Phospholipid metabolism in cholesterol-loaded macrophages

Macrophage foam cells in atherosclerotic lesions accumulate free cholesterol as well as cholesteryl ester. In addition, these cells have an increased rate of phospholipid biosynthesis and accumulate intracellular phospholipid-containing membrane structures ('whorls'). Studies with cultured macrophages have revealed the possible molecular mechanism and biological relevance of these observations. A rate-limiting enzyme of phosphatidylcholine biosynthesis, cytidine triphosphate: phosphocholine cytidylyltransferase, is post-translationally activated in response to the accumulation of free cholesterol in macrophages. This leads to an increase in phosphatidylcholine mass and the appearance of membrane whorls in these cells. We have advanced the hypothesis that this alteration in cellular phospholipid metabolism is an adaptive response to prevent the cellular free cholesterol: phospholipid ratio from reaching cytotoxic levels. Support for this hypothesis was obtained by demonstrating a direct relationship between the free cholesterol: phospholipid ratio and cellular necrosis in cultured macrophages, especially under conditions in which the phosphatidylcholine response was experimentally blunted. We propose that the eventual inability of this phospholipid response to keep up with free cholesterol accumulation in lesional macrophages in vivo may be an important cause of macrophage necrosis and, thus, plaque progression and clinical events in advanced atherosclerotic lesions.