Apolipoprotein A-II induces acute-phase response associated AA amyloidosis in mice through conformational changes of plasma lipoprotein structure

Abstract

During acute-phase response (APR), there is a dramatic increase in serum amyloid A (SAA) in plasma high density lipoproteins (HDL). Elevated SAA leads to reactive AA amyloidosis in animals and humans. Herein, we employed apolipoprotein A-II (ApoA-II) deficient (Apoa2−/−) and transgenic (Apoa2Tg) mice to investigate the potential roles of ApoA-II in lipoprotein particle formation and progression of AA amyloidosis during APR. AA amyloid deposition was suppressed in Apoa2−/− mice compared with wild type (WT) mice. During APR, Apoa2−/− mice exhibited significant suppression of serum SAA levels and hepatic Saa1 and Saa2 mRNA levels. Pathological investigation showed Apoa2−/− mice had less tissue damage and less inflammatory cell infiltration during APR. Total lipoproteins were markedly decreased in Apoa2−/− mice, while the ratio of HDL to low density lipoprotein (LDL) was also decreased. Both WT and Apoa2−/− mice showed increases in LDL and very large HDL during APR. SAA was distributed more widely in lipoprotein particles ranging from chylomicrons to very small HDL in Apoa2−/− mice. Our observations uncovered the critical roles of ApoA-II in inflammation, serum lipoprotein stability and AA amyloidosis morbidity, and prompt consideration of therapies for AA and other amyloidoses, whose precursor proteins are associated with circulating HDL particles.

Suppression of Mouse AApoAII Amyloidosis Progression by Daily Supplementation with Oxidative Stress Inhibitors

“…Before injection, the fibril samples were sonicated (Fig. S1) and used immediately as described previously [20].…”

“…AApoAII and AA fibrils were also detected by immunohistochemistry (IHC) with specific rabbit antiserum against mouse ApoA-II or mouse AA, which were produced against guanidine hydrochloride-denatured AApoAII or AA fibrils in our laboratory [20, 21, 33, 38]. Four-micron (4 μ m) thick sections of fixed organs were treated with 3% H 2 O 2 in methanol for 30 minutes (min) to inactivate endogenous peroxidase and were blocked with 5% bovine serum albumin in PBS.…”

“…Some studies have found that ApoA-II protein is related to lipid transport from peripheral organs to the liver and binding of plasma proteins with HDL [17–19]. In a previous study, we found that ApoA-II modifies the binding of the plasma acute phase inflammatory response protein serum amyloid A (SAA) with plasma lipoproteins and plays a role in regulating the inflammatory response and AA amyloid fibril formation [20]. We found that ApoA-II proteins form amyloid fibrils (AApoAII) and deposit extracellularly in a number of organs (except the brain) and are associated with aging in senescence-accelerated mouse prone-1 (SAMP1) strains of mice.…”

Gene expression profiling of skeletal muscles

“…Tspo2 traffics free cholesterol in erythroid cells [13]. Apoa2 regulates steroid concentrations by modulating cholesterol transport [14], the precursor of steroid hormones.…”

Metabolomic and Proteomic Stratification of Equine Osteoarthritis

“…ApoA2 has previously been identified to be involved in the acute phase response which is associated with reactive amyloid A amyloidosis, via lipoprotein conformational changes, an associated complication of rheumatoid arthritis (104).…”