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.
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This work was supported by the US Department of Veterans Affairs Awards CX000975 (L.R.T.) and CX000773 (N.R.W.) and National Institutes of Health Grants HL134731 (N.R.W., F.C.D.B.), HL092969 (A.C.), AT007177 (L.d.H.), and P20 GM103527 (support for used cores). Mass spectrometric analysis was performed at the University of Kentucky, Proteomics Core Facility. This core facility is supported in part by funds from the Office of the Vice President for Research.
Tannock, Lisa R.; de Beer, Maria C.; Ji, Ailing; Shridas, Preetha; Noffsinger, Victoria P.; den Hartigh, Laura; Chait, Alan; de Beer, Frederick C.; and Webb, Nancy R., "Serum Amyloid A3 is a High Density Lipoprotein-Associated Acute-Phase Protein" (2017). Internal Medicine Faculty Publications. 132.