Abstract 18385: Serum Amyloid A is an Evolutionary Conserved Apolipoprotein That Functions to “Fine Tune” Reverse Cholesterol Transport During the Acute-Phase Response
In response to severe injury, the acute-phase protein, serum amyloid A (SAA) can replace apoA-I as the major apo-protein of HDL. The inclusion of SAA in HDL changes a number of HDL's properties. Our data indicates that SAA's presence reduces HDL's capacity to accept free cholesterol. SAA also increases HDL's binding affinity for macrophages and is dependent on the cell surface glycosaminoglycan, heparin sulfate (HS). SAA contains two HS binding sites and HS binding to SAA can cause it to dissociate from HDL, leaving behind lipid poor apoA-I rich oligomers, with enhanced cholesterol accepting potential. Under "amyloidogenic" condition this dissociated SAA can be readily converted into amyloid fibrils by macrophages and our data suggests this occurs largely on the cell surface. SAA can also be taken up by macrophages and once in the cytoplasm we have shown that it can stimulate neutral cholesteryl ester hydrolase (nCEH) and inhibit acetyl-coenzyme A acetyltransferase (ACAT) activities, respectively, with the net effect of mobilizing stored cholesteryl ester and making it available for export via the ABCA1/ABCG1 transporters. Under experimental conditions SAA can promote the export of over 70% of the cholesterol loaded into macrophages within 24 h. SAA's activities complement those of apoA-I/HDL by increasing the pool of exportable (de-esterified) cholesterol for efflux to an extracellular cholesterol acceptor like apoA-I/HDL and entry into the reverse cholesterol transport (RCT) pathway. The nCEH and ACAT modulating domains of SAA have been identified and as synthetic peptides have been also demonstrated to be potent promoters and inhibitors of nCEH and ACAT activities, respectively, with purified enzyme preparations, intact cells in culture and in vivo in mice, consistent with an allosteric mechanisms of action. When delivered in liposomes to a mouse apoE knockout model of atherosclerosis, these SAA peptides were shown to be highly effective in the prevention and regression of atherosclerotic lesions. We believe SAA has been evolutionary conserved to aid in the recycling of cellular cholesterol.
- © 2011 by American Heart Association, Inc.