Apolipoprotein B stimulates formation of monocyte-macrophage surface-connected compartments and mediates uptake of low density lipoprotein-derived liposomes into these compartments

Much of the cholesterol that accumulates in atherosclerotic plaques is foun d within monocyte-macrophages transforming these cells into "foam cells." N ative low density lipoprotein (LDL) does not cause foam cell formation. Tre atment of LDL with cholesterol esterase converts LDL into cholesterol-rich liposomes having >90% cholesterol in unesterified form. Similar cholesterol -rich liposomes are found in early developing atherosclerotic plaques surro unding foam cells. We now show that cholesterol-rich liposomes produced fro m cholesterol esterase-treated LDL can cause human monocyte-macrophage foam cell formation inducing a 3-5-fold increase in macrophage cholesterol cont ent of which >60% is esterified. Although cytochalasin D inhibited LDL lipo some-induced macrophage cholesteryl eater accumulation, LDL liposomes did n ot enter macrophages by phagocytosis. Rather, the LDL liposomes induced and entered surface-connected compartments within the macrophages, a unique en docytic pathway in these cells that we call patocytosis, LDL liposome apoB rather than LDL liposome lipid mediated LDL liposome uptake by macrophages, This was shown by the findings that: 1) protease treatment of the LDL lipo somes prevented macrophage cholesterol accumulation; 2) liposomes prepared from LDL lipid extracts did not cause macrophage cholesterol accumulation; and 3) purified apoB induced and accumulated within macrophage surface-conn ected compartments. Although apoB mediated the macrophage uptake of LDL lip osomes, this uptake did not occur through LDL, LDL receptor-related protein , or scavenger receptors, Also, LDL liposome uptake was not sensitive to tr eatment of macrophages with trypsin or heparinase, Cholesterol esterase-med iated transformation of LDL into cholesterol-rich liposomes is an LDL modif ication that: 1) stimulates uptake of LDL cholesterol by apoB-dependent end ocytosis into surface-connected compartments, and 2) causes human monocyte- macrophage foam cell formation.