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

1. Pedersen KO. Fetuin, a new globulin isolated from serum. Nature. 1944;154:575-7.10.1038/154575a0Search in Google Scholar

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

3. Schmid K, Burgi W. Preparation and properties of the human Ba-a2 glycoproteins. Biochim Biophys Acta. 1961;47:440-3.10.1016/0006-3002(61)90539-XSearch in Google Scholar

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):827-33.10.1016/S0140-6736(03)12710-9Search in Google Scholar

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;350:589-97.10.1042/bj3500589Search in Google Scholar

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;376:135-45.10.1042/bj20030676Search in Google Scholar

7. Gejyo, F. Schmid K. Purification and characterization of the two forms of human plasma a2HS- glycoprotein. Biochim Biophys Acta. 1981;671(1):78-84.10.1016/0005-2795(81)90096-9Search in Google Scholar

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;89:410-8.10.1016/j.biochi.2006.10.01217110014Search in Google Scholar

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;271:31735-41.10.1074/jbc.271.49.317358940198Search in Google Scholar

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; 28:6491-9.10.1021/bi00441a0502477056Search in Google Scholar

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;243:753-61.10.1111/j.1432-1033.1997.00753.x9057842Search in Google Scholar

12. Haglund AC, Bo EK, Pia EK. Phosphorylation of human plasma alpha2-Heremans-Schmid glycoprotein (human fetuin) in vivo. Biochem J. 2001;357:437-45.10.1042/bj3570437Search in Google Scholar

13. Hortin GL, Schilling M, Graham JP. Inhibitors of the sulfation of proteins, glycoproteins, and proteoglycans. Biochem Biophys Res Comm.1988;150:342-8.10.1016/0006-291X(88)90526-8Search in Google Scholar

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- 40.10.1016/0092-8674(89)90098-6Search in Google Scholar

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;164:87-98.10.1016/S0303-7207(00)00237-9Search in Google Scholar

16. Naseem F, Khan RH,Haq SK, Naeem A. Characterization of molten globule state of fetuin at low pH. Biochim Biophys Acta. 2003;1649:164-70.10.1016/S1570-9639(03)00169-9Search in Google Scholar

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- 68.10.1016/j.jprot.2014.05.022Search in Google Scholar

18. IshidaT, Kinoshita K. PrDOS: prediction of disordered protein regions from amino acid sequence. Nucleic Acids Res. 2007;(Web Server issue):W460-4.10.1093/nar/gkm363Search in Google Scholar

19. Willi JD, Alexander H, Cora S, Markus K, Dwight AT. Fetuin-A Regulation of Calcified Matrix Metabolism. Circulation Research. 2011;108:1494-509.10.1161/CIRCRESAHA.110.234260Search in Google Scholar

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):321-31.10.1016/j.str.2013.02.004Search in Google Scholar

21. Elzanowski A, Barker WC, Hunt LT, Seibel-Ross E. Cystatin domains in alpha-2-HS-glycoprotein and fetuin. FEBS Lett. 1988;227(2):167-70.10.1016/0014-5793(88)80890-1Search in Google Scholar

22. BrownWM, Dziegielewska KM. Friends and relations of the cystatin superfamily - new members and their evolution. Protein Sci. 1997;6:5-12.10.1002/pro.5560060102Search in Google Scholar

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- 14128.10.1016/S0021-9258(18)71651-7Search in Google Scholar

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;8:22-27.10.1159/000263743Search in Google Scholar

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;423:373-88.10.1002/1096-9861(20000731)423:3<373::AID-CNE2>3.0.CO;2-DSearch in Google Scholar

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;106:319-30.10.1007/BF02473242Search in Google Scholar

27. Martin H, Cora S, Claudia O, Willi JD. The Physiologic Development of Fetuin-Serum Concentrations in Children. Pediatr Res. 2009;66(6):660-4.10.1203/PDR.0b013e3181bc3f60Search in Google Scholar

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):853-7.10.2337/diacare.29.04.06.dc05-1938Search in Google Scholar

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):28324-30.10.1074/jbc.C113.495473Search in Google Scholar

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;112:357-66.10.1172/JCI17202Search in Google Scholar

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;17:33.10.1186/s12865-016-0171-ySearch in Google Scholar

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;185:174-83.10.1002/1097-4652(200011)185:2<174::AID-JCP2>3.0.CO;2-XSearch in Google Scholar

33. BroderC, Becker C. The metalloproteases meprin α and meprin β: unique enzymes in inflammation, neurodegeneration, cancer and fibrosisPAULY1. Biochem J. 2013;450:253-64.10.1042/BJ20121751Search in Google Scholar

34. Robinson KN, Teran-Garcia M. From infancy to aging: Biological and behavioral modifiers of Fetuin-A. Biochimie. 2016;124:141-49.10.1016/j.biochi.2015.12.016Search in Google Scholar

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):e16945.10.1371/journal.pone.0016945Search in Google Scholar

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;15:2857-67.10.1097/01.ASN.0000141960.01035.28Search in Google Scholar

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;20:1264-74.10.1681/ASN.2008060572Search in Google Scholar

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;26:155-61.10.1007/BF02013251Search in Google Scholar

39. Termine JD, Belcourt AB, Conn KM, Kleinman HK. Mineral and collagen-binding proteins of fetal calf bone. J Biol Chem. 1981;256:10403-8.10.1016/S0021-9258(19)68633-3Search in Google Scholar

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;271:20789-96.10.1074/jbc.271.34.20789Search in Google Scholar

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;86:379-89.10.1007/s00109-007-0294-ySearch in Google Scholar

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):925-33.10.5551/jat.3830Search in Google Scholar

43. Jersmann HP, Dransfield I, Hart SP. Fetuin/alpha2-HS glycoprotein enhances phagocytosis of apoptotic cells and macropinocytosis by human macrophages. Clin Sci. 2003;105:27-78.10.1042/CS20030126Search in Google Scholar

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;278:13333-41.10.1074/jbc.M210868200Search in Google Scholar

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- 9.10.1016/j.msec.2014.03.022Search in Google Scholar

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):3986-95.10.1016/j.bpj.2010.10.030Search in Google Scholar

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):980-90.10.1016/j.cellsig.2010.11.003Search in Google Scholar

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.Search in Google Scholar

49. Wang H, Sama AE. Anti-inflammatory role of Fetuin-A in Injury and Infection. Curr Mol Med. 2012;12(5):625-33.10.2174/156652412800620039Search in Google Scholar

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):493-504.10.1038/jcbfm.2009.247Search in Google Scholar

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):79-81.10.1016/0014-5793(90)81055-SSearch in Google Scholar

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):826-3.10.5114/aoms.2012.31616350623823185191Search in Google Scholar

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):290-6.10.1016/j.atherosclerosis.2009.07.03219709661Search in Google Scholar

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;15:181-5.10.1097/00024382-200115030-0000411236900Search in Google Scholar

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):1685-91.10.2169/internalmedicine.46.626917938521Search in Google Scholar

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.Search in Google Scholar

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):804-11.10.1111/j.1365-2362.2008.02032.x19021697Search in Google Scholar

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/ajpendo00262.2017.10.1152/ajpendo00262.2017Open DOISearch in Google Scholar

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):4479-85.10.1210/jc.2008-150518728159Search in Google Scholar

60. Norbert S, Hans-Ulrich H. The role of hepatokines in metabolism. Nature Reviews Endocrinology. 2013;9:144-52.10.1038/nrendo.2012.25823337953Search in Google Scholar

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.Search in Google Scholar

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):459-67.10.18388/abp.2016_125227262842Search in Google Scholar

63. Heinrichsdorff J, Olessky JM. Fetuin-A: the missing link in lipid-induced inflammation. Nat Med. 2012;18:1182-3.10.1038/nm.286922869185Search in Google Scholar

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- 10.10.1530/EJE-11-086422170794Search in Google Scholar

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;115:988-94.10.1152/japplphysiol.00237.2013379881823928114Search in Google Scholar

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):68-88.10.1016/j.bbapap.2011.10.002710520822024571Search in Google Scholar

67. Rossi A, Deveraux Q, Turk B, Sali A. Comprehensive search for cysteine cathepsins in the human genome. Biol Chem. 2004;385:363- 72.10.1515/BC.2004.04015195995Search in Google Scholar

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):8599-607.10.1021/bi100423820806899Search in Google Scholar

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.Search in Google Scholar

70. Mellgren RL, Huang X. Fetuin A stabilizes m-calpain and facilitates plasma membrane repair. J Biol Chem. 2007;282:35868-77.10.1074/jbc.M70692920017942392Search in Google Scholar

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):499-506.10.1158/0008-5472.499.65.2Search in Google Scholar