Alpha-2-HS-glycoprotein explained

alpha-2-HS-glycoprotein (AHSG, Alpha-2-Heremans-Schmid Glycoprotein) also known as fetuin-A is a protein that in humans is encoded by the AHSG gene.^{[1] [2] [3]} Fetuin-A belongs to the fetuin class of plasma binding proteins and is more abundant in fetal than adult blood.

Function

Alpha2-HS glycoprotein, a glycoprotein present in the serum, is synthesized by hepatocytes and adipocytes.^[4] The AHSG molecule consists of two polypeptide chains, which are both cleaved from a proprotein encoded from a single mRNA. It is involved in several functions, such as endocytosis, brain development and the formation of bone tissue. The protein is commonly present in the cortical plate of the immature cerebral cortex and bone marrow hemopoietic matrix, and it has therefore been postulated that it participates in the development of the tissues. However, its exact significance is still obscure.

The choroid plexus is an established extrahepatic expression site. The mature circulating AHSG molecule consists of two polypeptide chains, which are both cleaved from a proprotein encoded from a single mRNA. Multiple post-translational modifications have been reported.^[5] Thus AHSG is a secreted partially phosphorylated glycoprotein with complex proteolytic processing that circulates in blood and extracellular fluids. In the test tube AHSG can bind multiple ligands and therefore has been claimed to be involved in several functions, such as endocytosis, brain development and the formation of bone tissue. Most of these functions await confirmation in vivo.

Clinical significance

Fetuins are carrier proteins like albumin. Fetuin-A forms soluble complexes with calcium and phosphate and thus is a carrier of otherwise insoluble calcium phosphate.^{[6] [7] [8]} Thus fetuin-A is a potent inhibitor of pathological calcification, in particular Calciphylaxis.^[9] Mice deficient in fetuin-A show systemic calcification of soft tissues.^{[10] [11]} Fetuin-A can inhibit calcification, and inhibits osteogenesis in bone. Fetuin-A appears to promote calcification in coronary artery disease, but oppose calcification in peripheral artery disease.

High levels of Fetuin-A are associated with obesity and insulin resistance. Fetuin-A promotes insulin resistance by enhancing the binding of free fatty acids to TLR4. In adipose tissue, Fetuin-A downregulates the expression of adiponectin, thereby increasing inflammation and insulin resistance. Also in adipose tissue, Fetuin-A reduces lipogenesis and increases lipolysis, thereby increasing obesity and insulin resistance.

Supervised exercise (that is not associated with weight reduction) reduces Fetuin-A.

See also

• Fetuin-B

Further reading

• Ketteler M, Vermeer C, Wanner C . Novel insights into uremic vascular calcification: role of matrix Gla protein and alpha-2-Heremans Schmid glycoprotein/fetuin. . Blood Purif. . 20 . 5 . 473–6 . 2003 . 12207096 . 10.1159/000063554 . 46761031 . etal.
• Ketteler M . Fetuin-A and extraosseous calcification in uremia. . Curr. Opin. Nephrol. Hypertens. . 14 . 4 . 337–42 . 2005 . 15931001 . 10.1097/01.mnh.0000172719.26606.6f . 10131227 .
• Yang F, Schwartz Z, Swain LD . Alpha 2-HS-glycoprotein: expression in chondrocytes and augmentation of alkaline phosphatase and phospholipase A2 activity. . Bone . 12 . 1 . 7–15 . 1991 . 2054237 . 10.1016/8756-3282(91)90048-N . etal.
• Araki T, Yoshioka Y, Schmid K . The position of the disulfide bonds in human plasma alpha 2 HS-glycoprotein and the repeating double disulfide bonds in the domain structure. . Biochim. Biophys. Acta . 994 . 3 . 195–9 . 1989 . 2645941 . 10.1016/0167-4838(89)90293-8. free .
• 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. . 264 . 24 . 14121–8 . 1989 . 10.1016/S0021-9258(18)71651-7 . 2760061 . free .
• Magnuson VL, McCombs JL, Lee CC . Human alpha 2-HS-glycoprotein localized to 3q27----q29 by in situ hybridization . Cytogenet. Cell Genet. . 47 . 1–2 . 72–4 . 1988 . 3356172 . 10.1159/000132509 . etal.
• Lee CC, Bowman BH, Yang FM . Human alpha 2-HS-glycoprotein: the A and B chains with a connecting sequence are encoded by a single mRNA transcript. . Proc. Natl. Acad. Sci. U.S.A. . 84 . 13 . 4403–7 . 1987 . 3474608 . 10.1073/pnas.84.13.4403 . 305097 . 1987PNAS...84.4403L . free .
• Keeley FW, Sitarz EE . Identification and quantitation of alpha 2-HS-glycoprotein in the mineralized matrix of calcified plaques of atherosclerotic human aorta. . Atherosclerosis . 55 . 1 . 63–9 . 1985 . 3924066 . 10.1016/0021-9150(85)90166-2 .
• Yoshioka Y, Gejyo F, Marti T . The complete amino acid sequence of the A-chain of human plasma alpha 2HS-glycoprotein. . J. Biol. Chem. . 261 . 4 . 1665–76 . 1986 . 10.1016/S0021-9258(17)35992-6 . 3944104 . etal. free .
• Matsushima K, Cheng M, Migita S . Purification and physicochemical characterization of human alpha 2-HS-glycoprotein. . Biochim. Biophys. Acta . 701 . 2 . 200–5 . 1982 . 6803836 . 10.1016/0167-4838(82)90114-5.
• Gejyo F, Chang JL, Bürgi W . Characterization of the B-chain of human plasma alpha 2HS-glycoprotein. The complete amino acid sequence and primary structure of its heteroglycan. . J. Biol. Chem. . 258 . 8 . 4966–71 . 1983 . 10.1016/S0021-9258(18)32522-5 . 6833285 . etal. free .
• Rizzu P, Baldini A . Three members of the human cystatin gene superfamily, AHSG, HRG, ((and KNG)), map within one megabase of genomic DNA at 3q27 . Cytogenet. Cell Genet. . 70 . 1–2 . 26–8 . 1995 . 7736783 . 10.1159/000133984 .
• Srinivas PR, Wagner AS, Reddy LV . Serum alpha 2-HS-glycoprotein is an inhibitor of the human insulin receptor at the tyrosine kinase level. . Mol. Endocrinol. . 7 . 11 . 1445–55 . 1994 . 10.1210/mend.7.11.7906861 . 7906861 . etal. free .
• Nawratil P, Lenzen S, Kellermann J . Limited proteolysis of human alpha2-HS glycoprotein/fetuin. Evidence that a chymotryptic activity can release the connecting peptide. . J. Biol. Chem. . 271 . 49 . 31735–41 . 1997 . 8940198 . 10.1074/jbc.271.49.31735 . etal. free .
• Osawa M, Umetsu K, Ohki T . Molecular evidence for human alpha 2-HS glycoprotein (AHSG) polymorphism. . Hum. Genet. . 99 . 1 . 18–21 . 1997 . 9003486 . 10.1007/s004390050302 . 12674184 . etal.
• Osawa M, Umetsu K, Sato M . Structure of the gene encoding human alpha 2-HS glycoprotein (AHSG) . Gene . 196 . 1–2 . 121–5 . 1997 . 9322749 . 10.1016/S0378-1119(97)00216-3 . etal.
• Umekawa T, Iguchi M, Konya E . Localization and inhibitory activity of alpha(2)HS-glycoprotein in the kidney. . Urol. Res. . 27 . 5 . 315–8 . 2000 . 10550518 . 10.1007/s002400050157 . 22262322 . etal.
• Olivier E, Soury E, Ruminy P . Fetuin-B, a second member of the fetuin family in mammals. . Biochem. J. . 350 . 2. 589–97 . 2001 . 10947975 . 10.1042/0264-6021:3500589. 1221288 . etal.
• Osawa M, Yuasa I, Kitano T . Haplotype analysis of the human alpha2-HS glycoprotein (fetuin) gene. . Ann. Hum. Genet. . 65 . Pt 1 . 27–34 . 2001 . 11415520 . 10.1046/j.1469-1809.2001.6510027.x . 83617933 . etal. free .
• Haglund AC, Ek B, Ek P . Phosphorylation of human plasma alpha2-Heremans-Schmid glycoprotein (human fetuin) in vivo. . Biochem. J. . 357 . Pt 2 . 437–45 . 2001 . 11439093 . 10.1042/0264-6021:3570437 . 1221970 .

Notes and References

1. Rizzu P, Baldini A . Three members of the human cystatin gene superfamily, AHSG, HRG, and KNG, map within one megabase of genomic DNA at 3q27 . Cytogenet. Cell Genet. . 70 . 1–2 . 26–8 . 1995 . 7736783 . 10.1159/000133984.
2. Osawa M, Umetsu K, Sato M, Ohki T, Yukawa N, Suzuki T, Takeichi S . Structure of the gene encoding human alpha 2-HS glycoprotein (AHSG) . Gene . 196 . 1–2 . 121–5 . September 1997 . 9322749 . 10.1016/S0378-1119(97)00216-3 .
3. Web site: Entrez Gene: AHSG alpha-2-HS-glycoprotein.
4. Ramírez-Vélez R, García-Hermoso A, Hackney AC, Izquierdo M . Effects of exercise training on Fetuin-a in obese, type 2 diabetes and cardiovascular disease in adults and elderly: a systematic review and Meta-analysis . Lipids in Health and Disease . 18 . 1 . 23 . 2019 . 10.1186/s12944-019-0962-2 . 6343360 . 30670052 . free .
5. Jahnen-Dechent W, Trindl A, Godovac-Zimmermann J, Müller-Esterl W . Posttranslational processing of human alpha 2-HS glycoprotein (human fetuin). Evidence for the production of a phosphorylated single-chain form by hepatoma cells . Eur. J. Biochem. . 226 . 1 . 59–69 . November 1994 . 7525288 . 10.1111/j.1432-1033.1994.tb20026.x.
6. Heiss A, Eckert T, Aretz A, Richtering W, van Dorp W, Schäfer C, Jahnen-Dechent W . Hierarchical role of fetuin-A and acidic serum proteins in the formation and stabilization of calcium phosphate particles . J. Biol. Chem. . 283 . 21 . 14815–25 . May 2008 . 18364352 . 10.1074/jbc.M709938200 . free .
7. 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. . 86 . 4 . 379–89 . April 2008 . 18080808 . 10.1007/s00109-007-0294-y . 20960971 .
8. Bourebaba L, Marycz K . Pathophysiological Implication of Fetuin-A Glycoprotein in the Development of Metabolic Disorders: A Concise Review . Journal of Clinical Medicine . 8 . 12 . E2033 . 2019 . 10.3390/jcm8122033 . 6947209 . 31766373. free .
9. Bojincă. Violeta Claudia. Bojincă. Mihai. Iosif. Cristina Ileana. Bălănescu. Şerban Mihai. Bălănescu. Andra Rodica. 2018. Diagnostic challenges in a patient with calciphylaxia - a case report. Romanian Journal of Morphology and Embryology = Revue Roumaine de Morphologie et Embryologie. 59. 2. 591–594. 1220-0522. 30173268.
10. Westenfeld R, Schäfer C, Smeets R, Brandenburg VM, Floege J, Ketteler M, Jahnen-Dechent W . Fetuin-A (AHSG) prevents extraosseous calcification induced by uraemia and phosphate challenge in mice . Nephrol. Dial. Transplant. . 22 . 6 . 1537–46 . June 2007 . 17389622 . 10.1093/ndt/gfm094 . free .
11. Schafer C, Heiss A, Schwarz A, Westenfeld R, Ketteler M, Floege J, Muller-Esterl W, Schinke T, Jahnen-Dechent W . The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification . J. Clin. Invest. . 112 . 3 . 357–66 . August 2003 . 12897203 . 166290 . 10.1172/JCI17202 .