Cholesterol uptake cellular mechanisms

Exposure of cholesterol-starved cells to LDL is followed by massive buildup of intracellular free cholesterol pools. HMG-CoA reductase is suppressed, shutting down cellular cholesterol synthesis [84,85]. ACAT is stimulated as much as 500-fold by a process that apparently is independent of protein synthesis [86]. Subsequently, the number of LDL receptors declines dramatically with a calculated half-life of 15-20 h [29,31]. Since the rate of decline under conditions which block protein synthesis is comparable to the LDL-mediated rate of decline [29,87], down-regulation may be due to suppression of receptor synthesis. Excess eholesterol is esterified and stored in the c)rtoplasm as cholesteryl esters. A steady-state characterized by large cholesteryl ester and free cholesterol pools and by basal levels of both HMG-CoA reductase and LDL receptors is ultimately attained. This regulatory mechanism allows cells to control their rate of cholesterol uptake, synthesis, and storage in response to the available supply of lipoprotein cholesterol. 

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 principal mechanism for cellular uptake of cholesterol involves receptor-mediated endocytosis of plasma lipoproteins. Brown and Goldstein eluci-... 

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. 

A typical feature of caveola-mediated endocytosis is the formation of non-coated invaginations composed of detergent-resistant membrane components rich in cholesterol and sphingolipids, known as lipid rafts [56]. The importance of the caveola-mediated mechanism in the PTD-mediated internalization was confirmed in an experiment where the cellular uptake of Tat peptide was affected by drugs that either disrupt lipid rafts or alter caveolar trafficking [57]. Moreover, Tat-PTD-fused protein showed colocalization with a marker of caveolar uptake, caveolin, further strengthening the importance of the mechanism in the PTD-mediated internalization [57]. 

It can be expected that all plasma lipoprotein classes, defined in one way or another, consist of a variety of subfractions, simply because plasma lipoproteins form a dynamic system. Plasma lipoprotein metabolism starts as soon as the nascent particles are secreted. Subsequent intravascular metabolism includes the actions of lipoprotein lipase, hepatic lipase, lecithin cholesterol acyltransferase (LCAT), and lipid transfer proteins (LTP). In addition, most lipoproteins can bind to lipoprotein receptors. This can be foUowed by uptake and irreversible intracellular degradation of the holo-particle, or by reappearance in plasma of a modified form of the lipoprotein. The modifications may be due to the transfer of cellular lipids to plasma lipoproteins or to the specific transfer of lipoprotein components to the cells. Both mechanisms may include retroendocytosis. 

In addition to its eflect on SR-Bl, niacin can also stimulate ABCA-1 mediated cholesterol efflux from macrophages, which will contribute to niadn-mediated increases in HDL-C (Morgan et al. 2007 Rubic et al. 2004). Niacin also increases the ability of HDL to take up additional cholesterol from peripheral cells and tissues, as well as its ability to mediate cholesterol transport via SB-Bl, via inhibition of hepatic uptake of small HDL by endocytosis—in effect recycling HDL (Morgan et al. 2007). Thus niacin has been shown to promote cellular cholesterol release via more than one mechanism. 

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