Macrophage Foam Cell Formation without LDL Modification

摘要

Low-density lipoprotein (LDL) is believed to be the main source of cholesterol that accumulates in rnonocyte-derived macrophages within atherosclerotic plaques converting these macrophages into enlarged foam cells. Previously, only modified but not native LDL has been shown to produce macrophage cholesterol accumulation. We have found that activation of human monocyte-derived macrophages with phorbol 12-inyristate 13-acetate (PMA) stimulates native LDL uptake and degradation, and acyl-CoA: cholesterol acyltransferase (ACAT)-mediated esteri-fication of LDL-derived cholesterol, resulting in massive macrophage cholesterol accumulation. The mechanism of LDL uptake by these macrophages is PMA-stimulated endocytosis of LDL taken up as part of the bulk-phase fluid (i.e., fluid-phase endocytosis). This novel mechanism of macrophage cholesterol accumulation shows that modification of LDL is not necessary for foam cell formation to occur. In addition, the findings direct attention to macrophage fluid-phase endocytosis as a relevant pathway to target for modulating macrophage cholesterol accumulation in atherosclerosis.