Sterol synthesis is up-regulated in cholesterol-loaded pigeon macrophages during induction of cholesterol efflux

The extent to which cholesterol synthesis is modulated in macrophage foam c ells by changes in cholesterol influx and efflux was determined using thiog lycollale-elicited peritoneal macrophages from normal and cholesterol-fed W hite Carneau (WC) and Show Racer (SR) pigeons, In peritoneal macrophages fr om normocholesterolemic pigeons, sterol synthesis from [C-14]-acetate tvas down-regulated by more than 90% following incubation in vitro with beta-VLD L, Sterol synthesis was increased when the cellular free cholesterol concen tration was decreased in response to stimulation of cholesterol efflux with apoHDL/phosphatidyicholine vesicles and cyclodextrin. Peritoneal macrophag es isolated from hypercholesterolemic pigeons were loaded with cholesterol to levels similar to foam cells from atherosclerotic plaques (375-614 mu g cell protein), and had an extremely low rate of sterol synthesis, When chol esterol efflux was stimulated in these cells, sterol synthesis increased 8 to 10-fold, even though the cells remained grossly loaded with cholesterol. Cholesterol efflux also stimulated HMG-CoA reductase activity and LDL rece ptor expression. This suggests that only a small portion of the total chole sterol pool in macrophage foam cells was responsible for regulation of ster ol synthesis, and that cholesterol generated by hydrolysis of cholesteryl e sters was directed away from the regulatory pool by efflux from the cells. When the increase in sterol synthesis was blocked with the HMG-CoA reductas e inhibitor mevinolin, there was no difference in the cholesterol content o f the cells, or in the mass efflux of cholesterol into the culture medium. jlr Thus, under these conditions, the increase in cholesterol synthesis dur ing stimulation of cholesterol efflux does not appear to contribute signifi cantly to the mass of cholesterol in these macrophage foam cells. Whether a similar situation exists in vivo is unknown.