Cellular cholesterol efflux, mechanisms

Sphingolipids Can Regulate Key Mechanisms of Cellular Cholesterol Efflux... 

Cholesterol efflux is one mechanism that maintains cellular cholesterol homeostasis. An important regulator of cellular cholesterol efflux is the ATP-binding cassette receptor Al (ABCA-1). ABCA-1 is critical for the formation of plasma high-density lipoproteins (HDL) that are inversely related to cardiovascular disease risk (Schaefer et al., 1994). Two groups investigated the role of... 

Squalene is converted into the first sterol, lanosterol, by the action of squalene epoxidase and oxidosqualene lanosterol cyclase. The catalytic mechanism for the cyclase s four cyclization reactions was revealed when the crystal stmcture of the human enzyme was obtained (R. Thoma, 2004). Oxidosqualene lanosterol cyclase is considered an attractive target for developing inhibitors of the cholesterol biosynthetic pathway because its inhibition leads to the production of 24,25-epoxycholesterol (M.W. Huff, 2005). This oxysterol is a potent ligand activator of the liver X receptor (LXR) and leads to expression of several genes that promote cellular cholesterol efflux, such as ABCAl, ABCG5, and ABCG8 (Section 4.1). Thus, inhibitors of oxidosqualene lanosterol cyclase could be therapeutically advantageous because they would reduce cholesterol synthesis and promote cholesterol efflux (M.W. Huff, 2005). 

HDL HDL promote the cholesterol efflux from arterial. In addition, HDL protect LDL from oxidation and induction of subsequent cytotoxicity (Von Eckardstein et al., 2001 Kwiterovich, 1998 Berliner and Heinecke, 1996). This effect is apparently due to the presence of 2 enzymes (paraoxonase and PAF-acetylhydrolase bound to HDL) which may hydrolyse the oxidized lipids of LDL, thus blocking the subsequent biological responses (Hajjar and Haberland, 1997). Moreover, HDL could reduce hydroperoxides to their corresponding hydroxides, or extract oxidized lipids from oxidized LDL (Bonnefont-Rousselot et al., 1999). HDL inhibit oxidized LDL cytotoxicity (Hessler et al., 1979), through inhibition of oxT, DT. -induced stress and calcium rise. HDL act as an anti-oxidant lowering the oxidative modification of LDL, and preventing the cells of arterial wall from the deleterious effect of oxidized LDL, but their precise cellular mechanism of protection still remains unknown. 

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. 

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. 

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...

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