptor, the cyclodextrins Vmax values that not the fibroblasts and cells L-cells were 1) the efflux from cells to cyclodextrins is with values of 2) Vmax values for cells to and are the there is little or Vmax for cholesterol efflux among cell to cyclodextrins, and Vmax values among cells when HDL is the acceptor, and, with the cell type the rate of release to HDL is much than to To test efflux mediated by cyclodextrins was to the of the cyclodextrins (i.e. with cells, we the of to L-cells a to the cell were compared with the for cholesterol efflux at the was cholesterol efflux a maximal with a of 2OHpβCD at was the In the of cyclodextrin associated with the cells was very of the in the extracellular of their ability to and hydrophobic cyclodextrins have been used extensively as drug delivery J. Irie T. Sklar P.B. Nye J.S. Life Sci. 1988; 43: 493-502Crossref PubMed Scopus (228) Google Scholar, K. Drug 3: Google Scholar). The three general of cyclodextrins are by the of in these cyclic and are: α β and 8 units, The of the cyclodextrins can be by a of different modifications the of groups to the D. Minutes of the 5th International Symposium on Cyclodextrins. Editions de Sante, Paris, France1990Google Scholar, K. Drug 3: Google Scholar). The ability to molecules in a function of the of the hydrophobic cavity within cyclodextrins, and this cavity has been estimated to in and 8 on the specific K. Drug 3: Google Scholar). the three cyclodextrins used in this have an for cholesterol from cells in The efflux of cholesterol is and, at the of an 8-h with 10 mM from to of the cholesterol has been from L-cell fibroblasts In this in which the cyclodextrins are in the medium in the of of cholesterol, efflux of cholesterol is an of the of cellular The extensive of cell results in membrane as by the of and a is cell and release Although this could be a in cell which not result in as extensive cell not result in in The kinetics of cholesterol efflux to cyclodextrins are different from with a cholesterol acceptor as the HDL3 used in the we have demonstrated that cell cholesterol efflux generally first order kinetics W.J. Mahlberg F.H. Rothblat G.H. Phillips M.C. Biochim. Biophys. Acta. 1991; 1085: 273-298Crossref PubMed Scopus (389) Google Scholar) and that in cells cholesterol to be released from J. Biol. 1991; PubMed Scopus Google Scholar, F.H. Rothblat G.H. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar, G.H. Mahlberg F.H. W.J. Phillips M.C. J. Lipid Res. 1992; 33: Full Text PDF PubMed Google Scholar). can be from the efflux with cyclodextrins is much than with HDL and to cells and are is demonstrated by the the estimated of cholesterol to cyclodextrin molecules after 8 h of with mM of and 2OHpβCD are and and these are when cyclodextrin are to mM Although it has been suggested that cyclodextrins can complexes with K. Drug 3: Google Scholar), the high in this an cell and acceptor, as well as the that other compounds from cells or medium with cholesterol for within the particular is the that the cell specificity of the cholesterol release rate that has been with and acceptor G.H. M. Phillips M.C. PubMed Scopus Google Scholar, F.H. Rothblat G.H. J. Biol. 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PubMed Scopus Google Scholar) and 2) the differences in efflux among cell was a function of the of the plasma membrane that the rate of of cholesterol W.J. Mahlberg F.H. Rothblat G.H. Phillips M.C. Biochim. Biophys. Acta. 1991; 1085: 273-298Crossref PubMed Scopus (389) Google Scholar, M.C. W.J. Rothblat G.H. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). was by studies that the in efflux cell was when efflux was plasma membrane as cholesterol Phillips M.C. C. Rothblat G.H. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). Although we have a in efflux among cell G.H. M. Phillips M.C. PubMed Scopus Google Scholar, F.H. Rothblat G.H. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar), a of studies has that the estimated rate of cell cholesterol release is not the for acceptor and can be modified by acceptor and the estimated Vmax for cholesterol efflux from L-cells to HDL phospholipid or in the and Vmax with with phospholipid in the phase or values of W.J. Rothblat Phillips M.C. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). of the effect of acceptor has demonstrated that the estimated Vmax values for efflux from L-cells for HDL for and for W.J. Rothblat G.H. Phillips M.C. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). The very high efficiency of cyclodextrins for cholesterol efflux these and the of acceptor on the Vmax for cell cholesterol The plasma membrane of cholesterol the cell by the aqueous diffusion mechanism which the of cholesterol molecules from the W.J. Mahlberg F.H. Rothblat G.H. Phillips M.C. Biochim. Biophys. Acta. 1991; 1085: 273-298Crossref PubMed Scopus (389) Google Scholar, M.C. W.J. Rothblat G.H. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). high acceptor the cholesterol efflux rate on the rate constant for cholesterol from the plasma membrane as well as the of plasma membrane cholesterol that is for the that Vmax It that the high values of Vmax with the cyclodextrins could because of in this is not to these in could from that cholesterol in the of plasma membrane cholesterol for could to HDL cyclodextrin molecules can of the cell The of acceptor at the cell on could be a of the of the in of either the the cell or membrane by plasma membrane or particular is the that very high of cholesterol release can be from cells with the It has been that of the major in cell cholesterol efflux was the of cholesterol from the plasma in cells efflux to be than transport W.J. Mahlberg F.H. Rothblat G.H. Phillips M.C. Biochim. Biophys. Acta. 1991; 1085: 273-298Crossref PubMed Scopus (389) Google Scholar, W.J. Phillips M.C. Rothblat G.H. J. Biol. Chem. Full Text PDF PubMed Google Scholar, T. M. Lange Y. J. Lipid Res. 1995; 36: Full Text PDF PubMed Google Scholar). acceptors with efflux that of cyclodextrins efflux be and in of cholesterol release. is not to a of cyclodextrins cell cholesterol. However, can be The that there is a very in the release of cholesterol and phospholipid that membrane or is not this were the the release of cholesterol and phospholipid to their in the plasma In the very of cyclodextrins with cells that are not a in cholesterol studies be to the underlying the of cholesterol from cells by In to the of cyclodextrins as tools for studies on cholesterol transport and membrane the cyclodextrins and compounds Chem. 33: Scopus Google Scholar) have the potential to as agents that could on either the or of the atherosclerotic plaque. of of these compounds could the of cholesterol the and plasma by the acceptor molecules as a for cholesterol. the other it is that of cyclodextrins could function as cholesterol and enhancing of not being in to It is this that is and