Cell and Tissue Research

, Volume 269, Issue 3, pp 375–382 | Cite as

Distribution of the α2-macroglobulin receptor/low density lipoprotein receptor-related protein in human tissues

  • Søren K. Moestrup
  • Jørgen Gliemann
  • Gorm Pallesen


The hepatic α1-macroglobulin receptor (α2MR)/low density lipoprotein receptor-related protein (LRP) binds and endocytoses α2-macroglobulin-proteinase complexes in plasma. In addition, it binds lipoproteins, a novel 40 kDa protein, and complexes between plasminogen activators and plasminogen activator inhibitor type-1. This study shows, for the first time, the tissue distribution of α2MR/LRP as determined by immunohistochemistry with specific monoclonal antibodies. The analysis revealed α2MR/LRP-expression in a restricted spectrum of cell types, including neurons and astrocytes in the central nervous system, epithelial cells of the gastrointestinal tract, smooth muscle cells, fibroblasts, Leydig cells in testis, granulosa cells in ovary, and dendritic interstitial cells of kidney. Monocytederived cells displayed marked α2MR/LRP expression in the phagocytes of liver, lung and lymphoid tissues, but no or low expression in antigen-presenting cells including Langerhans' cells of the skin. The high abundance of α2MR/LRP in certain cell types of most organs suggests two main routes for α2MR/LRP ligand clearance: (1) systemic removal in liver of circulating ligands, and (2) non-hepatic interstitial removal in different organs, including the brain.

Key words

α2-Macroglobulin receptor Low-density lipoprotein receptor-related protein Tissue distribution Brain Macrophages Immunohistochemistry Man 


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  1. Ashcom JD, Tiller SE, Dickerson K, Cravens JL, Argraves WS, Strickland DK (1990) The human α2-macroglobulin receptor: identification of a 420-kDa cell surface glycoprotein specific for the activated conformation of α2-macroglobulin. J Cell Biol 110:1041–1048Google Scholar
  2. Bauer J, Strauss S, Schreiter-Gasser U, Ganter U, Schlegel P, Witt I, Yolk B, Berger M (1991) Interleukin 6 and α2-macroglobulin indicate an acute phase state in Alzheimer's disease cortices. FEBS Lett 285:111–114Google Scholar
  3. Beisiegel U, Weber W, Ihrke G, Herz J, Stanley KK (1989) The LDL-receptor related protein, LRP, is an apolipoprotein-E binding protein. Nature 341:162–164Google Scholar
  4. Brown MS, Herz J, Kowal RC, Goldstein JL (1991) The lowdensity lipoprotein receptor-related protein: double agent or decoy. Curr Opin Lipidol 2:65–72Google Scholar
  5. Cheng CY, Grima J, Stahler MS, Guglielmotti A, Silvestrini B, Bardin CW (1990) Sertoli cell synthesizes a proteinase inhibitor, α2-macroglobulin. Biochemistry 29:1063–1068Google Scholar
  6. Christensen EI, Gliemann J, Moestrup SK (1992) Renal tubule gp 330 is a calcium-bindung receptor for endocytic uptake of protein. J Histochem Cytochem (in press)Google Scholar
  7. Cordell JL, Falini B, Erber WN, Ghosh AK, Abdulaziz Z, Mac-Donald S, Pulford KAF, Stein H, Mason DY (1984) Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal antiphosphatase (APAAP complexes). J Histochem Cytochem 32:219–229Google Scholar
  8. Davidsen O, Christensen EI, Gliemann J (1985) The plasma clearance of human α2-macroglobulin-trypsin complex is mainly accounted for by uptake into hepatocytes. Biochim Biophys Acta 846:85–92Google Scholar
  9. Ganter U, Strauss S, Jonas U, Weidemann A, Beyreuther K, Bolk B, Berger M, Bauer J (1991) α2-Macroglobulin synthesis in interleukin-6 stimulated human neuronal (SH-SY5Y neuroblastoma) cells. FEBS Lett 282:127–131Google Scholar
  10. Gebicke-Haerter PJ, Bauer J, Brenner A, Gerok W (1987) α2-Macroglobulin synthesis in an astrocyte subpopulation. J Neurochem 49:1139–1145Google Scholar
  11. Gliemann J, Davidsen O (1986) Characterization of receptors for α2-macroglobulin-trypsin complex in rat hepatocytes. Biochim Biophys Acta 885:49–57Google Scholar
  12. Haye KR, Foster RF, Goff JP, Kaufman SJ (1986) Endocytosis of α2-macroglobulin is developmentally regulated during myogenesis. Dev Biol 114:470–474Google Scholar
  13. Herz J, Hamann U, Rogne S, Myklebost O, Gausepohl H, Stanley KK (1988) Surface location and high affinity for calcium of a 500 kd liver membrane protein closely related to the LDL-receptor suggest a physiological role as lipoprotein receptor. EMBO J 7:4119–4127Google Scholar
  14. Herz J, Kowal RC, Goldstein JL, Brown MS (1990) Proteolytic processing of the 600 kd low density lipoprotein receptor-related protein (LRP) occurs in a trans-Golgi compartment. EMBO J 9:1769–1776Google Scholar
  15. Herz J, Goldstein JL, Strickland DK, Ho YK, Brown MS (1991) 39-kDa protein modulates binding of ligands to the low density lipoprotein receptor-related protein/α2 receptor. J Biol Chem 266:21232–21238Google Scholar
  16. Jensen PH, Moestrup SK, Sottrup-Jensen L, Petersen CM, Gliemann J (1988) Receptors for α2-macroglobulin and pregnancy zone protein-proteinase complexes in the human placental syncytotrophoblast. Placenta 9:463–477Google Scholar
  17. Jensen PH, Moestrup SK, Gliemann J (1989) Purification of the human placental α2-macroglobulin receptor. FEBS Lett 255:275–280Google Scholar
  18. Kaplan J, Nielsen ML (1979) Analysis of macrophage surface receptors. Binding of α2-macroglobulin-proteinase complexes to rabbit alveolar macrophages. J Biol Chem 254:7323–7335Google Scholar
  19. Kerjaschki WA, Farquhar MG (1982) The pathogenetic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border. Proc Natl Acad Sci USA 79:5557–5561Google Scholar
  20. Kowal RC, Herz J, Goldstein JL, Esser V, Brown MS (1989) Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters derived form apoprotein E-enriched lipoproteins. Proc Natl Acad Sci USA 86:5810–5814Google Scholar
  21. Kristensen T, Moestrup SK, Gliemann J, Bentsen L, Sand O, Sottrup-Jensen L (1990) Evidence that the newly cloned low density lipoprotein receptor-related protein (LRP) is the α2-macroglobulin receptor. FEBS Lett 276:151–155Google Scholar
  22. Mahley RW (1989) Apolipoprotein E: cholesterol transport protein with expanding role for cell biology. Science 240:622–630Google Scholar
  23. Moestrup SK, Gliemann J (1989) Purification of the rat hepatic α2-macroglobulin receptor as an approximately 440-kDa single chain protein. J Biol Chem 264:15574–15577Google Scholar
  24. Moestrup SK, Gliemann J (1991) Analysis of ligand recognition by the purified α2-macroglobulin receptor (low density lipoprotein receptor-related protein). Evidence that high affinity of α2-macroglobulin complexes is achieved by binding to adjacent receptors. J Biol Chem 266:14011–14017Google Scholar
  25. Moestrup SK, Kaltoft K, Petersen CM, Pedersen S, Gliemann J, Christensen EI (1990) Immunocytochemical identification of the human α2-macroglobulin receptor in monocytes and fibroblasts: monoclonal antibodies define the receptor as a monocyte differentiation antigen. Exp Cell Res 190:195–203Google Scholar
  26. Monard D (1988) Cell-derived proteases and protease inhibitors as regulators of neurite outgrowth. Trends Neurosci 12:541–544Google Scholar
  27. Mori T, Iijima N, Kitabatake K, Kohsaka S (1990) α2-macroglobulin is an astroglia-derived neurite-promoting factor for cultured neurons from rat central nervous system. Brain Res 527:55–61Google Scholar
  28. Mosher DF, Wing DA (1979) Synthesis and secretion of α2-macroglobulin in cultured human fibroblasts. J Exp Med 143:462–467Google Scholar
  29. Nykjær A, Petersen CM, Møller B, Jensen PH, Moestrup SK, Holtet TL, Etzerodt M, Thøgersen HC, Munch M, Andreasen PA, Gliemann J (1992) Purified α2-macroglobulin receptor/(LDL) receptor-related protein binds urokinase: plasminogen activator inhibitor type-1 complex. J Biol Chem (in press)Google Scholar
  30. Pallesen G, Beverley PCL, Lane EB, Madsen M, Mason DY, Stein H (1984) Nature of non-B, non-T lymphomas: an immunohistological study on frozen tissues using monoclonal antibodies. J Clin Pathol 37:911–918Google Scholar
  31. Petersen CM, Ejlersen E, Wendelboe-Hansen P, Gliemann J (1987) Binding of α2-macroglobulin-trypsin complex to human monocytes in culture. Scand J Clin Lab Invest 47:55–61Google Scholar
  32. Petersen CM, Christiansen BS, Heickendorf L, Ingerslev J (1988) Synthesis and secretion of α2-macroglobulin by human hepatocytes in culture. Eur J Clin Lab Invest 18:543–548Google Scholar
  33. Pietromonaco S, Kerjaschi D, Binder S, Ullrich R, Farquhar MG (1990) Molecular cloning of a cDNA encoding a major pathogenic domain of the Heymann nephritis antigen gp330. Proc Natl Acad Sci USA 87:1811–1815Google Scholar
  34. Raychowddhury R, Niles JL, McCluskey RT, Smith JA (1989) Autoimmune target in Heymann nephritis is a glycoprotein with homology to the LDL receptor. Science 244:1163–1165Google Scholar
  35. Shi DL, Savona C, Gagnon J, Cochet C, Chambaz EM, Feige JJ (1990) Transforming growth factor-β stimulates the expression of α2-macroglobulin by cultured bovine adrenocortical cells. J Biol Chem 265:2881–2887Google Scholar
  36. Sottrup-Jensen L (1989) α2-Macroglobulins: structure, shape, and mechanism of proteinase complex formation. J Biol Chem 264:11539–11542Google Scholar
  37. Strickland DK, Ashcom JD, Williams S, Burgess WH, Migliorini M, Argraves WS (1990) Sequence identity between the α2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor. J Biol Chem 265:17401–17404Google Scholar
  38. Strickland DK, Ashcom JD, Williams S, Battey F, Behre E, McTigue K, Battey JF, Argraves WS (1991) Primary structure of α2-macroglobulin receptor-associated protein. Human homologue of Heymann nephritis antigen. J Biol Chem 266:13364–13369Google Scholar
  39. Van Dijk MCM, Gijsbertus JZ, Boers W, Linthorst C, Busterbosch MK, Van Berkel TJC (1991) Recognition of chylomiron remnants and β-migrating very low density lipoproteins by the remnant receptor of parenchymal liver cells is distinct from the liver α2-macroglobulin site. Biochem J 279:863–870Google Scholar
  40. Van Leuven F, Cassimann JJ, Van den Berghe H (1979) Demonstration of an α2-macroglobulin receptor in human fibroblast, absent in tumor-derived cell lines. J Biol Chem 254:5155–5160Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Søren K. Moestrup
    • 1
  • Jørgen Gliemann
    • 1
  • Gorm Pallesen
    • 2
  1. 1.Institute of Medical BiochemistryAarhus UniversityAarhus CDenmark
  2. 2.Laboratory of Immunohistology, Institute of PathologyAarhus University HospitalAarhus CDermark

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