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

Regina S. Komsa-Penkova; Georgi M. Golemanov; Zdravka V. Radionova; Pencho T. Tonchev; Sergej D. Iliev; Veselin V. Penkov

doi:10.1515/jbcr-2017-0015

.blurhash-client-img { display: none !important; }

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

Journal of Biomedical and Clinical Research

Volume 10 (2017): Issue 2 (December 2017)

By: Regina S. Komsa-Penkova, Georgi M. Golemanov, Zdravka V. Radionova, Pencho T. Tonchev, Sergej D. Iliev and Veselin V. Penkov

Open Access

|Jun 2018

Abstract

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.

References

1. Pedersen KO. Fetuin, a new globulin isolated from serum. Nature. 1944;154:575-7.10.1038/154575a0
Search in Google Scholar Back to article
2. Hermans JF. Les Globuline, Sériques du Système Gamma. Masson et Cie, editor. Paris: Arscia-Bruxelles; 1960.
Search in Google Scholar Back to article
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-X
Search in Google Scholar Back to article
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)12710-9
Search in Google Scholar Back to article
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/bj3500589
Search in Google Scholar Back to article
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/bj20030676
Search in Google Scholar Back to article
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)90096-9
Search in Google Scholar Back to article
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.2006.10.01217110014
Search in Google Scholar Back to article
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.271.49.317358940198
Search in Google Scholar Back to article
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/bi00441a0502477056
Search in Google Scholar Back to article
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.x9057842
Search in Google Scholar Back to article
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/bj3570437
Search in Google Scholar Back to article
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)90526-8
Search in Google Scholar Back to article
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)90098-6
Search in Google Scholar Back to article
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)00237-9
Search in Google Scholar Back to article
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)00169-9
Search in Google Scholar Back to article
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.2014.05.022
Search in Google Scholar Back to article
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/gkm363
Search in Google Scholar Back to article
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.110.234260
Search in Google Scholar Back to article
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.2013.02.004
Search in Google Scholar Back to article
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)80890-1
Search in Google Scholar Back to article
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.5560060102
Search in Google Scholar Back to article
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)71651-7
Search in Google Scholar Back to article
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;8:22-27.10.1159/000263743
Search in Google Scholar Back to article
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-D
Search in Google Scholar Back to article
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/BF02473242
Search in Google Scholar Back to article
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.0b013e3181bc3f60
Search in Google Scholar Back to article
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.dc05-1938
Search in Google Scholar Back to article
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.C113.495473
Search in Google Scholar Back to article
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/JCI17202
Search in Google Scholar Back to article
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-y
Search in Google Scholar Back to article
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-X
Search in Google Scholar Back to article
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/BJ20121751
Search in Google Scholar Back to article
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.2015.12.016
Search in Google Scholar Back to article
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.0016945
Search in Google Scholar Back to article
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.0000141960.01035.28
Search in Google Scholar Back to article
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.2008060572
Search in Google Scholar Back to article
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/BF02013251
Search in Google Scholar Back to article
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)68633-3
Search in Google Scholar Back to article
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.271.34.20789
Search in Google Scholar Back to article
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-y
Search in Google Scholar Back to article
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.3830
Search in Google Scholar Back to article
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/CS20030126
Search in Google Scholar Back to article
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.M210868200
Search in Google Scholar Back to article
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.2014.03.022
Search in Google Scholar Back to article
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.2010.10.030
Search in Google Scholar Back to article
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.2010.11.003
Search in Google Scholar Back to article
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 Back to article
49. Wang H, Sama AE. Anti-inflammatory role of Fetuin-A in Injury and Infection. Curr Mol Med. 2012;12(5):625-33.10.2174/156652412800620039
Search in Google Scholar Back to article
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.2009.247
Search in Google Scholar Back to article
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-S
Search in Google Scholar Back to article
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.2012.31616350623823185191
Search in Google Scholar Back to article
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.2009.07.03219709661
Search in Google Scholar Back to article
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;15:181-5.10.1097/00024382-200115030-0000411236900
Search in Google Scholar Back to article
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.46.626917938521
Search in Google Scholar Back to article
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 Back to article
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.x19021697
Search in Google Scholar Back to article
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/ajpendo00262.2017
Open DOI Search in Google Scholar Back to article
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.2008-150518728159
Search in Google Scholar Back to article
60. Norbert S, Hans-Ulrich H. The role of hepatokines in metabolism. Nature Reviews Endocrinology. 2013;9:144-52.10.1038/nrendo.2012.25823337953
Search in Google Scholar Back to article
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 Back to article
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_125227262842
Search in Google Scholar Back to article
63. Heinrichsdorff J, Olessky JM. Fetuin-A: the missing link in lipid-induced inflammation. Nat Med. 2012;18:1182-3.10.1038/nm.286922869185
Search in Google Scholar Back to article
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-11-086422170794
Search in Google Scholar Back to article
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.00237.2013379881823928114
Search in Google Scholar Back to article
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.2011.10.002710520822024571
Search in Google Scholar Back to article
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.2004.04015195995
Search in Google Scholar Back to article
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/bi100423820806899
Search in Google Scholar Back to article
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 Back to article
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.M70692920017942392
Search in Google Scholar Back to article
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):499-506.10.1158/0008-5472.499.65.2
Search in Google Scholar Back to article

Articles in this issue

DOI: https://doi.org/10.1515/jbcr-2017-0015 | Journal eISSN: 1313-9053

Journal RSS Feed

Language: English

Page range: 90 - 97

Submitted on: Dec 12, 2017

Accepted on: Feb 27, 2018

Published on: Jun 30, 2018

Published by: Sciendo

In partnership with: Paradigm Publishing Services

Publication frequency: 2 issues per year

Keywords:

Related subjects:

Clinical medicine, other,

© 2018 Regina S. Komsa-Penkova, Georgi M. Golemanov, Zdravka V. Radionova, Pencho T. Tonchev, Sergej D. Iliev, Veselin V. Penkov, published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

Volume 10 (2017): Issue 2 (December 2017)