Serum amyloid A

An acute phase apolipoprotein and precursor of AA amyloid

Gudmund Marhaug, S. Bruce Dowton

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Serum amyloid A is an acute phase protein complexed to HDL as an apoprotein. The molecular weight is 11.4-12.5 kDa in different species and the protein has from 104 to 112 amino acids, without or with an insertion of eight amino acids at position 72. The protein is very well conserved throughout evolution, indicating an important biological function. The N-terminal part of the molecule is hydrophobic and probably responsible for the lipid binding properties. The most conserved part is from position 38 to 52 and this part is therefore believed to be responsible for the until now unknown biological function. The protein is coded on chromosome 11p in man, and chromosome 7 in mice, and found in all mammals until now investigated, and also in the Peking duck. In the rat a truncated SAA mRNA has been demonstrated, but no equivalent serum protein has been reported. Acute phase SAA is first of all produced in hepatocytes after induction by cytokines, but extrahepatic expression of both acute phase and constitutive SAA proteins have been demonstrated. Several cytokines, first of all IL-1, IL-6 and TNF are involved in the induction of SAA synthesis, but the mutual importance of these cytokines seems to be cell-type specific and to vary in various experimental settings. The role of corticosteroids in SAA induction is somewhat confusing. In most in vitro studies corticosteroids show an enhancing or synergistic effect with cytokines on SAA production in cultured cell. However, in clinical studies and in vivo studies in animals an inhibitory effect of corticosteroids is evident, probably due to the all over anti-inflammatory effect of the drug. Until now no drug has been found that selectively inhibits SAA production by hepatocytes. Effective anti-inflammatory or antibacterial treatment is the only tool for reducing SAA concentration in serum and reducing the risk of developing secondary amyloidosis. The function of SAA is still unclear. Interesting theories, based on current knowledge of the lipid binding properties of the protein and the relation to macrophages, in the transportation of cholesterol from damaged tissues has been advanced. A putative role in cholesterol metabolism is supported by the findings of SAA as an inhibitor of LCAT. The potential that SAA is a modifying protein in inflammation influencing the function of neutrophils and platelets is interesting and more directly related to the inflammatory process itself. SAA is the most sensitive acute phase protein characterized to date. Serum levels of SAA have been used both in diagnosis and monitoring of inflammatory and infectious diseases, and because of its sensitivity it should probably be used more for these purposes. However, fast and reliable commercial assays have not until recently been available. Since SAA is the precursor of protein AA in secondary amyloid monitoring of SAA concentrations in patients threatened by this complication seems important. Even if the role of SAA in amyloidogenesis is unclear, it it obvious that an increased serum level of SAA for a long time is a most important pathogenetic factor. Theories of impaired degradation of SAA and formation of an intermediate product, protein AA, which is incorporated in amyloid fibril is interesting, but partly contradicted by the fact that full length SAA proteins are often found in secondary amyloid. A special 'amyloid prone' isoform of SAA is found in mice, but this is probably not a universal phenomenon, as this is not the case in all species. The ability of fibril formation of SAA and SAA degradation products seems to be connected to the N-terminal hydrophobic portion of the protein, but the interactions between protein AA, amyloid P component and glucosaminoglycans in the tissues which result in fibril formation are still to be elucidated.

Original languageEnglish
Pages (from-to)553-573
Number of pages21
JournalBailliere's Clinical Rheumatology
Volume8
Issue number3
DOIs
Publication statusPublished - 1994

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