Serum Amyloid A (SAA) Proteins

  • George H. SackJr.Email author
Part of the Subcellular Biochemistry book series (SCBI, volume 94)


As normal constituents of blood serum, the Serum Amyloid A (SAA) proteins are small (104 amino acids in humans) and remarkably well-conserved in mammalian evolution. They are synthesized prominently, but not exclusively, in the liver. Fragments of SAA can associate into insoluble fibrils (called “amyloid”) characteristic of “secondary” amyloid disease in which they can interrupt normal physiology and lead to organ failure. SAA proteins comprise a family of molecules, two members of which (SAA1 and SAA2) are (along with C-reactive protein, CRP) the most prominent members of the acute phase response (APR) during which their serum levels rise dramatically after trauma, infection and other stimuli. Biologic function(s) of SAA are unresolved but features are consistent with a prominent role in primordial host defense (including the APR). SAA proteins are lipophilic and contribute to high density lipoproteins (HDL) and cholesterol transport. SAA proteins interact with specific receptors and have been implicated in tissue remodeling through metalloproteinases, local tissue changes in atherosclerosis, cancer metastasis, lung inflammation, maternal–fetal health and intestinal physiology. Molecular details of some of these are emerging.


Serum amyloid A SAA Acute phase reaction Lipoproteins Inflammation Cytokine Atherosclerosis Metastasis Arthritis Amyloidosis APR HDL 


  1. Aly H, Hamed Z, Mohsen L et al (2011) Serum amyloid A protein and hypoxic ischemic encephalopathy in the newborn. J Perinatol 31:263–268. Scholar
  2. Atarashi K, Tanoue T, Ando M et al (2015) Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 163:367–380Google Scholar
  3. Benson MD, Buxbaum JN, Eisenberg DS et al (2019) Amyloid nomenclature 2018: recommendations by the International Society of Amyloidosis (ISA) nomenclature committee. Amyloid 5pp.
  4. Bozinovski S, Hutchinson A, Thompson M et al (2008) Serum amyloid A is a biomarker of acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 177:269–278CrossRefGoogle Scholar
  5. Bozinovski S, Uddin M, Thompson M et al (2012) Serum amyloid A opposes lipoxin A4 to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease. Proc Natl Acad Sci 109:935–940CrossRefGoogle Scholar
  6. Brinckerhoff CE, Mitchell TI, Karmilowicz MJ et al (1989) Autocrine induction of collagenase by serum amyloid A-like and B2-microglobulin-like proteins. Science 243:655–657CrossRefGoogle Scholar
  7. Burgess EJ, Hoyt LR, Randall MJ et al (2018) Bacterial lipoproteins constitute the TLR-stimulating activity of serum amyloid A. J Immunol 201:2377–2384CrossRefGoogle Scholar
  8. Chen ES, Song Z, Willett MH et al (2010) Serum Amyloid A regulates granulomatous inflammation in sarcoidosis through toll-like receptor-2. Am J Respir Crit Care Med 181:360–373CrossRefGoogle Scholar
  9. Cheng N, Liang Y, Du X et al (2018) Serum amyloid A promotes LPS clearance and suppresses LPS-induced inflammation and tissue injury. EMBO Rep (e45517):14pp. Scholar
  10. Claus S, Meinhardt K, Aumuller T et al (2017) Cellular mechanism of fibrila formation from serum amyloid A1 protein. EMBO Rep 18(8):1352–1366CrossRefGoogle Scholar
  11. Cohen AS, Calkins E (1959) Electron microscopic observations on a fibrous component in amyloid of diverse origins. Nature 183:1202–1203Google Scholar
  12. Connolly M, Marelli A, Blades M et al (2010) Acute serum amyloid A induces migration, angiogenesis, and inflammation in synovial cells in vitro and in a human rheumatoid arthritis/SCID mouse chimera model. J Immunol 184:6427–6437CrossRefGoogle Scholar
  13. Connolly M, Mullan RH, McCormick J et al (2012) Acute=phase serum amyloid A regulates tumor necrosis factor alpha and matric turnover and preficts disease progression in pastients with inflammatory arthritis before and after biologic therapy. Arthritis Rheum 64(4):1035–1045CrossRefGoogle Scholar
  14. De Buck M, Gouwy M, Wang JM et al (2016a) The cytokine-serum amyloid A-Chemokine network. Cytokine Growth Factor Rev 30:55–69CrossRefGoogle Scholar
  15. De Buck M, Gouwy M, Wang JM et al (2016b) Structure and expression of different serum amyloid A (SAA) variants and their concentration-dependent functions during host insults. Curr Med Chem 23:1725–1755CrossRefGoogle Scholar
  16. Hari-Dass R, Shah C, Meyer DJ et al (2005) Serum amyloid A proteins binds to outer membrane protein A of gram-negative bacteria. J Biol Chem 280(19):18562–18567CrossRefGoogle Scholar
  17. Ibrahim M, Ramy AR, Abdelhamid A et al (2017) Maternal serum amyloid A level as a novel marker of primary unexplained recurrent early pregnancy loss. Int J Gynecol Obstet 136:298–303CrossRefGoogle Scholar
  18. Ivanov II, Atarashi K, Manel N et al (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139:485–498Google Scholar
  19. King VL, Thompson J, Tannock LR (2011) Serum amyloid A in atherosclerosis. Curr Opin Lipidol 22:302–307CrossRefGoogle Scholar
  20. Kisilevsky R, Manley PN (2012) Acute-phase serum amyloid A: perspectives on its physiological and pathological roles. Amyloid 19(1):5–14CrossRefGoogle Scholar
  21. Knebel FH, Uno M, Galatro TF, Bellé LP, Oba-Shinjo SM, Marie SKN, Campa A (2017) Serum amyloid A1 is upregulated in human glioblastoma. J Neuro-Oncol 132(3):383–391Google Scholar
  22. Kushner I (1982) The phenomenon of the acute phase response. Ann N Y Acad Sci 39–48Google Scholar
  23. Landskron G, De La Fuente M, Thuwajit P et al (2014) Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res 2014:149185.
  24. Larson MA, Weber A, Weber AT et al (2005) Differential expression and secretion of bovine serum amyloid A3 (SAA3) by mammary epithelial cells stimulated with prolactin or lipopolysaccharide. Vet Immunol Immunopathol 107:255–264CrossRefGoogle Scholar
  25. Lee JW, Stone ML, Porrett PM et al (2019) Hepatocytes direct the formation of a pro-metastatic niche in the liver. Nature 567:249–252Google Scholar
  26. Linke RP, Meinel A, Chalcroft JP et al (2017) Serum amyloid A (SAA) treatment enhances the recovery of aggravated polymicrobial sepsis in mice, whereas blocking SAA's invariant peptide results in early death. Amyloid 24(S1):149–150Google Scholar
  27. Lu J, Yu Y, Zhu I et al (2014) Structural mechanism of serum amyloid A-mediated inflammatory amyloidosis. Proc Natl Acad Sci 111(14):5189–5194CrossRefGoogle Scholar
  28. Luhrs T, Ritter C, Adrian M et al (2005) 3D structure of Alzheimer's amyloid-β(1–42) fibrils. Proc Natl Acad Sci USA 102(48):17341–17347CrossRefGoogle Scholar
  29. Mack DR, McDonald TL, Larson MA et al (2003) The conserved TFLK motif of mammary-associated Serum Amyloid A3 is responsible for Up-regulation of intestinal MUC3 mucin expression in vitro. Pediatr Res 53(1):137–142CrossRefGoogle Scholar
  30. McDonald TL, Larson MA, Mack DR et al (2001) Elevated extrahepatic expression and secretion of mammary-associated serum amyloid A3 (M-SAA3) into colostrum. Vet Immunol Immunopathol 83:203–211CrossRefGoogle Scholar
  31. Meeker AK, Sack GH Jr (1998) A fusion protein between serum amyloid A and staphylococcal nuclease—synthesis, purification, and structural studies. Proteins Struct Funct Genet 30:381–387Google Scholar
  32. Mithal LB, Palac HL, Yogev R et al (2017) Cord blood acute phase reactants predict early onset neonatal sepsis in preterm infants. PLoS ONE 12(1):E0168677. Scholar
  33. Morrow JF, Stearman RS, Peltzman CG et al (1981) Induction of hepatic synthesis of serum amyloid A protein and actin. Proc Natl Acad Sci USA 78:4718–4722CrossRefGoogle Scholar
  34. Moshkovskii SA (2012) Why do cancer cells produce serum amyloid A acute-phase protein? Biochemistry (Moscow) 77(4):339–341CrossRefGoogle Scholar
  35. Ridker PM, Everett BM, Thuren T et al (2017) Antiinflammatory therapy with Canakinumab for atherosclerotic disease. N Engl J Med 377(12):1119–1131CrossRefGoogle Scholar
  36. Sack GH Jr (2009) Amyloidosis (Chap. 46). In: Stone JH (ed) A clinician's pearls and myths in rheumatology. Springer, Dordrecht, pp 461–466Google Scholar
  37. Sack GH Jr (2018) Serum amyloid A - a review. Mol Med 24:46.
  38. Sack GH Jr (2019) The pathophysiology of amyloid fibril formation. In: Amyloidosis. IntechOpen, London.
  39. Sack GH Jr, Zink MC (1992) Serum amyloid A (SAA) gene expression in synovial cells in retroviral arthritis. Am J Pathol 141:525–529Google Scholar
  40. Sack GH Jr, Zachara N, Rosenblum N et al (2018) Serum amyloid A1 (SAA1) protein in human colostrum. FEBS OpenBio 8:435–441.
  41. Sano T, Huang W, Hall JA et al (2015) An IL-23/IL-22 circuit regulates epithelial serum amyloid A to promote local effector Th17 responses. Cell 163:381–393Google Scholar
  42. Shah C, Hari-Dass R, Raynes JG (2006) Serum amyloid A is an innate immune opsonin for Gram-negative bacteria. Blood 108:1751–1757CrossRefGoogle Scholar
  43. Sipe JD (1999) Revised nomenclature for serum Amyloid A (SAA). Nomenclature committee for the international society of amyloidosis. Part 1. Amyloid 6:67–70CrossRefGoogle Scholar
  44. Sun L, Ye RD (2016) Serum amyloid A1: structure, function and gene polymorphism. Gene 583:48–57CrossRefGoogle Scholar
  45. Yang Q, Whitin JC, Ling XB et al (2009) Plasma biomarkers in a mouse model of preterm labor. Pediatr Res 66(1):11–16CrossRefGoogle Scholar
  46. Ye RD, Sun L (2015) Emerging functions of serum amyloid A in inflammation. J Leukoc Biol 98(6):923–929CrossRefGoogle Scholar
  47. Zhou H, Chen M, Zhang G et al (2017) Suppression of lipopolysaccharide-induced inflammatory response by fragments from serum amyloid A. J Immunol 199:1105–1112CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Departments of Biological Chemistry and MedicineThe Johns Hopkins University School of MedicineBaltimoreUSA

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