Serum amyloid A3 is a high density lipoprotein-associated acute-phase protein

Abstract

Serum amyloid A (SAA) is a family of acute-phase reactants. Plasma levels of human SAA1/SAA2 (mouse SAA1.1/2.1) can increase ≥1,000-fold during an acute-phase response. Mice, but not humans, express a third relatively understudied SAA isoform, SAA3. We investigated whether mouse SAA3 is an HDL-associated acute-phase SAA. Quantitative RT-PCR with isoform-specific primers indicated that SAA3 and SAA1.1/2.1 are induced similarly in livers (∼2,500-fold vs. ∼6,000-fold, respectively) and fat (∼400-fold vs. ∼100-fold, respectively) of lipopolysaccharide (LPS)-injected mice. In situ hybridization demonstrated that all three SAAs are produced by hepatocytes. All three SAA isoforms were detected in plasma of LPS-injected mice, although SAA3 levels were ∼20% of SAA1.1/2.1 levels. Fast protein LC analyses indicated that virtually all of SAA1.1/2.1 eluted with HDL, whereas ∼15% of SAA3 was lipid poor/free. After density gradient ultracentrifugation, isoelectric focusing demonstrated that ∼100% of plasma SAA1.1 was recovered in HDL compared with only ∼50% of SAA2.1 and ∼10% of SAA3. Thus, SAA3 appears to be more loosely associated with HDL, resulting in lipid-poor/free SAA3. We conclude that SAA3 is a major hepatic acute-phase SAA in mice that may produce systemic effects during inflammation.

Identification of robust genetic signatures associated with lipopolysaccharide-induced acute lung injury onset and astaxanthin therapeutic effects by integrative analysis of RNA sequencing data and GEO datasets

“…In our study, Saa3 was the most significantly inhibited gene by AST application in LPS-induced ALI mice, and its downregulation was further confirmed by qRT-PCR and IHC. SAA3, the one of three isoforms of SAA expressed in mice, is stimulated intensely in LPS-induced acute systemic inflammation, which is consistent with our findings [ 35 ]. High expression of SAA3 in response to acute inflammation may be repressed by an interaction with noncoding RNAs.…”

Serum amyloid A3 is required for normal weight and immunometabolic function in mice

“…SAA1 and SAA2 are found in the circulation bound to HDL, and a link between these forms of SAA and metabolic diseases has been speculated upon [ 36 , 37 ]. However, SAA3 does not bind HDL to the same extent as SAA1 [ 38 , 39 ], and is found at far lower concentrations in the serum, indicating that acute production of SAA3 is more critical in localized tissue responses. How SAA3 specifically affects metabolic homeostasis and regulates adipokine and insulin-sensitive gene expression is less clear.…”

Structural Basis for Vital Function and Malfunction of Serum Amyloid A: an Acute-Phase Protein that Wears Hydrophobicity on Its Sleeve

“…Multiple functions have been reported for SAA depending on its isoform, expression site, lipidation status, and other factors. Of the four major SAA isoforms, acute-phase SAA1 and SAA2 (in mice and men) and SAA3 (in mice) are expressed in response to pro-inflammatory cytokines such as IL1, IL6, and TNF-α, while SAA4 is constitutively expressed [ 20 , 24 , 28 , 29 •, 30 ]. SAA is secreted mainly by hepatocytes into plasma, where it reversibly binds to HDL [ 29 •, 31 ] but can also form transient SAA-only lipoproteins that are distinct from HDL [ 32 •].…”

“…Of the four major SAA isoforms, acute-phase SAA1 and SAA2 (in mice and men) and SAA3 (in mice) are expressed in response to pro-inflammatory cytokines such as IL1, IL6, and TNF-α, while SAA4 is constitutively expressed [ 20 , 24 , 28 , 29 •, 30 ]. SAA is secreted mainly by hepatocytes into plasma, where it reversibly binds to HDL [ 29 •, 31 ] but can also form transient SAA-only lipoproteins that are distinct from HDL [ 32 •]. SAA can bind and activate HDL receptor SR-B1 and other cell scavenger receptors such as LOX1 and RAGE that bind modified lipoproteins; by doing so, SAA can reroute HDL transport from the reverse cholesterol transport pathway, whereby excess cellular cholesterol is removed from the body via bile, to cholesterol recycling (reviewed in [ 14 ]).…”