Fetuin-A – Alpha2-Heremans-Schmid Glycoprotein: From Structure to a Novel Marker of Chronic Diseases Part 1. Fetuin-A as a Calcium Chaperone and Inflammatory Marker

Open access


Fetuin-A is a major plasma glycoprotein released mainly by the liver. Its functions include inhibition of the activity of insulin receptor, regulation of response to inflammation, inhibition of calcified matrix metabolism and ectopic mineralization, etc. Three major functional domains of fetuin-A have been identified: one similar to the Ca-binding domains, one inhibiting cysteine protease, and a domain with high affinity to insulin receptor. The fetuin-A molecule may be considered as a highly pleomorphic protein with an important impact in a variety of clinically expressed metabolic and pathological processes. It could be used as a marker in clinical practice in the future.

1. Pedersen KO. Fetuin, a new globulin isolated from serum. Nature. 1944;154:575-7.

2. Hermans JF. Les Globuline, Sériques du Système Gamma. Masson et Cie, editor. Paris: Arscia-Bruxelles; 1960.

3. Schmid K, Burgi W. Preparation and properties of the human Ba-a2 glycoproteins. Biochim Biophys Acta. 1961;47:440-3.

4. Kettler M, Bongartz P, Westenfeld R, Wildberger JE, Mahnken AH, et al. Association of low fetuin-A (AHSG) concentration in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. The Lancet. 2003;361(9360):827-33.

5. Olivier E, Soury E, Ruminy P, Husson A, Parmentier F, Daveau M, et al. Fetuin-B, a second member of the fetuin family in mammals. Biochem J. 2000;350:589-97.

6. Denecke B, Gräber S, Schäfer C, Heiss A, Wöltje M, Jahnen-Dechent W. Tissue distribution and activity testing suggest a similar but not identical function of fetuin-B and fetuin-A. Biochem J. 2003;376:135-45.

7. Gejyo, F. Schmid K. Purification and characterization of the two forms of human plasma a2HS- glycoprotein. Biochim Biophys Acta. 1981;671(1):78-84.

8. Külbler D, Gosenca D, Wind M, Heid H, Friedberg I, Jahnen-Dechent W, et al. Proteolytic processing by matrix metalloproteinases and phosphorylation by protein kinase CK2 of fetuin-A, the major globulin of fetal calf serum. Biochimie. 2007;89:410-8.

9. Nawratil P, Lenzen S, Kellermann J, Haupt H, Schinke T, Mülller-Esterl W, et al. Limited proteolysis of human alpha2-HS glycoprotein/fetuin. Evidence that a chymotryptic activity can release the connecting peptide. J Biol Chem. 1996;271:31735-41.

10. Bendiak B, Harris-Brandts M, Michnick SW, Carver JP, Cumming DA. Separation of the complex asparagine-linked oligosaccharides of the glycoprotein fetuin and elucidation of three triantennary structures having sialic acids linked only to galactose residues. Biochemistry.1989; 28:6491-9.

11. Ohnishi T, Nakamura O, Arakaki N, Daikuhara Y. Effect of phosphorylated rat fetuin on the growth of hepatocytes in primary culture in the presence of human hepatocyte-growth factor. Evidence that phosphorylated fetuin is a natural modulator of hepatocyte-growth factor. Eur J Biochem. 1997;243:753-61.

12. Haglund AC, Bo EK, Pia EK. Phosphorylation of human plasma alpha2-Heremans-Schmid glycoprotein (human fetuin) in vivo. Biochem J. 2001;357:437-45.

13. Hortin GL, Schilling M, Graham JP. Inhibitors of the sulfation of proteins, glycoproteins, and proteoglycans. Biochem Biophys Res Comm.1988;150:342-8.

14. Auberger P, Falquerho L, Contreres JO, Pages G, Le Cam G, Rossi B, et al. Characterization of a natural inhibitor of the insulin receptor tyrosine kinase: cDNA cloning, purification, and anti-mitogenic activity. Cell. 1989;58:631- 40.

15. Mathews ST, Chellam N, Srinivas PR, Cintron VJ, Leon MA, Goustin AS, et. al. Alpha2- HSG, a specific inhibitor of insulin receptor autophosphorylation, interacts with the insulin receptor. Mol Cell Endocrinol. 2000;164:87-98.

16. Naseem F, Khan RH,Haq SK, Naeem A. Characterization of molten globule state of fetuin at low pH. Biochim Biophys Acta. 2003;1649:164-70.

17. Windwarder M, Altmann F. Site-specific analysis of the O-glycosylation of bovine fetuin by electron-transfer dissociation mass spectrometry. J Proteomics. 2014;28(108):258- 68.

18. IshidaT, Kinoshita K. PrDOS: prediction of disordered protein regions from amino acid sequence. Nucleic Acids Res. 2007;(Web Server issue):W460-4.

19. Willi JD, Alexander H, Cora S, Markus K, Dwight AT. Fetuin-A Regulation of Calcified Matrix Metabolism. Circulation Research. 2011;108:1494-509.

20. Guttman M, Patrick W, Andrej S, Kelly K. Atom Ensemble Modeling to Analyze Small-Angle X-Ray Scattering of Glycosylated Proteins. Structure. 2013;21(3):321-31.

21. Elzanowski A, Barker WC, Hunt LT, Seibel-Ross E. Cystatin domains in alpha-2-HS-glycoprotein and fetuin. FEBS Lett. 1988;227(2):167-70.

22. BrownWM, Dziegielewska KM. Friends and relations of the cystatin superfamily - new members and their evolution. Protein Sci. 1997;6:5-12.

23. Kellermann J, Haupt H, Auerswald EA, Müller- Ester W. The arrangement of disulfide loops in human alpha 2-HS glycoprotein. Similarity to the disulfide bridge structures of cystatins and kininogens J Biol Chem. 1989:264;14121- 14128.

24. Dziegielewska KM, Matthews N, Saunders NR, Wilkinson G Alpha 2HSglycoprotein is expressed at high concentration in human fetal plasma and cerebrospinal fluid. Fetal Diagn Ther. 1993;8:22-27.

25. Dziegielewska KM, Daikuhara Y, Ohnishi T, Waite MP, Ek J, Habgood MD, et all. Fetuin in the developing neocortex of the rat: distribution and origin. J Comp Neurol. 2000;423:373-88.

26. Dziegielewska K, Brown WM, Deal A, Foster KA, Fry EJ, Saunders NR. The expression of fetuin in the development and maturation of the hemopoietic and immune systems. Histochem Cell Biol. 1996;106:319-30.

27. Martin H, Cora S, Claudia O, Willi JD. The Physiologic Development of Fetuin-Serum Concentrations in Children. Pediatr Res. 2009;66(6):660-4.

28. Stefan N, Hennige AM, Steiger H, Machann J, Schick F, Kröber SM, et all. A2-Heremans- Schmid,Glycoprotein/Fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans. Diabetes Care. 2006;29(4):853-7.

29. Chatterjee P, Seal S, Mukherjee S, Kundu R, Mukherjee S, Ray S, et al. Adipocyte fetuin-A contributes to macrophage migration into adipose tissue and polarization of macrophages. J Biol Chem. 2013;288(39):28324-30.

30. Schäfer C, Heiss A, Schwarz A, Westenfeld R, Ketteler M, Floege J, et all. The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification. J Clin Invest. 2003;112:357-66.

31. Sindhu S, Akhter N, Shenouda S, Wilson A, Ahmad R. Plasma fetuin-A/α 2-HS-glycoprotein correlates negatively with inflammatory cytokines, chemokines and activation biomarkers in individuals with type-2 diabetes. BMC Immunology. 2016;17:33.

32. Tajirian T, Dennis JW, Swallow CJ. Regulation of human monocyte proMMP-9 production by fetuin, an endogenous TGF-beta antagonist. J Cell Physiol. 2000;185:174-83.

33. BroderC, Becker C. The metalloproteases meprin α and meprin β: unique enzymes in inflammation, neurodegeneration, cancer and fibrosisPAULY1. Biochem J. 2013;450:253-64.

34. Robinson KN, Teran-Garcia M. From infancy to aging: Biological and behavioral modifiers of Fetuin-A. Biochimie. 2016;124:141-49.

35. Li W, Zhu S, Li J, Huang Y, Zhou R, Fan X, et al. A hepatic protein, fetuin-A, occupies a protective role in lethal systemic inflammation. PLoS One. 2011;6(2):e16945.

36. Reynolds JL, Joannides AJ, Skepper JN, McNair R, Schurgers LJ, Proudfoot D, et al. Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD. J Am Soc Nephrol. 2004;15:2857-67.

37. Westenfeld R, Schäfer C, Krüger T, Haarmann C, Schurgers LJ, Reutelingsperger C, et al. Fetuin-A protects against atherosclerotic calcification in CKD. J Am Soc Nephrol. 2009;20:1264-74.

38. Triffitt JT, Owen ME, Ashton BA, Wilson JM. Plasma disappearance of rabbit alpha2HS- glycoprotein and its uptake by bone tissue. Calcif Tissue Res.1978;26:155-61.

39. Termine JD, Belcourt AB, Conn KM, Kleinman HK. Mineral and collagen-binding proteins of fetal calf bone. J Biol Chem. 1981;256:10403-8.

40. Schinke T, Amendt C, Trindl A, Pöschke O, Müller-Esterl W, Jahnen-Dechent W. The serum protein α2-HS glycoprotein/fetuin inhibits apatite formation in vitro and in mineralizing calvaria cells. A possible role in mineralization and calcium homeostasis. J Biol Chem. 1996;271:20789-96.

41. Jahnen-Dechent W, Schäfer C, Ketteler M, McKee MD. Mineral chaperones: a role for fetuin-A and osteopontin in the inhibition and regression of pathologic calcification. J Mol Med. 2008;86:379-89.

42. Ishibashi A, Ikeda Y, Ohguro T, Kumon Y, Yamanaka S, Takata H, et al. Serum fetuin-A is an independent marker of insulin resistance in Japanese men. J Atheroscler Thromb. 2010;17(9):925-33.

43. Jersmann HP, Dransfield I, Hart SP. Fetuin/alpha2-HS glycoprotein enhances phagocytosis of apoptotic cells and macropinocytosis by human macrophages. Clin Sci. 2003;105:27-78.

44. Heiss A, DuChesne A, Denecke B, Grötzinger J, Yamamoto K, Renné T, et al. Structural basis of calcification inhibition by α2-HS glycoprotein/fetuin-A: formation of colloidal calciprotein particles. J Biol Chem. 2003;278:13333-41.

45. Dey S, Das M, Balla VK. Effectofhydroxyapatite particle size, morphology and crystallinity on proliferation of colon cancer HCT116 cells. Mater Sci Eng C Mater Biol Appl. 2014;39:336- 9.

46. Heiss A, VitaliyP, Willi JD, Dietmar S. Fetuin-A Is a Mineral Carrier Protein: Small Angle Neutron Scattering Provides New Insight on Fetuin-A Controlled Calcification Inhibition. Biophys J. 2010;99(12):3986-95.

47. Anton-Scott G, Abdul B, Abou S. The “thrifty” gene encoding Ahsg/Fetuin-A meets the insulin receptor: Insights into the mechanism of insulin resistance. Cell Signal. 2011;23(6):980-90.

48. Anna Maria D, Jerzy ST, Beat WD, Dariusz D. Fetuin-a (ahsg) and its usefulness in clinical practice. Review of the literature Biomed Pap. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015;159(3):352-9.

49. Wang H, Sama AE. Anti-inflammatory role of Fetuin-A in Injury and Infection. Curr Mol Med. 2012;12(5):625-33.

50. Wang H, Li W, Zhu S, Li J, D’Amore J, Ward MF, Yang H, et al. Peripheral administration of fetuin-A attenuates early cerebral ischemic injury in rats. J Cereb Blood Flow Metab. 2010;30(3):493-504.

51. Daveau M, Davrinche C, Djelassi N, Lemetayer J, Julen N, Hiron M, et al. Partial hepatectomy and mediators of inflammation decrease the expression of liver 2-HS glycoprotein gene in rats. FEBS Lett. 1990;273(1-2):79-81.

52. Ismail NA, Ragab S, Abd El Dayem SM, Elbaky AA, Salah N, Hamed M, et al. Fetuin-A levels in obesity: differences in relation to metabolic syndrome and correlation with clinical and laboratory variables. Arch Med Sci. 2012;8(5):826-3.

53. Tuttolomondo A, Di Raimondo D, Di Sciacca R, Casuccio A, Bivona G, Bellia C, et al. Fetuin-A and CD40 L plasma levels in acute ischemic stroke: differences in relation to TOAST subtype and correlation with clinical and laboratory variables. Atherosclerosis. 2010;208(1):290-6.

54. Ombrellino M, Wang H, Yang H, Zhang M, Vishnubhakat J, et al. Fetuin, a negative acute phase protein, attenuates TNF synthesis and the innate inflammatory response to carrageenan. Shock. 2001;15:181-5.

55. Sato H, Kazama JJ, Wada Y, Kuroda T, Narita I, Gejyo F, et al. Decreased levels of circulating alpha2- Heremans-Schmid glycoprotein/Fetuin-A (AHSG) in patients with rheumatoid arthritis. Intern Med. 2007;46(20):1685-91.

56. Kusnierz-Cabala B, Gurda-Duda A, Panek J, Fedak D, Dumnicka P, Solnica B, et al. Serum fetuin A concentrations in patients with acute pancreatitis. Clin Lab. 2010;56(5-6):191-5.

57. Metry G, Stenvinkel P, Qureshi AR, Carrero JJ, Yilmaz MI, Barany P, et al. Low serum fetuin-A concentration predicts poor outcome only in the presence of inflammation in prevalent haemodialysis patients. Eur J Clin Invest. 2008;38(11):804-11.

58. Peter A, Kovarova M, Staiger H, Machann J, Schick F1, Königsrainer A, et al. The Hepatokines Fetuin-A and Fetuin-B are up- regulated in the State of Hepatic Steatosis and have an impact on Glucose Homeostasis in Humans. Am J Physiol Endocrinol Metab. 2017 Nov 14:ajpendo002622017. doi: 10.1152/ajpendo00262.2017.

59. Reinehr T, Roth CL. Fetuin-A and its relation to metabolic syndrome and fatty liver disease in obese children before and after weight loss. J Clin Endocrinol Metab. 2008;93(11):4479-85.

60. Norbert S, Hans-Ulrich H. The role of hepatokines in metabolism. Nature Reviews Endocrinology. 2013;9:144-52.

61. Takata H, Ikeda Y, Suehiro T, Ishibashi A, Inoue M, Kumon Y, et al. High glucose induces transactivation of the α2-HS glycoprotein gene through the ERK1/2 signaling pathway. J AtherosclerThromb. 2009;16:448-56.

62. Lebensztejn DM, Flisiak-Jackiewicz M, Białokoz-Kalinowska I, Bobrus-Chociej A, Kowalska I. Hepatokines and non-alcoholic fatty liver disease. Acta Biochim Pol. 2016;63(3):459-67.

63. Heinrichsdorff J, Olessky JM. Fetuin-A: the missing link in lipid-induced inflammation. Nat Med. 2012;18:1182-3.

64. Haukeland JW, Dahl TB, Yndestad A, Gladhaug IP, Loberg EM, Haaland T, et al. Fetuin A in nonalcoholic fatty liver disease: in vivo and in vitro studies. Eur J Endocrinol. 2012;166:503- 10.

65. Malin SK, Mulya A, Fealy CE, Haus JM, Pagadala MR, Scelsi AR, et al. Fetuin-A is linked to improved glucose tolerance after short- term exercise training in nonalcoholic fatty liver disease. J Appl Physiol. 2012;115:988-94.

66. Turk V, Stoka V, Vasiljeva O, Renko M, Sun T, Turk B, et al. Cysteinecathepsins: From structure, function and regulation to new frontiers. Biochim Biophys Acta. 2012;1824(1):68-88.

67. Rossi A, Deveraux Q, Turk B, Sali A. Comprehensive search for cysteine cathepsins in the human genome. Biol Chem. 2004;385:363- 72.

68. Hedrich J, Lottaz D, Meyer K, Yiallouros Ir, Jahnen-Dechent W, Stöcker Wr, et al. Fetuin-A and Cystatin C Are Endogenous Inhibitors of Human Meprin Metalloproteases. Biochemistry. 2010;49(39):8599-607.

69. Leite-Browning ML, McCawley LJ, Choi OH, Matrisian LM, Ochieng J. Interactions of alpha2-HS- glycoprotein (fetuin) with MMP-3 and murine squamous cell carcinoma cells. Int J Oncol. 2002;21:965-7.

70. Mellgren RL, Huang X. Fetuin A stabilizes m-calpain and facilitates plasma membrane repair. J Biol Chem. 2007;282:35868-77.

71. Kundranda MN, Henderson M, Carter KJ, Gorden L, Binhazim A, Ray S, et al. The serum glycoprotein fetuin-A promotes Lewis lung carcinoma tumorigenesis via adhesive- dependent and adhesive-independent mechanisms. Cancer Res. 2005;65(2):499-506.

Journal Information


All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 374 348 39
PDF Downloads 317 307 33