The major source of these lipids is mainly plasma-derived lipoproteins such as low-density lipoprotein (LDL). Foam cell formation is believed to occur through uptake of lipoprotein-derived cholesterol. The reason why the homeostatic mechanisms, that normally limit lipid accumulation, fail is not known. It has been suggested that the cells are unable to control their rate of lipoprotein uptake because LDL undergoes modifications in the intima that target it to unregulated receptor-mediated uptake pathways in macrophages. These modifications include aggregation and oxidation. However, even under conditions where LDL uptake is increased, there are other mechanisms that normally will limit cellular lipid accumulation. The fact that foam cells develop, indicates that either reverse cholesterol transport (i.e. hydrolysis of esterified cholesterol from lipid droplets and its export from the cell) and/or lysosomal hydrolysis and export of endocytosed lipoprotein-derived lipids, are also dysfunctional.
There is some evidence that oxidized LDL is present in atherosclerotic lesions and that oxidized lipids are present in macrophage foam cells isolated from human lesions. Various oxidation products may affect several aspects of foam cell formation. Early lipid oxidation products, such as cholesteryl linoleate hydroperoxide, can inhibit lysosomal hydrolysis of unoxidised CE. This may promote lysosomal storage of unoxidized lipids. More advanced LDL oxidation products are intrinsically resistant to lysosomal hydrolysis and also remain trapped in the lysosomal system. Oxidation of cholesterol generates a characteristic spectrum of oxysterols, the major product being 7-ketocholesterol (7KC). This can escape the lysosome and is incorporated into membranes or esterified and stored in lipid droplets. Within the plasma membrane, 7KC displaces cholesterol from lipid rafts, sterol-rich areas of the membrane involved in many signalling events. Lipid rafts also participate in reverse cholesterol transport, and 7KC accumulation can inhibit this, leading to cholesterol accumulation. Besides these direct effects on cholesterol accumulation, 7KC and other oxysterols may affect many aspects of macrophage function.
In summary, lipid oxidation products appear to be generated in
atherosclerotic lesions and have the potential to promote macrophage
lipid accumulation at several stages. The challenge ahead is to
determine which, if any, of these products are active in vivo, and how
to prevent their generation or to promote their removal.
Key words:
macrophage, atherosclerosis, cholesterol, oxysterol, oxidation
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