Fetuin-A – Alpha2-Heremans-Schmid Glycoprotein: From Structure to a Novel Marker of Chronic Diseases Part 2. Fetuin-A – A Marker of Insulin Resistance and Related Chronic Diseases

Regina S. Komsa-Penkova 1 , Katya S. Kovacheva 2 , Georgy M. Golemanov 1 , Veselin P. Penkov 3 , Zdravka V. Radionova 4 , Galia B. Georgieva-Alexandrova 1 , and Alim V. Izmajlov 1
  • 1 Division of Biochemistry, Medical University – Pleven, Bulgaria
  • 2 Division of Medical Genetics, Medical University – Pleven, Bulgaria
  • 3 Repromed Medical Centrum – Pleven, , Bulgaria
  • 4 Division of Pedagogy and Psychology, Medical University – Pleven, Bulgaria

Summary

Fetuin-A is a secretory liver glycoprotein with multiple physiological functions such as regulation of insulin resistance, tissue calcification, bone metabolism, cellular proteolytic activity, and self-proliferative signaling.

Fetuin-A is a unique molecule which binds to the insulin receptor, modulating its sensitivity, and transducing “the physiological conditions” (serum levels of the metabolites like glucose, free fatty acids, inflammatory signals) from outside into inside the cells. Plasma fetuin-A levels correlate with reduced glucose tolerance and insulin resistance. Impaired insulin sensitivity leads to the development of metabolic syndrome, an increased risk for type 2 diabetes (T2DM), dyslipidaemias and cardiovascular diseases (CVDs). Furthermore, fetuin-A inversely correlates with inflammatory and activation biomarkers, e.g. in patients with T2DM. Thus, circulatory fetuin-A levels may have plausible predictive importance as a biomarker of risk of diabetes and negative acute phase protein. Dysregulated, it plays a crucial role in the pathogenesis of some metabolic disorders and clinical inflammatory conditions like metabolic syndrome, T2DM, CVDs, polycystic ovary syndrome (PCOS), etc.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. Mori K, Emoto M, Inaba M. Fetuin-A: a multifunctional protein. Recent Pat Endocr Metab Immune Drug Discov. 2011;5(2):124–46.

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

  • 5. Gejyo, F, Schmid K. Purification and characterization of the two forms of human plasma α2 HS-glycoprotein. Biochim Biophys Acta. 1981; 671(1):78-84.

  • 6. Kübler 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(3):410-8.

  • 7. 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(15):6491-9.

  • 8. 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(3):753-61.

  • 9. Haglund AC, Ek B, Ek P. Phosphorylation of human plasma alpha2-Heremans-Schmid glycoprotein (human fetuin) in vivo. Biochem J. 2001;357(2):437-45.

  • 10. Hortin GL, Schilling M, Graham JP. Inhibitors of the sulfation of proteins, glycoproteins, and proteoglycans. Biochem Biophys Res Commun.1988;150(1):342-8.

  • 11. Naseem F, Khan RH, Haq SK, Naeem A. Characterization of molten globule state of fetuin at low pH. Biochim Biophys Acta. 2003;1649(2):16-70.

  • 12. Guttman M, Weinkam P,2 Sali A, Lee KK. All-atom ensemble modeling to analyze small-angle x-ray scattering of glycosylated proteins. Structure. 2013; 21(2):321-31.

  • 13. 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(4):631-40.

  • 14. Mathews ST, Chellam N, Srinivas PR, Cintron VJ, Leon MA, Goustin AS. Alpha2-HSG, a specific inhibitor of insulin receptor autophosphorylation, interacts with the insulin receptor. Mol Cell Endocrinol. 2000;164(1-2):87-98.

  • 15. Brown WM, Dziegielewska KM, Saunders’ NR, Christie DL, Nawratil P, Muller-Esterl W. The nucleotide and deduced amino acid structures of sheep and pig fetuin. Common structural features of the mammalian fetuin family. Eur J Biochem. 1992;205(1):321-31.

  • 16. 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(3):319-30.

  • 17. Carvalho BM, Abdalla Saad MJ. Influence of gut microbiota on subclinical inflammation and insulin resistance. Mediators Inflamm. 2013;1-13.

  • 18. Cintrón VJ, Ko MS, Chi KD, Gross JP, Srinivas PR, Goustin AS, et al. Genetic mapping and functional studies of a natural inhibitor of the insulin receptor tyrosine kinase: the mouse ortholog of human alpha2-HS glycoprotein. Int J Exp Diabetes Res. 2001;1(4):249-63.

  • 19. Mathews ST, Rakhade S, Zhou X, Parker GC, Coscina DV, Grunberger G. Fetuin-null mice are protected against obesity and insulin resistance associated with aging. Biochem Biophys Res Commun. 2006;350(2):437-43.

  • 20. Dabrowska AM, Tarach JS, Wojtysiak-Duma B, Duma D. Fetuin-A (AHSG) and its usefulness in clinical practice. Review of the literature. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015;159(3):352-9.

  • 21. Ix JH, Shlipak MG, Brandenburg VM, Ali S, Ketteler M, Whooley MA. Association between human fetuin-A and the metabolic syndrome: data from the Heart and Soul Study. Circulation. 2006;113(14):1760-7.

  • 22. Taylor R. Insulin resistance and type 2 diabetes. Diabetes. 2012; 61(4):778-9.

  • 23. Goustin AS, Derar N,.Abou-Samra AB. Ahsgfetuin blocks the metabolic arm of insulin action through its interaction with the 95-kD β-subunit of the insulin receptor. Cell Signal. 2013;25(4):981-8.

  • 24. Goustin A-S. Human Ahsg (fetuin-A) mature protein (model in PyMol) [Internet]. 2012 Jun [cited 2018 Jun 10]. Available from: https://www.youtube.com/watch?v=C212S_owySw

  • 25. WHO. Global report on diabetes [Internet]. 2016 [cited 2018 Jun 10]. Available from:http://apps.who.int/iris/bitstream/handle/10665/204871/9789241565257_eng.pdf;jsessionid=B0D9E4564FCBF06628ABAC20F1CC29D6?sequence=1

  • 26. Jacobs S, Kröger J, Floegel A, Boeing H, Drogan D, Pischon T, et al. Evaluation of various biomarkers as potential mediators of the association between coffee consumption and incident type 2 diabetes in the EPIC-Potsdam Study..Am J Clin Nutr. 2014;100(3):891-900.

  • 27. Lorant DP, Grujicic M, Hoebaus C, Brix JM, Hoellerl F, Schernthaner G, et al. Fetuin-A levels are increased in patients with type 2 diabetes and peripheral arterial disease. Diabetes Care. 2011;34(1):156-61.

  • 28. Norbert S, Fritsche A, Weikert C, Boeing H, Joost HG, Haring HU, et al. Plasma fetuin-A levels and the risk of type 2 diabetes. Diabetes. 2008;57(10):2762-7.

  • 29. 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.

  • 30. Siddiq A, Lepretre F, Hercberg S, Froguel P, Gibson F. A synonymous coding polymorphism in the alpha2-Heremans-schmid glycoprotein gene is associated with type 2 diabetes in French Caucasians. Diabetes. 2005;54(8):2477-81.

  • 31. Sindhu S, Akhter N, Shenouda S, Wilson A, Ahmad R. Plasma fetuin-A/α2-HS-glycoprotein correlates negatively with inflammatory cytokines, chemokines and activation biomarkers in individuals with type-2 diabetes. BMC Immunol. 2016;17:33.

  • 32. 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.

  • 33. Guo VY, Cao B, Cai C, Cheng KK, Cheung BMY. Fetuin-A levels and risk of type 2 diabetes mellitus: a systematic review and meta-analysis. Acta Diabetol. 2018;55(1):87-98.

  • 34. Roshanzamir F, Miraghajani M, Rouhani MH, Mansourian M, Ghiasvand R, Safavi SM. The association between circulating fetuin-A levels and type 2 diabetes mellitus risk: systematic review and meta-analysis of observational studies.. J Endocrinol Invest. 2018;41(1):33-47.

  • 35. Erdmann J, Salmhofer H, Knauß A, Mayr M, Wagenpfeil S, Sypchenko O, et al. Relationship of fetuin-A levels to weight-dependent insulin resistance and type 2 diabetes mellitus. Regul Pept. 2012;178(1-3):6-10.

  • 36. 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):826-33.

  • 37. Xu Y, Xu M, Bi Y, Song A, Huang Y, Liu Y, et al. Serum fetuin-A is corretaled with metabolic syndrome in middle-aged and elderly Chinese. Atherosclerosis. 2011;216(1):180-6.

  • 38. Ix JH, Chertow GM, Shlipak MG, Brandenburg VM, Ketteler M, Whooley MA. Association of fetuin-A with mitral annular calcification and aortic stenosis among persons with coronary heart disease: data from the Heart and Soul Study. Circulation. 2007;115(19):2533-9.

  • 39. Hennige AM, Staiger H, Wicke C, Machicao F, Fritsche A, Häring HU, et al. Fetuin-A induces cytokine expression and suppresses adiponectin production. PLoS One. 2008;3(3):e1765.

  • 40. Kaushik SV, Plaisance EP, Kim T, Huang EY, Mahurin AJ, Grandjean PW, et al. Extended-release niacin decreases serum fetuin-A concentrations in individuals with metabolic syndrome. Diabetes Metab Res Rev. 2009;25(5):427-34.

  • 41. Goustin AS, Abou-Samra AB. The “thrifty” gene encoding Ahsg/Fetuin-A meets the insulin receptor: insights into the mechanism of insulin resistance. Cell Signalling. 2011;23(6):980-90.

  • 42. Brix JM, Stingl H, Hollerl F, Schernthaner GH, Kopp HP, Schernthaner G. Elevated fetuin-A concentrations in morbid obesity decrease after dramatic weight loss. J Clin Endocrinol Metab. 2010; 95(11):4877-81.

  • 43. Alvarez-Llamas G, Szalowska E, de Vries MP, Weening D, Landman K, Hoek A, et al. Characterization of the human visceral adipose tissue secretome. Mol Cell Proteomics. 2007; 6(4):589-600.

  • 44. Roca-Rivada A, Al-Massadi O, Castelao C, Senín LL, Alonso J, Seoane LM, et al. Muscle tissue as an endocrine organ: comparative secretome profiling of slow-oxidative and fast-glycolytic rat muscle explants and its variation with exercise. JProteomics. 2012;75(17):5414-25.

  • 45. Perez-Sotelo D, Roca-Rivada A, Larrosa-Garcia M, Castelao C, Baamonde I, Baltar J, et al. Visceral and subcutaneous adipose tissue express and secrete functional alpha2hsglycoprotein (fetuin a) especially in obesity. Endocrine. 2017;55(2):435-46.

  • 46. Pal D, Dasgupta S, Kundu R, Maitra S, Dias G, Mukhopadhyay S, et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med. 2012;18(8):1279-85.

  • 47. Weikert C, Stefan N, Schultze MB, Pischon T, Berger K, Joost HG, et al. Plasma fetuin-A levels and the risk of myocardial infarction and ischemic stroke. Circulation. 2008;118(24):2555-62.

  • 48. Laughlin G A, Cummins KM, Wassel CL, Daniels LB, Ix JH. The association of fetuin-A with cardiovascular disease mortality in older community-dwelling adults: the Rancho Bernardo study. J Am Coll Cardiol. 2012;59(19):1688-96.

  • 49. Mori K, Emoto M, Araki T, Yokoyama H, Teramura M, Lee E, et al. Association of serum fetuin-A with carotid arterial stiffness. Clin Endocrinol (Oxf). 2007;66(2):246-50.

  • 50. Mukhopadhyay S, Mondal SA, Kumar M, Dutta D. Proinflammatory and antiinflammatory attributes of fetuin-a: a novel hepatokine modulating cardiovascular and glycemic outcomes in metabolic syndrome. Endocr Pract. 2014;20(12):1345–51.

  • 51. Bilgir O, Kebapcilar L, Bilgir F, Bozkaya G, Yildiz Y, Pinar P, et al. Decreased serum fetuin-A levels are associated with coronary artery diseases. Intern Med. 2010;49(13):1281-5.

  • 52. Ix JH, Katz R, de Boer IH, Kestenbaum BR, Peralta CA, Jenny NS, et al. Fetuin-A is inversely associated with coronary artery calcification in community-living persons: the Multi-Ethnic Study of Atherosclerosis. Clin Chem. 2012;58(5):887-95.

  • 53. Sun ZL, Xie QY, Guo GL, Ma K, Huang YY. Serum fetuin-A levels in patients with cardiovascular disease: a meta-analysis. BioMed Research International. 2014;2014: 691540.

  • 54. Laugsand LE, Ix JH, Bartz TM, Djousse L, Kizer JR, Tracy RP, et al. Fetuin-A and risk of coronary heart disease: a Mendelian randomization analysis and a pooled analysis of AHSG genetic variants in 7 prospective studies. Atherosclerosis. 2015;243(1):44-52.

  • 55. Sun Q, Jimenez MC, Townsend MK, Rimm EB, Manson JE, Albert CM, et al. Plasma levels of fetuin-A and risk of coronary heart disease in US women: the Nurses’ Health Study. J Am Heart Assoc. 2014;24(3):e000939.

  • 56. Roos M, Oikonomou D, von Eynatten M, Luppa PB, Heemann U, Lutz J, et al. Associations of fetuin-A levels with vascular disease in type 2 diabetes patients with early diabetic nephropathy. Cardiovasc Diabetol. 2010;9:48.

  • 57. Sezer S, Uçar F, Ulusoy EK, Erdogan S, Bilen S, Züngün C, et al. Serum amyloid A, fetuin-A, and pentraxin-3 levels in patients with ischemic stroke: novel prognostic biomarkers?. Turk J Med Sci. 2014;44(1):16-23.

  • 58. Weikert C, Berger K, Heidemann C, Bergmann MM, Hoffmann K, Klipstein-Grobusch K, et al. Joint effects of risk factors for stroke and transient ischemic attack in a German population: the EPIC Potsdam Study. J Neurol. 2007;254(3):315-21.

  • 59. Wang YJ, Gong ZQ, Bi XM, Li YL. Correlation of plasma soluble cluster of differentiation 40 ligand, alpha fetoprotein A, and pregnancy-associated plasma protein A with carotid plaque in patients with ischemic stroke. Genet Mol Res. 2015;14(3):8091-9.

  • 60. Jiménez MC, Sun Q, Schürks M, Hu FB, Manson JE, Rexrode KM. Circulating fetuin-A and risk of ischemic stroke in women. Clin Chem. 2014;60(1):165-73.

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

  • 62. Asuncion M, Calvo RM, San Millan JL, Sancho J, Avila S, Escobar-Morreale HE. A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab. 2000;85(7):2434-8.

  • 63. Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol. 2013;6:1-13.

  • 64. Hart R, Hickey M, Franks S. Definitions, prevalence and symptoms of polycystic ovaries and polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2004;18(5):671-83.

  • 65. Dunaif A Insulin resistance and the polycystic ovarysyndrome: mechanism and implications for pathogenesis. Endocr Rev. 1997;18(6):774-800.

  • 66. Enli Y, Fenkci SM, Fenkci V, Oztekin O. Serum fetuin-A levels, insulin resistance and oxidative stress in women with polycystic ovary syndrome. Gynecol Endocrinol. 2013;29(12):1036-9.

  • 67. Hasan AL-Aboudy NF, Hussain AL-Ani NK, Reda AlKawaz UM. The effect of different ovarian stimulation protocols on multifunctional fetuin_A concentration in the serum and follicular fluid of women with PCOS undergoing ICSI/IVF. Int. J. of Adv. Res. 2017;5(9):1012-9.

  • 68. Okohue JE, Onuh SO, Ikimalo JI. Comparison of IVF/ICSI outcome in patients with polycystic ovarian syndrome or tubal factor infertility. Niger J Clin Pract. 2013;16(2):207-10.

  • 69. Farhan S, Handisurya A, Todoric J, Tura A, Pacini G, Wagner O, et al. Fetuin-A characteristics during and after pregnancy: result from a case control pilot study. Int J Endocrinol. 2012;896736.

  • 70. Kalabay L, Cseh K, Pajor A, Baranyi E, Csákány GM, Melczer Z, et al. Correlation of maternal serum fetuin/alpha2-HS-glycoprotein concentration with maternal insulin resistance and anthropometric parameters of neonates in normal pregnancy and gestational diabetes. Eur J Endocrinol. 2002;147(2):243-8.

  • 71. Abali R, Celik C, Tasdemir N, Guzel S, Alpsoy S, Yuksel A, et al. The serum protein α2-Heremans-Schmid glycoprotein/fetuin-A concentration and caroid intima-media thickness in women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2013;169(1):45-9.

  • 72. Gulhan I, Bozkaya G, Ozetkin D, Uyar I, Kebapsilar AG, Pamuk B. Serum fetuin-A levels in women with polycystic ovary syndrome. Arch Gynecol Obstet. 2012;286(6):1473-6.

OPEN ACCESS

Journal + Issues

Search