Blood low density lipoproteins (LDLs) carry cholesterol into blood vessel walls where the cholesterol can accumulate causing atherosclerotic plaques, the cause of heart attacks and most strokes. Massive accumulation of cholesterol by monocyte-derived macrophages (called foam cells) is a prominent feature of these atherosclerotic plaques. Because macrophages trap this cholesterol in lesions, it is important to understand the process by which these cells take up LDL. Although human monocyte-derived macrophages do not take up or accumulate cholesterol when exposed to normal LDL, we described a unique endocytosis pathway by which these macrophages take up LDL that has been aggregated or converted to liposomes through hydrolysis of LDL cholesteryl ester. Both of these forms of LDL occur in atherosclerotic plaques. We showed that these modified forms of LDL induce and enter a membranous labyrinth of surface-connected compartments (SCC) by a process we have named patocytosis. During the past year we learned more about this new endocytosis pathway. A common property among particles that stimulate patocytosis is their hydrophobic nature. This explains why disturbed LDL particles trigger this uptake pathway because LDL contains a protein, apo B, whose very hydrophobic domains are hidden in normal LDL but would be exposed in disrupted LDL. Uptake by patocytosis was limited to hydrophobic particles less than 0.5 micrometers in diameter (for rigid spherical particles), while particles this size and greater entered macrophages by phagocytosis (where particles enter the macrophage in completely enclosed vacuoles). We have also learned how macrophage SCC form. SCC form from plasma membrane invaginations that connect with spaces created by unfolding of stacks of internal membrane folds within the macrophage cytoplasm. In future work, we will undertake studies to determine the fate of aggregated LDL that enters macrophage SCC by the process of patocytosis. - atherosclerosis, cholesterol, macrophages, lipoproteins, endocytosis, LDL, foam cells, patocytosis
Showing the most recent 10 out of 23 publications
