Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Feb 15;99(4):773–780. doi: 10.1172/JCI119223

Cyclodextrins as catalysts for the removal of cholesterol from macrophage foam cells.

V M Atger 1, M de la Llera Moya 1, G W Stoudt 1, W V Rodrigueza 1, M C Phillips 1, G H Rothblat 1
PMCID: PMC507862  PMID: 9045882

Abstract

Low concentrations of cyclodextrins (< 1.0 mM) added to serum act catalytically, accelerating the exchange of cholesterol between cells and lipoproteins. J774 macrophages incubated with serum and 2-hydroxypropyl-beta-cyclodextrin (< or = 1 mM) released fivefold more labeled cholesterol than with serum alone. Increased efflux was not accompanied by a change in cell cholesterol mass; thus, cyclodextrin functioned as a cholesterol shuttle, enhancing cholesterol bidirectional flux without changing the equilibrium cholesterol distribution between cells and medium. The addition of phospholipid vesicles to serum and cyclodextrin shifted the equilibrium distribution to favor the medium, producing rapid and extensive depletion of cell cholesterol mass. The combination of serum, phospholipid vesicles, and cyclodextrin also stimulated the rapid clearance of both free and esterified cholesterol from mouse peritoneal macrophages loaded with free and esterified cholesterol. This study: (a) demonstrates that a compound can function as a catalyst to enhance the movement of cholesterol between cells and serum, (b) illustrates the difference between cholesterol exchange and net transport in a cell/serum system, (c) demonstrates how net movement of cholesterol is linked to concentration gradients established by phospholipids, (d) provides a basis for the development of the shuttle/sink model for the first steps in reverse cholesterol transport, (e) validates the model using artificial shuttles (cyclodextrins) and sinks (large unilamellar vesicles), and (f) suggests that cyclodextrin-like cholesterol shuttles might be of pharmacological significance in treating unstable atherosclerotic plaques.

Full Text

The Full Text of this article is available as a PDF (222.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Atger V., de la Llera Moya M., Bamberger M., Francone O., Cosgrove P., Tall A., Walsh A., Moatti N., Rothblat G. Cholesterol efflux potential of sera from mice expressing human cholesteryl ester transfer protein and/or human apolipoprotein AI. J Clin Invest. 1995 Dec;96(6):2613–2622. doi: 10.1172/JCI118326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Badimon J. J., Badimon L., Galvez A., Dische R., Fuster V. High density lipoprotein plasma fractions inhibit aortic fatty streaks in cholesterol-fed rabbits. Lab Invest. 1989 Mar;60(3):455–461. [PubMed] [Google Scholar]
  3. Bernard D. W., Rodriguez A., Rothblat G. H., Glick J. M. Influence of high density lipoprotein on esterified cholesterol stores in macrophages and hepatoma cells. Arteriosclerosis. 1990 Jan-Feb;10(1):135–144. doi: 10.1161/01.atv.10.1.135. [DOI] [PubMed] [Google Scholar]
  4. Bernard D. W., Rodriguez A., Rothblat G. H., Glick J. M. cAMP stimulates cholesteryl ester clearance to high density lipoproteins in J7774 macrophages. J Biol Chem. 1991 Jan 15;266(2):710–716. [PubMed] [Google Scholar]
  5. Brown B. G., Zhao X. Q., Sacco D. E., Albers J. J. Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease. Circulation. 1993 Jun;87(6):1781–1791. doi: 10.1161/01.cir.87.6.1781. [DOI] [PubMed] [Google Scholar]
  6. Castro G. R., Fielding C. J. Early incorporation of cell-derived cholesterol into pre-beta-migrating high-density lipoprotein. Biochemistry. 1988 Jan 12;27(1):25–29. doi: 10.1021/bi00401a005. [DOI] [PubMed] [Google Scholar]
  7. Davidson W. S., Rodrigueza W. V., Lund-Katz S., Johnson W. J., Rothblat G. H., Phillips M. C. Effects of acceptor particle size on the efflux of cellular free cholesterol. J Biol Chem. 1995 Jul 21;270(29):17106–17113. doi: 10.1074/jbc.270.29.17106. [DOI] [PubMed] [Google Scholar]
  8. FEDOROFF S., DOERR J. Effect of human blood serum on tissue cultures. III. A natural cytotoxic system in human blood serum. J Natl Cancer Inst. 1962 Aug;29:331–353. [PubMed] [Google Scholar]
  9. FEDOROFF S. Effect of human blood serum on tissue cultures. I. Some properties and specificity of toxic human serum, and its interaction with strain L cells. Tex Rep Biol Med. 1958;16(1):31–47. [PubMed] [Google Scholar]
  10. Fielding C. J., Fielding P. E. Molecular physiology of reverse cholesterol transport. J Lipid Res. 1995 Feb;36(2):211–228. [PubMed] [Google Scholar]
  11. Fournier N., de la Llera Moya M., Burkey B. F., Swaney J. B., Paterniti J., Jr, Moatti N., Atger V., Rothblat G. H. Role of HDL phospholipid in efflux of cell cholesterol to whole serum: studies with human apoA-I transgenic rats. J Lipid Res. 1996 Aug;37(8):1704–1711. [PubMed] [Google Scholar]
  12. Francone O. L., Fielding C. J. Initial steps in reverse cholesterol transport: the role of short-lived cholesterol acceptors. Eur Heart J. 1990 Aug;11 (Suppl E):218–224. doi: 10.1093/eurheartj/11.suppl_e.218. [DOI] [PubMed] [Google Scholar]
  13. Hara H., Yokoyama S. Role of apolipoproteins in cholesterol efflux from macrophages to lipid microemulsion: proposal of a putative model for the pre-beta high-density lipoprotein pathway. Biochemistry. 1992 Feb 25;31(7):2040–2046. doi: 10.1021/bi00122a021. [DOI] [PubMed] [Google Scholar]
  14. Irie T., Fukunaga K., Garwood M. K., Carpenter T. O., Pitha J., Pitha J. Hydroxypropylcyclodextrins in parenteral use. II: Effects on transport and disposition of lipids in rabbit and humans. J Pharm Sci. 1992 Jun;81(6):524–528. doi: 10.1002/jps.2600810610. [DOI] [PubMed] [Google Scholar]
  15. Irie T., Fukunaga K., Pitha J. Hydroxypropylcyclodextrins in parenteral use. I: Lipid dissolution and effects on lipid transfers in vitro. J Pharm Sci. 1992 Jun;81(6):521–523. doi: 10.1002/jps.2600810609. [DOI] [PubMed] [Google Scholar]
  16. Ishikawa T. T., MacGee J., Morrison J. A., Glueck C. J. Quantitative analysis of cholesterol in 5 to 20 microliter of plasma. J Lipid Res. 1974 May;15(3):286–291. [PubMed] [Google Scholar]
  17. Johnson W. J., Bamberger M. J., Latta R. A., Rapp P. E., Phillips M. C., Rothblat G. H. The bidirectional flux of cholesterol between cells and lipoproteins. Effects of phospholipid depletion of high density lipoprotein. J Biol Chem. 1986 May 5;261(13):5766–5776. [PubMed] [Google Scholar]
  18. Johnson W. J., Mahlberg F. H., Chacko G. K., Phillips M. C., Rothblat G. H. The influence of cellular and lipoprotein cholesterol contents on the flux of cholesterol between fibroblasts and high density lipoprotein. J Biol Chem. 1988 Oct 5;263(28):14099–14106. [PubMed] [Google Scholar]
  19. Johnson W. J., Mahlberg F. H., Rothblat G. H., Phillips M. C. Cholesterol transport between cells and high-density lipoproteins. Biochim Biophys Acta. 1991 Oct 1;1085(3):273–298. doi: 10.1016/0005-2760(91)90132-2. [DOI] [PubMed] [Google Scholar]
  20. Jollis J. G., Peterson E. D., DeLong E. R., Mark D. B., Collins S. R., Muhlbaier L. H., Pryor D. B. The relation between the volume of coronary angioplasty procedures at hospitals treating Medicare beneficiaries and short-term mortality. N Engl J Med. 1994 Dec 15;331(24):1625–1629. doi: 10.1056/NEJM199412153312406. [DOI] [PubMed] [Google Scholar]
  21. Jonas A., Bottum K., Theret N., Duchateau P., Castro G. Transfer of cholesterol from Ob1771 cells or LDL to reconstituted, defined high density lipoproteins. J Lipid Res. 1994 May;35(5):860–870. [PubMed] [Google Scholar]
  22. Kilsdonk E. P., Yancey P. G., Stoudt G. W., Bangerter F. W., Johnson W. J., Phillips M. C., Rothblat G. H. Cellular cholesterol efflux mediated by cyclodextrins. J Biol Chem. 1995 Jul 21;270(29):17250–17256. doi: 10.1074/jbc.270.29.17250. [DOI] [PubMed] [Google Scholar]
  23. Klansek J. J., Yancey P., St Clair R. W., Fischer R. T., Johnson W. J., Glick J. M. Cholesterol quantitation by GLC: artifactual formation of short-chain steryl esters. J Lipid Res. 1995 Oct;36(10):2261–2266. [PubMed] [Google Scholar]
  24. Markwell M. A., Haas S. M., Bieber L. L., Tolbert N. E. A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples. Anal Biochem. 1978 Jun 15;87(1):206–210. doi: 10.1016/0003-2697(78)90586-9. [DOI] [PubMed] [Google Scholar]
  25. Miyazaki A., Sakuma S., Morikawa W., Takiue T., Miake F., Terano T., Sakai M., Hakamata H., Sakamoto Y., Natio M. Intravenous injection of rabbit apolipoprotein A-I inhibits the progression of atherosclerosis in cholesterol-fed rabbits. Arterioscler Thromb Vasc Biol. 1995 Nov;15(11):1882–1888. doi: 10.1161/01.atv.15.11.1882. [DOI] [PubMed] [Google Scholar]
  26. Pitha J., Irie T., Sklar P. B., Nye J. S. Drug solubilizers to aid pharmacologists: amorphous cyclodextrin derivatives. Life Sci. 1988;43(6):493–502. doi: 10.1016/0024-3205(88)90150-6. [DOI] [PubMed] [Google Scholar]
  27. Rajewski R. A., Traiger G., Bresnahan J., Jaberaboansari P., Stella V. J., Thompson D. O. Preliminary safety evaluation of parenterally administered sulfoalkyl ether beta-cyclodextrin derivatives. J Pharm Sci. 1995 Aug;84(8):927–932. doi: 10.1002/jps.2600840805. [DOI] [PubMed] [Google Scholar]
  28. Rodrigueza W. V., Pritchard P. H., Hope M. J. The influence of size and composition on the cholesterol mobilizing properties of liposomes in vivo. Biochim Biophys Acta. 1993 Nov 21;1153(1):9–19. doi: 10.1016/0005-2736(93)90270-a. [DOI] [PubMed] [Google Scholar]
  29. Rodrigueza W. V., Williams K. J., Rothblat G. H., Phillips M. C. Remodeling and shuttling. Mechanisms for the synergistic effects between different acceptor particles in the mobilization of cellular cholesterol. Arterioscler Thromb Vasc Biol. 1997 Feb;17(2):383–393. doi: 10.1161/01.atv.17.2.383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ross A. C., Go K. J., Heider J. G., Rothblat G. H. Selective inhibition of acyl coenzyme A:cholesterol acyltransferase by compound 58-035. J Biol Chem. 1984 Jan 25;259(2):815–819. [PubMed] [Google Scholar]
  31. Rothblat G. H., Mahlberg F. H., Johnson W. J., Phillips M. C. Apolipoproteins, membrane cholesterol domains, and the regulation of cholesterol efflux. J Lipid Res. 1992 Aug;33(8):1091–1097. [PubMed] [Google Scholar]
  32. Sloop C. H., Dory L., Roheim P. S. Interstitial fluid lipoproteins. J Lipid Res. 1987 Mar;28(3):225–237. [PubMed] [Google Scholar]
  33. Warner G. J., Stoudt G., Bamberger M., Johnson W. J., Rothblat G. H. Cell toxicity induced by inhibition of acyl coenzyme A:cholesterol acyltransferase and accumulation of unesterified cholesterol. J Biol Chem. 1995 Mar 17;270(11):5772–5778. doi: 10.1074/jbc.270.11.5772. [DOI] [PubMed] [Google Scholar]
  34. Yancey P. G., Bielicki J. K., Johnson W. J., Lund-Katz S., Palgunachari M. N., Anantharamaiah G. M., Segrest J. P., Phillips M. C., Rothblat G. H. Efflux of cellular cholesterol and phospholipid to lipid-free apolipoproteins and class A amphipathic peptides. Biochemistry. 1995 Jun 20;34(24):7955–7965. doi: 10.1021/bi00024a021. [DOI] [PubMed] [Google Scholar]
  35. Yancey P. G., Rodrigueza W. V., Kilsdonk E. P., Stoudt G. W., Johnson W. J., Phillips M. C., Rothblat G. H. Cellular cholesterol efflux mediated by cyclodextrins. Demonstration Of kinetic pools and mechanism of efflux. J Biol Chem. 1996 Jul 5;271(27):16026–16034. doi: 10.1074/jbc.271.27.16026. [DOI] [PubMed] [Google Scholar]
  36. de la Llera Moya M., Atger V., Paul J. L., Fournier N., Moatti N., Giral P., Friday K. E., Rothblat G. A cell culture system for screening human serum for ability to promote cellular cholesterol efflux. Relations between serum components and efflux, esterification, and transfer. Arterioscler Thromb. 1994 Jul;14(7):1056–1065. doi: 10.1161/01.atv.14.7.1056. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES