Cholesterol delivered to macrophages by oxidized low density lipoprotein is sequestered in lysosomes and fails to efflux normally

Oxidized low density lipoprotein (LDL) has been found to exhibit numerous p otentially atherogenic properties, including transformation of macrophages to foam cells. It is believed that high density lipoprotein (HDL) protects against atherosclerosis by removing excess cholesterol from cells of the ar tery wall, thereby retarding lipid accumulation by macrophages, In the pres ent study, the relative rates of HDL-mediated cholesterol efflux were measu red in murine resident peritoneal macrophages that had been loaded with ace tylated LDL or oxidized LDL, Total cholesterol content of macrophages incub ated for 24 h with either oxidized LDL or acetylated LDL was increased by 3 -fold. However, there was no release of cholesterol to HDL from cells loade d with oxidized LDL under conditions in which cells loaded with acetylated LDL released about one-third of their total cholesterol to HDL. Even mild d egrees of oxidation were associated with impairment of cholesterol efflux. Macrophages incubated with vortex-aggregated LDL also displayed impaired ch olesterol efflux, but aggregation could not account for the entire effect o f oxidized LDL. Resistance of apolipoprotein B (apoB) in oxidized LDL to ly sosomal hydrolases and inactivation of hydrolases by aldehydes in oxidized LDL were also implicated. The subcellular distribution of cholesterol in ox idized LDL-loaded cells and acetylated LDL-loaded cells was investigated by density gradient fractionation, and this indicated that cholesterol derive d from oxidized LDL accumulates within lysosomes. Thus impairment of choles terol efflux in oxidized LDL-loaded macrophages appears to be due to lysoso mal accumulation of oxidized LDL rather than to impaired transport of chole sterol from a cytosolic compartment to the plasma membrane.