ACUTE-INFLAMMATION, ACUTE-PHASE SERUM AMYLOID-A AND CHOLESTEROL-METABOLISM IN THE MOUSE

Acute inflammation results in a profound change in the apolipoprotein composition of high density lipoprotein (HDL). Several isoforms of the serum amyloid A (SAA) family, SAA(1) and SAA(2), become major compone nts of HDL. This structural relationship has suggested that acute phas e SAA plays some as yet unidentified role in HDL function, possibly re lated to cholesterol transport, during the course of acute inflammatio n. Using subcutaneous AgNO3 to induce a sterile abscess changes in pla sma cholesterol and SAA were monitored over the subsequent 144 h. Tota l plasma cholesterol began to increase within 12 h of the induction of inflammation and reached a peak in 24 h. Thereafter its plasma levels fell returning to normal values by 96-120 h. The bulk of the increase in plasma cholesterol was found in the free cholesterol fraction of H DL. This pattern of cholesterol increase corresponds to the establishe d temporal changes for acute phase SAA (AP-SAA). AP-SAA levels increas ed within 8 h of the induction of inflammation and reached a peak at 2 4 h. They began to decrease by 48 h with small quantites still present 120 h later. In concert, but inversely, with the changes in AP-SAA th e apoA-I, apoA-II, and apo-E, content of HDL decreased during the AP-S AA increases and increased as AP-SAA levels fell. The plasma appearanc e of cholesterol from the periphery, and central parts of the inflamma tory site was assessed by the use of radiolabelled cholesterol. The pe ripherally placed cholesterol rapidly reached a peak plasma concentrat ion within 24 h of injection. Cholesterol placed in the central parr o f the sterile abscess, a site relatively inaccessible to the vasculatu re required 48 h to reach its peak and was 5-times lower than that pla ced peripherally. The influence of AP-SAA on neutral cholesterol eater hydrolase (nCEH) activity in mouse liver homogenates, mouse peritonea l macrophage homogenates, and a purified porcine pancreatic enzyme wit h nCEH activity was also assessed. Following optimization with regard to pH, bile salt concentration, protein concentration and incubation t ime, mouse peritoneal macrophages had a significantly higher nCEH spec ific activity than that found in liver (7-8 fold). Purified AP-SAA, as sessed over a concentration range of 0-10 mu g/ml, enhanced nCEH activ ity at concentrations above 2 mu g/ml. The nCEH activity, regardless o f its source, increased by 3-7 fold in the presence of AP-SAA. Equival ent concentrations of apolipoprotein A-I (ape A-I) and bovine serum al bumin (BSA) failed to alter the activity of nCEH. The effect of AP-SAA on a purified form of nCEH suggests that AP-SAA may have a direct eff ect on the activity of this enzyme. The temporal correlation of circul ating AP-SAA and plasma cholesterol and the significant stimulation of nCEH by AP-SAA (but not apoA-I or BSA) provides further evidence that AP-SAA plays a role in cholesterol metabolism during the course of ac ute inflammation.