Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Jun 1;97(11):2660–2671. doi: 10.1172/JCI118716

Apolipoprotein A-I is required for cholesteryl ester accumulation in steroidogenic cells and for normal adrenal steroid production.

A S Plump 1, S K Erickson 1, W Weng 1, J S Partin 1, J L Breslow 1, D L Williams 1
PMCID: PMC507354  PMID: 8647961

Abstract

In addition to its ability to remove cholesterol from cells, HDL also delivers cholesterol to cells through a poorly defined process in which cholesteryl esters are selectively transferred from HDL particles into the cell without the uptake and degradation of the lipoprotein particle. The HDL-cholesteryl ester selective uptake pathway is known to occur in human, rabbit, and rodent hepatocytes where it may contribute to the clearance of plasma cholesteryl ester. The selective uptake pathway has been studied most extensively in steroidogenic cells of rodents in which it accounts for 90% or more of the cholesterol destined for steroid production or cholesteryl ester accumulation. In this study we have used apo A-I-, apo A-II-, and apo E-deficient mice created by gene targeting in embryonic stem cells to test the importance of the three major HDL proteins in determining cholesteryl ester accumulation in steroidogenic cells of the adrenal gland, ovary, and testis. apo E and apo A-II deficiencies were found to have only modest effects on cholesteryl ester accumulation. In contrast, apo A-I deficiency caused an almost complete failure to accumulate cholesteryl ester in steroidogenic cells. These results suggest that apo A-I is essential for the selective uptake of HDL-cholesteryl esters. The lack of apo A-I has a major impact on adrenal gland physiology causing diminished basal corticosteroid production, a blunted steroidogenic response to stress, and increased expression of compensatory pathways to provide cholesterol substrate for steroid production.

Full Text

The Full Text of this article is available as a PDF (1.0 MB).

Selected References

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

  1. Acton S., Rigotti A., Landschulz K. T., Xu S., Hobbs H. H., Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science. 1996 Jan 26;271(5248):518–520. doi: 10.1126/science.271.5248.518. [DOI] [PubMed] [Google Scholar]
  2. Allen J. M., Thompson G. R., Myant N. B. Normal adrenocortical response to adrenocorticotrophic hormone in patients with homozygous familial hypercholesterolaemia. Clin Sci (Lond) 1983 Jul;65(1):99–101. doi: 10.1042/cs0650099. [DOI] [PubMed] [Google Scholar]
  3. Andersen J. M., Dietschy J. M. Relative importance of high and low density lipoproteins in the regulation of cholesterol synthesis in the adrenal gland, ovary, and testis of the rat. J Biol Chem. 1978 Dec 25;253(24):9024–9032. [PubMed] [Google Scholar]
  4. Blue M. L., Williams D. L., Zucker S., Khan S. A., Blum C. B. Apolipoprotein E synthesis in human kidney, adrenal gland, and liver. Proc Natl Acad Sci U S A. 1983 Jan;80(1):283–287. doi: 10.1073/pnas.80.1.283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Boizel R., de Peretti E., Cathiard A. M., Halimi S., Bost M., Berthezene F., Saez J. M. Pattern of plasma levels of cortisol, dehydroepiandrosterone and pregnenolone sulphate in normal subjects and in patients with homozygous familial hypercholesterolaemia during ACTH infusion. Clin Endocrinol (Oxf) 1986 Oct;25(4):363–371. doi: 10.1111/j.1365-2265.1986.tb01702.x. [DOI] [PubMed] [Google Scholar]
  6. Brown M. S., Kovanen P. T., Goldstein J. L. Receptor-mediated uptake of lipoprotein-cholesterol and its utilization for steroid synthesis in the adrenal cortex. Recent Prog Horm Res. 1979;35:215–257. doi: 10.1016/b978-0-12-571135-7.50009-6. [DOI] [PubMed] [Google Scholar]
  7. Carr B. R., Simpson E. R. Lipoprotein utilization and cholesterol synthesis by the human fetal adrenal gland. Endocr Rev. 1981 Summer;2(3):306–326. doi: 10.1210/edrv-2-3-306. [DOI] [PubMed] [Google Scholar]
  8. Doering C. H., Shire J. G., Kessler S., Clayton R. B. Cholesterol ester concentration and corticosterone production in adrenals of the C57BL-10 and DBA-2 strains in relation to adrenal lipid depletion. Endocrinology. 1972 Jan;90(1):93–101. doi: 10.1210/endo-90-1-93. [DOI] [PubMed] [Google Scholar]
  9. Durand P., Cathiard A. M., Naaman E., Brieu V., Saez J. M. The influence of plasma lipoproteins on steroidogenesis of cultured ovine fetal and neonatal adrenal cells. J Steroid Biochem. 1987 Apr;26(4):425–431. doi: 10.1016/0022-4731(87)90051-3. [DOI] [PubMed] [Google Scholar]
  10. Erickson S. K., Lear S. R., Barker M. E., Musliner T. A. Regulation of cholesterol metabolism in the ethionine-induced premalignant rat liver. J Lipid Res. 1990 May;31(5):933–945. [PubMed] [Google Scholar]
  11. Glass C., Pittman R. C., Civen M., Steinberg D. Uptake of high-density lipoprotein-associated apoprotein A-I and cholesterol esters by 16 tissues of the rat in vivo and by adrenal cells and hepatocytes in vitro. J Biol Chem. 1985 Jan 25;260(2):744–750. [PubMed] [Google Scholar]
  12. Glass C., Pittman R. C., Weinstein D. B., Steinberg D. Dissociation of tissue uptake of cholesterol ester from that of apoprotein A-I of rat plasma high density lipoprotein: selective delivery of cholesterol ester to liver, adrenal, and gonad. Proc Natl Acad Sci U S A. 1983 Sep;80(17):5435–5439. doi: 10.1073/pnas.80.17.5435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Glomset J. A. The plasma lecithins:cholesterol acyltransferase reaction. J Lipid Res. 1968 Mar;9(2):155–167. [PubMed] [Google Scholar]
  14. Goldberg D. I., Beltz W. F., Pittman R. C. Evaluation of pathways for the cellular uptake of high density lipoprotein cholesterol esters in rabbits. J Clin Invest. 1991 Jan;87(1):331–346. doi: 10.1172/JCI114991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Goldstein J. L., Basu S. K., Brown M. S. Receptor-mediated endocytosis of low-density lipoprotein in cultured cells. Methods Enzymol. 1983;98:241–260. doi: 10.1016/0076-6879(83)98152-1. [DOI] [PubMed] [Google Scholar]
  16. Gordon T., Castelli W. P., Hjortland M. C., Kannel W. B., Dawber T. R. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977 May;62(5):707–714. doi: 10.1016/0002-9343(77)90874-9. [DOI] [PubMed] [Google Scholar]
  17. Green S. R., Pittman R. C. Comparative acyl specificities for transfer and selective uptake of high density lipoprotein cholesteryl esters. J Lipid Res. 1991 Mar;32(3):457–467. [PubMed] [Google Scholar]
  18. Gwynne J. T., Hess B. The role of high density lipoproteins in rat adrenal cholesterol metabolism and steroidogenesis. J Biol Chem. 1980 Nov 25;255(22):10875–10883. [PubMed] [Google Scholar]
  19. Gwynne J. T., Mahaffee D. D. Rat adrenal uptake and metabolism of high density lipoprotein cholesteryl ester. J Biol Chem. 1989 May 15;264(14):8141–8150. [PubMed] [Google Scholar]
  20. Gwynne J. T., Mahaffee D., Brewer H. B., Jr, Ney R. L. Adrenal cholesterol uptake from plasma lipoproteins: regulation by corticotropin. Proc Natl Acad Sci U S A. 1976 Dec;73(12):4329–4333. doi: 10.1073/pnas.73.12.4329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. HAVEL R. J., EDER H. A., BRAGDON J. H. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955 Sep;34(9):1345–1353. doi: 10.1172/JCI103182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Higashijima M., Kato K., Nawata H., Ibayashi H. Studies on lipoprotein and adrenal steroidogenesis: II. Utilization of low density lipoprotein- and high density lipoprotein-cholesterol for steroid production in functioning human adrenocortical adenoma cells in culture. Endocrinol Jpn. 1987 Oct;34(5):647–657. doi: 10.1507/endocrj1954.34.647. [DOI] [PubMed] [Google Scholar]
  23. Higashijima M., Nawata H., Kato K., Ibayashi H. Studies on lipoprotein and adrenal steroidogenesis: I. Roles of low density lipoprotein- and high density lipoprotein-cholesterol in steroid production in cultured human adrenocortical cells. Endocrinol Jpn. 1987 Oct;34(5):635–645. doi: 10.1507/endocrj1954.34.635. [DOI] [PubMed] [Google Scholar]
  24. Hoeg J. M., Loriaux L., Gregg R. E., Green W. R., Brewer H. B., Jr Impaired adrenal reserve in the Watanabe Heritable Hyperlipidemic rabbit: implications for LDL-receptor function in steroidogenesis. Metabolism. 1985 Feb;34(2):194–197. doi: 10.1016/0026-0495(85)90132-5. [DOI] [PubMed] [Google Scholar]
  25. Illingworth D. R., Kenny T. A., Orwoll E. S. Adrenal function in heterozygous and homozygous hypobetalipoproteinemia. J Clin Endocrinol Metab. 1982 Jan;54(1):27–33. doi: 10.1210/jcem-54-1-27. [DOI] [PubMed] [Google Scholar]
  26. Illingworth D. R., Orwoll E. S., Connor W. E. Impaired cortisol secretion in abetalipoproteinemia. J Clin Endocrinol Metab. 1980 May;50(5):977–979. doi: 10.1210/jcem-50-5-977. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Kovanen P. T., Goldstein J. L., Chappell D. A., Brown M. S. Regulation of low density lipoprotein receptors by adrenocorticotropin in the adrenal gland of mice and rats in vivo. J Biol Chem. 1980 Jun 25;255(12):5591–5598. [PubMed] [Google Scholar]
  29. Kovanen P. T., Schneider W. J., Hillman G. M., Goldstein J. L., Brown M. S. Separate mechanisms for the uptake of high and low density lipoproteins by mouse adrenal gland in vivo. J Biol Chem. 1979 Jun 25;254(12):5498–5505. [PubMed] [Google Scholar]
  30. Kowal J., Fiedler R. Arenal cells in tissue culture. I. Assay of steroid products; steroidogenic responses to peptide hormones. Arch Biochem Biophys. 1968 Nov;128(2):406–421. doi: 10.1016/0003-9861(68)90047-7. [DOI] [PubMed] [Google Scholar]
  31. Laue L., Hoeg J. M., Barnes K., Loriaux D. L., Chrousos G. P. The effect of mevinolin on steroidogenesis in patients with defects in the low density lipoprotein receptor pathway. J Clin Endocrinol Metab. 1987 Mar;64(3):531–535. doi: 10.1210/jcem-64-3-531. [DOI] [PubMed] [Google Scholar]
  32. Leblond L., Marcel Y. L. Uptake of high density lipoprotein cholesterol ester by HepG2 cells involves apolipoprotein E localized on the cell surface. J Biol Chem. 1993 Jan 25;268(3):1670–1676. [PubMed] [Google Scholar]
  33. Leitersdorf E., Israeli A., Stein O., Eisenberg S., Stein Y. The role of apolipoproteins of HDL in the selective uptake of cholesteryl linoleyl ether by cultured rat and bovine adrenal cells. Biochim Biophys Acta. 1986 Oct 3;878(3):320–329. doi: 10.1016/0005-2760(86)90239-0. [DOI] [PubMed] [Google Scholar]
  34. Levine D. M., Parker T. S., Donnelly T. M., Walsh A., Rubin A. L. In vivo protection against endotoxin by plasma high density lipoprotein. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):12040–12044. doi: 10.1073/pnas.90.24.12040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Liu A. C., Lawn R. M., Verstuyft J. G., Rubin E. M. Human apolipoprotein A-I prevents atherosclerosis associated with apolipoprotein[a] in transgenic mice. J Lipid Res. 1994 Dec;35(12):2263–2267. [PubMed] [Google Scholar]
  36. Miller G. J., Miller N. E. Plasma-high-density-lipoprotein concentration and development of ischaemic heart-disease. Lancet. 1975 Jan 4;1(7897):16–19. doi: 10.1016/s0140-6736(75)92376-4. [DOI] [PubMed] [Google Scholar]
  37. Moses H. L., Davis W. W., Rosenthal A. S., Garren L. D. Adrenal cholesterol: localization by electron-microscope autoradiography. Science. 1969 Mar 14;163(3872):1203–1205. doi: 10.1126/science.163.3872.1203. [DOI] [PubMed] [Google Scholar]
  38. Nicosia M., Prack M. M., Williams D. L. Differential regulation of apolipoprotein-E messenger RNA in zona fasciculata cells of rat adrenal gland determined by in situ hybridization. Mol Endocrinol. 1992 Feb;6(2):288–298. doi: 10.1210/mend.6.2.1373819. [DOI] [PubMed] [Google Scholar]
  39. Parks J. S., Li H., Gebre A. K., Smith T. L., Maeda N. Effect of apolipoprotein A-I deficiency on lecithin:cholesterol acyltransferase activation in mouse plasma. J Lipid Res. 1995 Feb;36(2):349–355. [PubMed] [Google Scholar]
  40. Pittman R. C., Glass C. K., Atkinson D., Small D. M. Synthetic high density lipoprotein particles. Application to studies of the apoprotein specificity for selective uptake of cholesterol esters. J Biol Chem. 1987 Feb 25;262(6):2435–2442. [PubMed] [Google Scholar]
  41. Pittman R. C., Knecht T. P., Rosenbaum M. S., Taylor C. A., Jr A nonendocytotic mechanism for the selective uptake of high density lipoprotein-associated cholesterol esters. J Biol Chem. 1987 Feb 25;262(6):2443–2450. [PubMed] [Google Scholar]
  42. Plump A. S., Scott C. J., Breslow J. L. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9607–9611. doi: 10.1073/pnas.91.20.9607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Plump A. S., Smith J. D., Hayek T., Aalto-Setälä K., Walsh A., Verstuyft J. G., Rubin E. M., Breslow J. L. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992 Oct 16;71(2):343–353. doi: 10.1016/0092-8674(92)90362-g. [DOI] [PubMed] [Google Scholar]
  44. Prack M. M., Nicosia M., Williams D. L., Gwynne J. Relationship between apolipoprotein E mRNA expression and tissue cholesterol content in rat adrenal gland. J Lipid Res. 1991 Oct;32(10):1611–1618. [PubMed] [Google Scholar]
  45. Prack M. M., Rothblat G. H., Erickson S. K., Reyland M. E., Williams D. L. Apolipoprotein E expression in Y1 adrenal cells is associated with increased intracellular cholesterol content and reduced free cholesterol efflux. Biochemistry. 1994 May 3;33(17):5049–5055. doi: 10.1021/bi00183a007. [DOI] [PubMed] [Google Scholar]
  46. Pászty C., Maeda N., Verstuyft J., Rubin E. M. Apolipoprotein AI transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice. J Clin Invest. 1994 Aug;94(2):899–903. doi: 10.1172/JCI117412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Rainey W. E., Rodgers R. J., Mason J. I. The role of bovine lipoproteins in the regulation of steroidogenesis and HMG-CoA reductase in bovine adrenocortical cells. Steroids. 1992 Apr;57(4):167–173. doi: 10.1016/0039-128x(92)90003-r. [DOI] [PubMed] [Google Scholar]
  48. Reaven E., Spicher M., Azhar S. Microvillar channels: a unique plasma membrane compartment for concentrating lipoproteins on the surface of rat adrenal cortical cells. J Lipid Res. 1989 Oct;30(10):1551–1560. [PubMed] [Google Scholar]
  49. Rinninger F., Brundert M., Jäckle S., Galle P. R., Busch C., Izbicki J. R., Rogiers X., Henne-Bruns D., Kremer B., Broelsch C. E. Selective uptake of high-density lipoprotein-associated cholesteryl esters by human hepatocytes in primary culture. Hepatology. 1994 May;19(5):1100–1114. [PubMed] [Google Scholar]
  50. Rinninger F., Pittman R. C. Regulation of the selective uptake of high density lipoprotein-associated cholesteryl esters by human fibroblasts and Hep G2 hepatoma cells. J Lipid Res. 1988 Sep;29(9):1179–1194. [PubMed] [Google Scholar]
  51. Rubin E. M., Krauss R. M., Spangler E. A., Verstuyft J. G., Clift S. M. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature. 1991 Sep 19;353(6341):265–267. doi: 10.1038/353265a0. [DOI] [PubMed] [Google Scholar]
  52. Smythe G. A., Bradshaw J. E., Vining R. F. Hypothalamic monoamine control of stress-induced adrenocorticotropin release in the rat. Endocrinology. 1983 Sep;113(3):1062–1071. doi: 10.1210/endo-113-3-1062. [DOI] [PubMed] [Google Scholar]
  53. Stein Y., Dabach Y., Hollander G., Halperin G., Stein O. Metabolism of HDL-cholesteryl ester in the rat, studied with a nonhydrolyzable analog, cholesteryl linoleyl ether. Biochim Biophys Acta. 1983 Jun 16;752(1):98–105. doi: 10.1016/0005-2760(83)90237-0. [DOI] [PubMed] [Google Scholar]
  54. Voyno-Yasenetskaya T. A., Dobbs L. G., Erickson S. K., Hamilton R. L. Low density lipoprotein- and high density lipoprotein-mediated signal transduction and exocytosis in alveolar type II cells. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4256–4260. doi: 10.1073/pnas.90.9.4256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Williams D. L., Dawson P. A., Newman T. C., Rudel L. L. Apolipoprotein E synthesis in peripheral tissues of nonhuman primates. J Biol Chem. 1985 Feb 25;260(4):2444–2451. [PubMed] [Google Scholar]
  56. Williams D. L., Wong J. S., Wissig S. L., Hamilton R. L. Cell surface "blanket" of apolipoprotein E on rat adrenocortical cells. J Lipid Res. 1995 Apr;36(4):745–758. [PubMed] [Google Scholar]

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

RESOURCES