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. 1990 Jun 15;268(3):685–691. doi: 10.1042/bj2680685

Evidence for reverse cholesterol transport in vivo from liver endothelial cells to parenchymal cells and bile by high-density lipoprotein.

H F Bakkeren 1, F Kuipers 1, R J Vonk 1, T J Van Berkel 1
PMCID: PMC1131494  PMID: 2363705

Abstract

Acetylated low-density lipoprotein (acetyl-LDL), biologically labelled in the cholesterol moiety of cholesteryl oleate, was injected into control and oestrogen-treated rats. The serum clearance, the distribution among the various lipoproteins, the hepatic localization and the biliary secretion of the [3H]cholesterol moiety were determined at various times after injection. In order to monitor the intrahepatic metabolism of the cholesterol esters of acetyl-LDL in vivo, the liver was subdivided into parenchymal, endothelial and Kupffer cells by a low-temperature cell-isolation procedure. In both control and oestrogen-treated rats, acetyl-LDL is rapidly cleared from the circulation, mainly by the liver endothelial cells. Subsequently, the cholesterol esters are hydrolysed, and within 1 h after injection, about 60% of the cell- associated cholesterol is released. The [3H]cholesterol is mainly recovered in the high-density lipoprotein (HDL) range of the serum of control rats, while low levels of radioactivity are detected in serum of oestrogen-treated rats. In control rats cholesterol is transported from endothelial cells to parenchymal cells (reverse cholesterol transport), where it is converted into bile acids and secreted into bile. The data thus provide evidence that HDL can serve as acceptors for cholesterol from endothelial cells in vivo, whereby efficient delivery to the parenchymal cells and bile is assured. In oestrogen-treated rats the radioactivity from the endothelial cells is released with similar kinetics as in control rats. However, only a small percentage of radioactivity is found in the HDL fraction and an increased uptake of radioactivity in Kupffer cells is observed. The secretion of radioactivity into bile is greatly delayed in oestrogen-treated rats. It is concluded that, in the absence of extracellular lipoproteins, endothelial cells can still release cholesterol, although for efficient transport to liver parenchymal cells and bile, HDL is indispensable.

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Selected References

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  1. Aviram M., Bierman E. L., Oram J. F. High density lipoprotein stimulates sterol translocation between intracellular and plasma membrane pools in human monocyte-derived macrophages. J Lipid Res. 1989 Jan;30(1):65–76. [PubMed] [Google Scholar]
  2. BLIGH E. G., DYER W. J. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959 Aug;37(8):911–917. doi: 10.1139/o59-099. [DOI] [PubMed] [Google Scholar]
  3. Barter P. J., Lally J. I. The activity of an esterified cholesterol transferring factor in human and rat serum. Biochim Biophys Acta. 1978 Nov 22;531(2):233–236. doi: 10.1016/0005-2760(78)90147-9. [DOI] [PubMed] [Google Scholar]
  4. Basu S. K., Goldstein J. L., Anderson G. W., Brown M. S. Degradation of cationized low density lipoprotein and regulation of cholesterol metabolism in homozygous familial hypercholesterolemia fibroblasts. Proc Natl Acad Sci U S A. 1976 Sep;73(9):3178–3182. doi: 10.1073/pnas.73.9.3178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blomhoff R., Drevon C. A., Eskild W., Helgerud P., Norum K. R., Berg T. Clearance of acetyl low density lipoprotein by rat liver endothelial cells. Implications for hepatic cholesterol metabolism. J Biol Chem. 1984 Jul 25;259(14):8898–8903. [PubMed] [Google Scholar]
  6. Bonorris G. G., Coyne M. J., Chung A., Schoenfield L. J. Mechanism of estrogen-induced saturated bile in the hamster. J Lab Clin Med. 1977 Dec;90(6):963–970. [PubMed] [Google Scholar]
  7. Brinton E. A., Kenagy R. D., Oram J. F., Bierman E. L. Regulation of high density lipoprotein binding activity of aortic endothelial cells by treatment with acetylated low density lipoprotein. Arteriosclerosis. 1985 Jul-Aug;5(4):329–335. doi: 10.1161/01.atv.5.4.329. [DOI] [PubMed] [Google Scholar]
  8. Brown M. S., Goldstein J. L., Krieger M., Ho Y. K., Anderson R. G. Reversible accumulation of cholesteryl esters in macrophages incubated with acetylated lipoproteins. J Cell Biol. 1979 Sep;82(3):597–613. doi: 10.1083/jcb.82.3.597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Brown M. S., Goldstein J. L. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem. 1983;52:223–261. doi: 10.1146/annurev.bi.52.070183.001255. [DOI] [PubMed] [Google Scholar]
  10. Brown M. S., Ho Y. K., Goldstein J. L. The cholesteryl ester cycle in macrophage foam cells. Continual hydrolysis and re-esterification of cytoplasmic cholesteryl esters. J Biol Chem. 1980 Oct 10;255(19):9344–9352. [PubMed] [Google Scholar]
  11. 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]
  12. Chao Y. S., Windler E. E., Chen G. C., Havel R. J. Hepatic catabolism of rat and human lipoproteins in rats treated with 17 alpha-ethinyl estradiol. J Biol Chem. 1979 Nov 25;254(22):11360–11366. [PubMed] [Google Scholar]
  13. Davis R. A., Roheim P. S. Pharmacologically induced hypolipidemia. The ethinyl estradiol-treated rat. Atherosclerosis. 1978 Aug;30(4):293–299. doi: 10.1016/0021-9150(78)90122-3. [DOI] [PubMed] [Google Scholar]
  14. Davis R. A., Showalter R., Kern F., Jr Reversal by triton WR-1339 of ethynyloestradiol-induced hepatic cholesterol esterification. Biochem J. 1978 Jul 15;174(1):45–51. doi: 10.1042/bj1740045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Funke H., Boyles J., Weisgraber K. H., Ludwig E. H., Hui D. Y., Mahley R. W. Uptake of apolipoprotein E-containing high density lipoproteins by hepatic parenchymal cells. Arteriosclerosis. 1984 Sep-Oct;4(5):452–461. doi: 10.1161/01.atv.4.5.452. [DOI] [PubMed] [Google Scholar]
  16. Glomset J. A. The plasma lecithins:cholesterol acyltransferase reaction. J Lipid Res. 1968 Mar;9(2):155–167. [PubMed] [Google Scholar]
  17. Goldstein J. L., Ho Y. K., Basu S. K., Brown M. S. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci U S A. 1979 Jan;76(1):333–337. doi: 10.1073/pnas.76.1.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Harkes L., van Berkel T. J. Cellular localization of the receptor-dependent and receptor-independent uptake of human LDL in the liver of normal and 17 alpha-ethinyl estradiol-treated rats. FEBS Lett. 1983 Apr 5;154(1):75–80. doi: 10.1016/0014-5793(83)80878-3. [DOI] [PubMed] [Google Scholar]
  19. Ho Y. K., Brown M. S., Goldstein J. L. Hydrolysis and excretion of cytoplasmic cholesteryl esters by macrophages: stimulation by high density lipoprotein and other agents. J Lipid Res. 1980 May;21(4):391–398. [PubMed] [Google Scholar]
  20. Karlin J. B., Johnson W. J., Benedict C. R., Chacko G. K., Phillips M. C., Rothblat G. H. Cholesterol flux between cells and high density lipoprotein. Lack of relationship to specific binding of the lipoprotein to the cell surface. J Biol Chem. 1987 Sep 15;262(26):12557–12564. [PubMed] [Google Scholar]
  21. Kuipers F., Havinga R., Bosschieter H., Toorop G. P., Hindriks F. R., Vonk R. J. Enterohepatic circulation in the rat. Gastroenterology. 1985 Feb;88(2):403–411. doi: 10.1016/0016-5085(85)90499-8. [DOI] [PubMed] [Google Scholar]
  22. Kuipers F., Nagelkerke J. F., Bakkeren H., Havinga R., Van Berkel T. J., Vonk R. J. Processing of cholesteryl ester from low-density lipoproteins in the rat. Hepatic metabolism and biliary secretion after uptake by different hepatic cell types. Biochem J. 1989 Feb 1;257(3):699–704. doi: 10.1042/bj2570699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  24. Miller N. E., La Ville A., Crook D. Direct evidence that reverse cholesterol transport is mediated by high-density lipoprotein in rabbit. Nature. 1985 Mar 7;314(6006):109–111. doi: 10.1038/314109a0. [DOI] [PubMed] [Google Scholar]
  25. Nagelkerke J. F., Bakkeren H. F., Kuipers F., Vonk R. J., van Berkel T. J. Hepatic processing of the cholesteryl ester from low density lipoprotein in the rat. J Biol Chem. 1986 Jul 5;261(19):8908–8913. [PubMed] [Google Scholar]
  26. Nagelkerke J. F., Barto K. P., van Berkel T. J. In vivo and in vitro uptake and degradation of acetylated low density lipoprotein by rat liver endothelial, Kupffer, and parenchymal cells. J Biol Chem. 1983 Oct 25;258(20):12221–12227. [PubMed] [Google Scholar]
  27. Nagelkerke J. F., van Berkel T. J. Rapid transport of fatty acids from rat liver endothelial to parenchymal cells after uptake of cholesteryl ester-labeled acetylated LDL. Biochim Biophys Acta. 1986 Feb 28;875(3):593–598. doi: 10.1016/0005-2760(86)90081-0. [DOI] [PubMed] [Google Scholar]
  28. Oram J. F., Johnson C. J., Brown T. A. Interaction of high density lipoprotein with its receptor on cultured fibroblasts and macrophages. Evidence for reversible binding at the cell surface without internalization. J Biol Chem. 1987 Feb 15;262(5):2405–2410. [PubMed] [Google Scholar]
  29. Phillips M. C., Johnson W. J., Rothblat G. H. Mechanisms and consequences of cellular cholesterol exchange and transfer. Biochim Biophys Acta. 1987 Jun 24;906(2):223–276. doi: 10.1016/0304-4157(87)90013-x. [DOI] [PubMed] [Google Scholar]
  30. Redgrave T. G., Roberts D. C., West C. E. Separation of plasma lipoproteins by density-gradient ultracentrifugation. Anal Biochem. 1975 May 12;65(1-2):42–49. doi: 10.1016/0003-2697(75)90488-1. [DOI] [PubMed] [Google Scholar]
  31. Robenek H., Schmitz G. Ca++ antagonists and ACAT inhibitors promote cholesterol efflux from macrophages by different mechanisms. II. Characterization of intracellular morphologic changes. Arteriosclerosis. 1988 Jan-Feb;8(1):57–67. doi: 10.1161/01.atv.8.1.57. [DOI] [PubMed] [Google Scholar]
  32. Schmitz G., Robenek H., Beuck M., Krause R., Schurek A., Niemann R. Ca++ antagonists and ACAT inhibitors promote cholesterol efflux from macrophages by different mechanisms. I. Characterization of cellular lipid metabolism. Arteriosclerosis. 1988 Jan-Feb;8(1):46–56. doi: 10.1161/01.atv.8.1.46. [DOI] [PubMed] [Google Scholar]
  33. Schmitz G., Robenek H., Lohmann U., Assmann G. Interaction of high density lipoproteins with cholesteryl ester-laden macrophages: biochemical and morphological characterization of cell surface receptor binding, endocytosis and resecretion of high density lipoproteins by macrophages. EMBO J. 1985 Mar;4(3):613–622. doi: 10.1002/j.1460-2075.1985.tb03674.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Schouten D., Kleinherenbrink-Stins M., Brouwer A., Knook D. L., Van Berkel T. J. Interaction in vivo and in vitro of apolipoprotein E-free high-density lipoprotein with parenchymal, endothelial and Kupffer cells from rat liver. Biochem J. 1988 Dec 1;256(2):615–621. doi: 10.1042/bj2560615. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Schwartz C. C., Halloran L. G., Vlahcevic Z. R., Gregory D. H., Swell L. Preferential utilization of free cholesterol from high-density lipoproteins for biliary cholesterol secretion in man. Science. 1978 Apr 7;200(4337):62–64. doi: 10.1126/science.204996. [DOI] [PubMed] [Google Scholar]
  36. Slotte J. P., Oram J. F., Bierman E. L. Binding of high density lipoproteins to cell receptors promotes translocation of cholesterol from intracellular membranes to the cell surface. J Biol Chem. 1987 Sep 25;262(27):12904–12907. [PubMed] [Google Scholar]
  37. Tauber J. P., Goldminz D., Gospodarowicz D. Up-regulation in vascular endothelial cells of binding sites of high density lipoprotein induced by 25-hydroxycholesterol. Eur J Biochem. 1981 Oct;119(2):327–339. doi: 10.1111/j.1432-1033.1981.tb05612.x. [DOI] [PubMed] [Google Scholar]
  38. Van Berkel T. J., Nagelkerke J. F., Harkes L., Kruijt J. K. Processing of acetylated human low-density lipoprotein by parenchymal and non-parenchymal liver cells. Involvement of calmodulin? Biochem J. 1982 Nov 15;208(2):493–503. doi: 10.1042/bj2080493. [DOI] [PMC free article] [PubMed] [Google Scholar]

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