Serum amyloid A1: Structure, function and gene polymorphism

Abstract

Inducible expression of serum amyloid A (SAA) is a hallmark of the acute-phase response, which is a conserved reaction of vertebrates to environmental challenges such as tissue injury, infection and surgery. Human SAA1 is encoded by one of the four SAA genes and is the best-characterized SAA protein. Initially known as a major precursor of amyloid A (AA), SAA1 has been found to play an important role in lipid metabolism and contributes to bacterial clearance, the regulation of inflammation and tumor pathogenesis. SAA1 has five polymorphic coding alleles (SAA1.1 – SAA1.5) that encode distinct proteins with minor amino acid substitutions. Single nucleotide polymorphism (SNP) has been identified in both the coding and non-coding regions of human SAA1. Despite high levels of sequence homology among these variants, SAA1 polymorphisms have been reported as risk factors of cardiovascular diseases and several types of cancer. A recently solved crystal structure of SAA1.1 reveals a hexameric bundle with each of the SAA1 subunits assuming a 4-helix structure stabilized by the C-terminal tail. Analysis of the native SAA1.1 structure has led to the identification of a competing site for high-density lipoprotein (HDL) and heparin, thus providing the structural basis for a role of heparin and heparan sulfate in the conversion of SAA1 to AA. In this brief review, we compares human SAA1 with other forms of human and mouse SAAs, and discuss how structural and genetic studies of SAA1 have advanced our understanding of the physiological functions of the SAA proteins.

Short bowel syndrome results in increased gene expression associated with proliferation, inflammation, bile acid synthesis and immune system activation: RNA sequencing a zebrafish SBS model

“…Early after induction of inflammation, IL6 is elevated and is required for efficient stimulation of epithelial cell proliferation after intestinal injury within a mouse model [44]. SAA1 is highly conserved and found to play a role in lipid metabolism as well as bacterial clearance and has a possible role in regulation of inflammation by extending the lifespan of neutrophils and activating proinflammatory cytokines (IL6, IL8, IL1beta, CXCL1, CXCL2) through several receptors including TLR2 and TLR4 [45]. …”

Association of Serum Amyloid A with Kidney Outcomes and All-Cause Mortality in American Indians with Type 2 Diabetes

“…SAA is a ligand for many receptors involved in immune functions, including toll-like receptors and the receptor for advanced glycation end products [30, 31], and it can trigger pro-inflammatory cascades through activation of transcription factors such as nuclear factor kappa B, activator protein 1, and interferon regulatory factor 3 [6, 32]. Advanced glycation end products induce up-regulation of SAA in podocytes [6] and SAA itself can bind the receptor for advanced glycation end products [33]. Notably, SAA can also amplify its own expression in an autocrine manner, along with a host of the aforementioned pro-inflammatory factors [6, 34].…”

Serum amyloid A4 is a procoagulant apolipoprotein that it is elevated in venous thrombosis patients

“…10 The SAA gene family has 4 members. SAAs can be divided into 2 subgroups, comprising acute-phase SAA1 and SAA2 associated with HDL and inflammation in the first subgroup 11 and SAA4 in the second subgroup. SAA3 is expressed in mice but not in humans.…”