Foam cells cellular uptake

LDL is oxidatively modified when incubated in vitro with three major cellular constituents of the vascular wall endothelial cells [35], vascular smooth muscle cells [35] and macrophages [35-37], The uptake of oxidised LDL occurs via the scavenger-receptor pathway, and expression of scavenger receptors has been demonstrated on macrophages, endothelial cells [38], fibroblasts [39] and smooth muscle cells [39]. Unlike the LDL receptor, expression of the scavenger receptor is not down-regulated by an increase in intracellular cholesterol [40]. Therefore, uptake of Ox-LDL contributes to the accumulation of cholesteryl esters in foam cells of atherosclerotic lesions [40]. Now, the question is Does oxidation of LDL-lipids influence the development of atherosclerosis ... 

Fig. 4 The lipid influx/efflux rheostat model maintains lipid uptake and export mechanisms in a balance. ATP synthase is regulated by apoA-I or apoE leading to enhanced conversion of ATP to ADP. The absence of apoA-I would lead to enhanced sinking in phagocytosis since actin can bind ATP, polymerize, and form F-actin which is essential for type 11 phagocytosis. Hence apoA-I could lead to increased influx. On the other hand, apoA-I binds to ABCAl leading to enhanced lipid efflux. Dysfunction of this equilibrium may lead to severe disturbances of cellular lipid traffic. This is obvious in Tangier disease patients where ABCAl is inoperative and apoA-/-dependent cholesterol is absent. Cholesterol influx, however, is enhanced due to apoA-Z-dependent stimulation of ATP synthase B leading to cholesteryl ester formation and enhanced foam cell formation...

The obvious conclusion based on this evidence is that an LDLR-lndependent mechanism is responsible for the cellular uptake of LDL cholesterol that leads to the formation of foam cells. One proposed mechanism is shown in Figure... 

From the point of view of atherosclerosis, the two most important peripheral trafficking pathways are those to the endoplasmic reticulum (ER), where cholesterol is esterified by acyl-CoA cholesterol acyltransferase (ACAT), and to the plasma membrane, where cholesterol can be transferred to extracellular acceptors in a process known as cholesterol efflux (Chapter 20). The former process leads to the massive CE accumulation seen in foam cells [14-16]. The ACAT reaction utilizes primarily oleoyl-CoA, thus ACAT-derived CE is rich in oleate. In contrast, plasma lipoprotein-CE tends to be rich in linoleate. As expected, therefore, the cholesteryl oleatexholesteryl linoleate ratio in foam cell-rich fatty streak lesions — 1.9 — is relatively high [17]. However, the ratio in advanced lesions is only 1.1, suggesting an increase in lipoprotein-CE in advanced atheromata due to poor cellular uptake of lipoproteins or to defective lysosomal hydrolysis following uptake by lesional cells. Further discussion of the cholesterol esterification pathway appears in Chapter 15, and cholesterol efflux, which is an important mechanism that may prevent or reverse foam cell formation, is covered in Chapter 20. 

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