Differential effects of lovastatin on the trafficking of endogenous and lipoprotein-derived cholesterol in human monocyte-derived macrophages

Lovastatin has been shown to reduce cholesterol esterification in cholesterol-loaded human macrophages. Surprisingly, in nonloaded macrophages, lovastatin produces the opposite effect, lowering free cholesterol and increasing cholesteryl ester levels, as measured by high-performance liquid chromatography. In cholesterol-loaded cells, lovastatin reduced the cholesteryl esters of unsaturated but not those of saturated fatty acids. In nonloaded cells, by contrast, the cholesteryl esters of unsaturated fatty acids tended to increase after lovastatin treatment. Total (free plus esterified) cellular cholesterol content in nonloaded cells fell by 18% with 12-mu mol/L lovastatin treatment but did not change in cholesterol-loaded cells. Lovastatin had no effect on the binding or uptake of acetylated low density lipoprotein, acyl coenzyme A:cholesterol acyltransferase (ACAT) activity, the secretion of [H-3]cholesterol into the medium, or lysosomal hydrolysis of cholesteryl esters. Apolipoprotein (apo) E mRNA levels increased but apoE secretion into the medium decreased with lovastatin treatment in both cholesterol-loaded and nonloaded cells. Cholesterol of exogenous origin has been shown to pass via the cell membrane before its esterification by ACAT. We postulate that this is not the case for endogenous cholesterol, which may have direct access to ACAT. Our findings therefore suggest that lovastatin hinders the delivery of intracellular cholesterol to the plasma membrane, resulting in increased free cholesterol and lower levels of cholesteryl ester in cholesterol-loaded cells. In nonloaded cells, virtually all cholesterol is of endogenous origin and is normally translocated to the cell membrane. Lovastatin prevents this process, thus shunting newly synthesized cholesterol toward esterification and leading to an increase in the concentration of cholesteryl esters, even in the face of a drop in total and free cholesterol levels. Intracellular apoE may play a role in this process.