Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Aug 15;98(4):984–995. doi: 10.1172/JCI118883

Regulation of scavenger receptor, class B, type I, a high density lipoprotein receptor, in liver and steroidogenic tissues of the rat.

K T Landschulz 1, R K Pathak 1, A Rigotti 1, M Krieger 1, H H Hobbs 1
PMCID: PMC507514  PMID: 8770871

Abstract

The scavenger receptor, class B, type I (SR-BI) binds HDL and mediates the selective transfer of cholesteryl esters from HDL to cultured cells. The tissue distribution of SR-BI in mice suggests that this receptor may deliver HDL-cholesterol to the liver and to nonplacental steroidogenic tissues. To examine the role of SR-BI in vivo, we determined its tissue and cell type-specific expression pattern and regulation in rats. High levels of immunodetectable SR-BI were present in the adrenal gland, ovary, and liver. In pregnant animals, the mammary gland also expressed high levels of the protein. SR-BI was localized by immunofluorescence to the surfaces of steroidogenic cells in the zona fasciculata and zona reticularis of the adrenal gland and to the corpus luteal cells of the ovary. High-dose estrogen treatment dramatically reduced SR-BI in the liver and increased SR-BI in the adrenal gland and corpus luteal cells of the ovary. These estrogen-induced increases in SR-BI in the adrenal gland and ovary were accompanied by enhanced in vivo uptake of fluorescent lipid from HDL. The administration of human chorionic gonadotropin induced a dramatic increase in SR-BI in the steroidogenic Leydig cells of the testes. These findings suggest that SR-BI mediates physiologically relevant uptake of cholesterol from HDL to nonplacental steroidogenic tissues in vivo.

Full Text

The Full Text of this article is available as a PDF (678.2 KB).

Selected References

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

  1. Acton S. L., Scherer P. E., Lodish H. F., Krieger M. Expression cloning of SR-BI, a CD36-related class B scavenger receptor. J Biol Chem. 1994 Aug 19;269(33):21003–21009. [PubMed] [Google Scholar]
  2. 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]
  3. Andersen J. M., Dietschy J. M. Regulation of sterol synthesis in adrenal gland of the rat by both high and low density human plasma lipoproteins. Biochem Biophys Res Commun. 1976 Oct 4;72(3):880–885. doi: 10.1016/s0006-291x(76)80214-8. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Azhar S., Stewart D., Reaven E. Utilization of cholesterol-rich lipoproteins by perfused rat adrenals. J Lipid Res. 1989 Nov;30(11):1799–1810. [PubMed] [Google Scholar]
  6. Balasubramaniam S., Goldstein J. L., Faust J. R., Brunschede G. Y., Brown M. S. Lipoprotein-mediated regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and cholesteryl ester metabolism in the adrenal gland of the rat. J Biol Chem. 1977 Mar 10;252(5):1771–1779. [PubMed] [Google Scholar]
  7. Brown M. S., Goldstein J. L. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986 Apr 4;232(4746):34–47. doi: 10.1126/science.3513311. [DOI] [PubMed] [Google Scholar]
  8. Burgess L. H., Handa R. J. Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone secretion, and glucocorticoid receptor-mediated functions in female rats. Endocrinology. 1992 Sep;131(3):1261–1269. doi: 10.1210/endo.131.3.1324155. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. 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]
  11. Chen Y. D., Kraemer F. B., Reaven G. M. Identification of specific high density lipoprotein-binding sites in rat testis and regulation of binding by human chorionic gonadotropin. J Biol Chem. 1980 Oct 10;255(19):9162–9167. [PubMed] [Google Scholar]
  12. 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]
  13. Eisenberg S. High density lipoprotein metabolism. J Lipid Res. 1984 Oct;25(10):1017–1058. [PubMed] [Google Scholar]
  14. Fielding C. J., Fielding P. E. Molecular physiology of reverse cholesterol transport. J Lipid Res. 1995 Feb;36(2):211–228. [PubMed] [Google Scholar]
  15. Ghosh D. K., Menon K. M. Induction of high-density-lipoprotein receptors in rat corpus luteum by human choriogonadotropin. Evidence of protein synthesis de novo. Biochem J. 1987 Jun 1;244(2):471–479. doi: 10.1042/bj2440471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gibori G., Chen Y. D., Khan I., Azhar S., Reaven G. M. Regulation of luteal cell lipoprotein receptors, sterol contents, and steroidogenesis by estradiol in the pregnant rat. Endocrinology. 1984 Feb;114(2):609–617. doi: 10.1210/endo-114-2-609. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. 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]
  19. Glomset J. A. The plasma lecithins:cholesterol acyltransferase reaction. J Lipid Res. 1968 Mar;9(2):155–167. [PubMed] [Google Scholar]
  20. 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]
  21. 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]
  22. Gwynne J. T., Strauss J. F., 3rd The role of lipoproteins in steroidogenesis and cholesterol metabolism in steroidogenic glands. Endocr Rev. 1982 Summer;3(3):299–329. doi: 10.1210/edrv-3-3-299. [DOI] [PubMed] [Google Scholar]
  23. Herz J., Goldstein J. L., Strickland D. K., Ho Y. K., Brown M. S. 39-kDa protein modulates binding of ligands to low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. J Biol Chem. 1991 Nov 5;266(31):21232–21238. [PubMed] [Google Scholar]
  24. Herz J., Kowal R. C., Ho Y. K., Brown M. S., Goldstein J. L. Low density lipoprotein receptor-related protein mediates endocytosis of monoclonal antibodies in cultured cells and rabbit liver. J Biol Chem. 1990 Dec 5;265(34):21355–21362. [PubMed] [Google Scholar]
  25. Hwang J., Menon K. M. Characterization of low density and high density lipoprotein receptors in the rat corpus luteum and regulation by gonadotropin. J Biol Chem. 1983 Jul 10;258(13):8020–8027. [PubMed] [Google Scholar]
  26. Illingworth D. R., Corbin D. K., Kemp E. D., Keenan E. J. Hormone changes during the menstrual cycle in abetalipoproteinemia: reduced luteal phase progesterone in a patient with homozygous hypobetalipoproteinemia. Proc Natl Acad Sci U S A. 1982 Nov;79(21):6685–6689. doi: 10.1073/pnas.79.21.6685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Illingworth D. R., Kenny T. A., Connor W. E., Orwoll E. S. Corticosteroid production in abetalipoproteinemia: evidence for an impaired response ACTH. J Lab Clin Med. 1982 Jul;100(1):115–126. [PubMed] [Google Scholar]
  28. Ishibashi S., Brown M. S., Goldstein J. L., Gerard R. D., Hammer R. E., Herz J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest. 1993 Aug;92(2):883–893. doi: 10.1172/JCI116663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Jokinen E. V., Landschulz K. T., Wyne K. L., Ho Y. K., Frykman P. K., Hobbs H. H. Regulation of the very low density lipoprotein receptor by thyroid hormone in rat skeletal muscle. J Biol Chem. 1994 Oct 21;269(42):26411–26418. [PubMed] [Google Scholar]
  30. Knecht T. P., Pittman R. C. A plasma membrane pool of cholesteryl esters that may mediate the selective uptake of cholesteryl esters from high-density lipoproteins. Biochim Biophys Acta. 1989 Apr 26;1002(3):365–375. doi: 10.1016/0005-2760(89)90351-2. [DOI] [PubMed] [Google Scholar]
  31. Kovanen P. T., Brown M. S., Goldstein J. L. Increased binding of low density lipoprotein to liver membranes from rats treated with 17 alpha-ethinyl estradiol. J Biol Chem. 1979 Nov 25;254(22):11367–11373. [PubMed] [Google Scholar]
  32. 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]
  33. 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]
  34. Krieger M., Herz J. Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu Rev Biochem. 1994;63:601–637. doi: 10.1146/annurev.bi.63.070194.003125. [DOI] [PubMed] [Google Scholar]
  35. 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]
  36. Leitersdorf E., Stein O., Eisenberg S., Stein Y. Uptake of rat plasma HDL subfractions labeled with [3H]cholesteryl linoleyl ether or with 125I by cultured rat hepatocytes and adrenal cells. Biochim Biophys Acta. 1984 Oct 24;796(1):72–82. doi: 10.1016/0005-2760(84)90240-6. [DOI] [PubMed] [Google Scholar]
  37. Ma P. T., Yamamoto T., Goldstein J. L., Brown M. S. Increased mRNA for low density lipoprotein receptor in livers of rabbits treated with 17 alpha-ethinyl estradiol. Proc Natl Acad Sci U S A. 1986 Feb;83(3):792–796. doi: 10.1073/pnas.83.3.792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Nabulsi A. A., Folsom A. R., White A., Patsch W., Heiss G., Wu K. K., Szklo M. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. The Atherosclerosis Risk in Communities Study Investigators. N Engl J Med. 1993 Apr 15;328(15):1069–1075. doi: 10.1056/NEJM199304153281501. [DOI] [PubMed] [Google Scholar]
  39. Nestler J. E., Bamberger M., Rothblat G. H., Strauss J. F., 3rd Metabolism of high density lipoproteins reconstituted with [3H]cholesteryl ester and [14C]cholesterol in the rat, with special reference to the ovary. Endocrinology. 1985 Aug;117(2):502–510. doi: 10.1210/endo-117-2-502. [DOI] [PubMed] [Google Scholar]
  40. Pathak R. K., Yokode M., Hammer R. E., Hofmann S. L., Brown M. S., Goldstein J. L., Anderson R. G. Tissue-specific sorting of the human LDL receptor in polarized epithelia of transgenic mice. J Cell Biol. 1990 Aug;111(2):347–359. doi: 10.1083/jcb.111.2.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Pathak R. K., Yokode M., Hammer R. E., Hofmann S. L., Brown M. S., Goldstein J. L., Anderson R. G. Tissue-specific sorting of the human LDL receptor in polarized epithelia of transgenic mice. J Cell Biol. 1990 Aug;111(2):347–359. doi: 10.1083/jcb.111.2.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Pieters M. N., Schouten D., Van Berkel T. J. In vitro and in vivo evidence for the role of HDL in reverse cholesterol transport. Biochim Biophys Acta. 1994 Jan 11;1225(2):125–134. doi: 10.1016/0925-4439(94)90069-8. [DOI] [PubMed] [Google Scholar]
  43. Pitas R. E., Innerarity T. L., Weinstein J. N., Mahley R. W. Acetoacetylated lipoproteins used to distinguish fibroblasts from macrophages in vitro by fluorescence microscopy. Arteriosclerosis. 1981 May-Jun;1(3):177–185. doi: 10.1161/01.atv.1.3.177. [DOI] [PubMed] [Google Scholar]
  44. 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]
  45. Reaven E., Boyles J., Spicher M., Azhar S. Evidence for surface entrapment of cholesterol-rich lipoproteins in luteinized ovary. Arteriosclerosis. 1988 May-Jun;8(3):298–309. doi: 10.1161/01.atv.8.3.298. [DOI] [PubMed] [Google Scholar]
  46. Reaven E., Shi X. Y., Azhar S. Interaction of lipoproteins with isolated ovary plasma membranes. J Biol Chem. 1990 Nov 5;265(31):19100–19111. [PubMed] [Google Scholar]
  47. 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]
  48. Reaven E., Tsai L., Azhar S. Cholesterol uptake by the 'selective' pathway of ovarian granulosa cells: early intracellular events. J Lipid Res. 1995 Jul;36(7):1602–1617. [PubMed] [Google Scholar]
  49. Rigotti A., Acton S. L., Krieger M. The class B scavenger receptors SR-BI and CD36 are receptors for anionic phospholipids. J Biol Chem. 1995 Jul 7;270(27):16221–16224. doi: 10.1074/jbc.270.27.16221. [DOI] [PubMed] [Google Scholar]
  50. 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]
  51. Rinninger F., Brundert M., Jäckle S., Kaiser T., Greten H. Selective uptake of low-density lipoprotein-associated cholesteryl esters by human fibroblasts, human HepG2 hepatoma cells and J774 macrophages in culture. Biochim Biophys Acta. 1995 Mar 16;1255(2):141–153. doi: 10.1016/0005-2760(94)00228-q. [DOI] [PubMed] [Google Scholar]
  52. Rinninger F., Jaeckle S., Pittman R. C. A pool of reversibly cell-associated cholesteryl esters involved in the selective uptake of cholesteryl esters from high-density lipoproteins by Hep G2 hepatoma cells. Biochim Biophys Acta. 1993 Feb 24;1166(2-3):275–283. doi: 10.1016/0005-2760(93)90108-l. [DOI] [PubMed] [Google Scholar]
  53. Rinninger F., Pittman R. C. Regulation of the selective uptake of high density lipoprotein-associated cholesteryl esters. J Lipid Res. 1987 Nov;28(11):1313–1325. [PubMed] [Google Scholar]
  54. Schaefer E. J., Foster D. M., Zech L. A., Lindgren F. T., Brewer H. B., Jr, Levy R. I. The effects of estrogen administration on plasma lipoprotein metabolism in premenopausal females. J Clin Endocrinol Metab. 1983 Aug;57(2):262–267. doi: 10.1210/jcem-57-2-262. [DOI] [PubMed] [Google Scholar]
  55. Spady D. K., Dietschy J. M. Rates of cholesterol synthesis and low-density lipoprotein uptake in the adrenal glands of the rat, hamster and rabbit in vivo. Biochim Biophys Acta. 1985 Sep 11;836(2):167–175. doi: 10.1016/0005-2760(85)90063-3. [DOI] [PubMed] [Google Scholar]
  56. Srivastava R. A., Baumann D., Schonfeld G. In vivo regulation of low-density lipoprotein receptors by estrogen differs at the post-transcriptional level in rat and mouse. Eur J Biochem. 1993 Sep 1;216(2):527–538. doi: 10.1111/j.1432-1033.1993.tb18171.x. [DOI] [PubMed] [Google Scholar]
  57. 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]
  58. Strauss J. F., 3rd, MacGregor L. C., Gwynne J. T. Uptake of high density lipoproteins by rat ovaries in vivo and dispersed ovarian cells in vitro. Direct correlation of high density lipoprotein uptake with steroidogenic activity. J Steroid Biochem. 1982 Apr;16(4):525–531. doi: 10.1016/0022-4731(82)90074-7. [DOI] [PubMed] [Google Scholar]
  59. Verschoor-Klootwyk A. H., Verschoor L., Azhar S., Reaven G. M. Role of exogenous cholesterol in regulation of adrenal steroidogenesis in the rat. J Biol Chem. 1982 Jul 10;257(13):7666–7671. [PubMed] [Google Scholar]
  60. Walsh B. W., Schiff I., Rosner B., Greenberg L., Ravnikar V., Sacks F. M. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med. 1991 Oct 24;325(17):1196–1204. doi: 10.1056/NEJM199110243251702. [DOI] [PubMed] [Google Scholar]
  61. Wenger N. K., Speroff L., Packard B. Cardiovascular health and disease in women. N Engl J Med. 1993 Jul 22;329(4):247–256. doi: 10.1056/NEJM199307223290406. [DOI] [PubMed] [Google Scholar]
  62. Willnow T. E., Sheng Z., Ishibashi S., Herz J. Inhibition of hepatic chylomicron remnant uptake by gene transfer of a receptor antagonist. Science. 1994 Jun 3;264(5164):1471–1474. doi: 10.1126/science.7515194. [DOI] [PubMed] [Google Scholar]
  63. Windler E. E., Kovanen P. T., Chao Y. S., Brown M. S., Havel R. J., Goldstein J. L. The estradiol-stimulated lipoprotein receptor of rat liver. A binding site that membrane mediates the uptake of rat lipoproteins containing apoproteins B and E. J Biol Chem. 1980 Nov 10;255(21):10464–10471. [PubMed] [Google Scholar]
  64. Wyne K. L., Pathak K., Seabra M. C., Hobbs H. H. Expression of the VLDL receptor in endothelial cells. Arterioscler Thromb Vasc Biol. 1996 Mar;16(3):407–415. doi: 10.1161/01.atv.16.3.407. [DOI] [PubMed] [Google Scholar]

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

RESOURCES