When rat macrophages were converted to foam cells with acetylated low density lipoprotein (acetyl-LDL) and then reacted with high density lipoprotein (HDL) and an inhibitor of acyl-coenzyme A:cholesterol acyltransferase (58-035) (sequential incubation system), 58-035 did not enhance HDL-induced cholesterol efflux. In contrast, when macrophages were exposed to acetyl-LDL in the presence of both HDL and 58-035 (simultaneous incubation system), HDL-induced cholesterol efflux was enhanced 1.6-fold by 58-035. Cholesterol efflux with HDL alone was 2-fold greater in simultaneous incubation than in sequential incubation. These results suggest the presence of an efficient cholesterol efflux pathway in simultaneous incubation which is not available in sequential incubation. This pathway, which we refer to as the neutral cholesterol ester hydrolase-independent pathway, is characterized by the efflux of lysosome-derived cholesterol without re-esterification.
