Extracellular cholesterol

Doukyu N, R Aono (1998) Purification of extracellular cholesterol oxidase with high activity in the presence of organic solvents from Pseudomonas sp. strain ST-200. Appl Environ Microbiol 64 1929-1932. 

Simionescu N, Vasile E, Lupu P, et al. (1986) Prelesional events in atherogenesis. Accumulation of extracellular cholesterol-rich liposomes in the arterial intima and cardiac valves of the hyperUpidemic rabbit. Am J Pathol 123 109-125... 

The major source of extracellular cholesterol for human tissues is Very-low-density lipoproteins (VLDLs)... 

Fig. 3. (A) Intracellular unesterified cholesterol accumulation in a lesional foam cell. Electron micrograph of the cytoplasm of a foam cell isolated ftom an advanced aortic atherosclerotic lesion in a cholesterol-fed rabbit. The cell was treated with filipin, which forms spicules with unesterified cholesterol. Multiple spicules are observed in vesicles, shown to be lysosomes (depicted by arrows). D , neutral lipid droplet. Bar 0.5 pm. From [34]. Lab. Invest. 41 160-167. (B) Extracellular cholesterol crystals in an advanced atherosclerotic lesion. The section is from the proximal aorta of a fat-fed apolipoprotein E knockout mouse. This mouse model is often used to study atherosclerosis in vivo because the high plasma levels of remnant lipoproteins resulting from absence of apolipoprotein E leads to a much greater degree of atherosclerosis lesion development than observed in wild-type mice. The arrows depict the areas of cholesterol crystals. Reproduced with permission from the publisher.

A 0-9% salt solution is considered to be isotonic with blood. Other electrolytes present include bicarbonate ions (HCOj ) and small amounts of potassium, calcium, magnesium, phosphate, sulphate and organic acid ions. Included among the complex compounds and present in smaller amounts are phospholipids, cholesterols, natural fats, proteins, glucose and amino acids. Under normal conditions the extracellular body fluid is slightly alkaline with a pH of 7-4. ... 

ABCA1 functions to translocate cholesterol and phospholipids outward across the plasma membrane after their delivery to the inner plasma membrane leaflet via vesicular pathways [35]. This occurs in astrocytes and developing neurons. Astrocytes also secrete apoE. Extracellular apoE binds and interacts with ABCA1 to promote cholesterol and PC efflux from cultured astrocytes through a mechanism that results in apoE-stabilized... 

Extracellular ligands (hormones, neurotrophins, carrier protein, adhesion molecules, small molecules, etc.) will bind to specific transmembrane receptors. This binding of specific ligand induces the concentration of the receptor in coated pits and internalization via clathrin-coated vesicles. One of the best studied and characterized examples of RME is the internalization of cholesterol by mammalian cells [69]. In the nervous system, there are a plethora of different membrane receptors that bind extracellular molecules, including neurotrophins, hormones and other cell modulators, being the best studied examples. This type of clathrin-mediated endocytosis is an amazingly efficient process, capable of concentrating... 

An old hypothesis is based on the observations of Dahlen et al. (D3), who demonstrated that above a certain concentration in plasma, Lp(a) could bind to glycosaminoglycans in the arterial wall (B12). Colocalization of Lp(a) and fibrin on the arterial wall can lead to oxidative changes in the lipid moiety of Lp(a) and induce the formation of oxidatively modified cholesterol esters, which in turn can influence the interaction of Lp(a) and its receptors on macrophages. This process is promoted by the presence of calcium ions. Cushing (C14), Loscalzo (L22), and Rath (R3) reported a colocalization of undegraded Lp(a) and apo-Bl00 in the extracellular space of the arterial wall. In contrast to LDL, Lp(a) is a substrate for tissue transglutaminase and Factor XUIa and can be altered to products that readily interact with cell surface structures (B21). 

In addition to extracellular degradation in tissues, endosomal acidification might also trigger PEG-lipid cleavage. We showed that despite the presence of the PEG, which slightly reduces lipoplex internalization into the cells, DNA transfection level almost reaches the level of the cationic lipo-plex (31). Cholesterol PEG incorporation into lipoplexes not only reduces lipoplex internalization, but also inhibits the transfection efficiency. 

Practically all available iodinated extracellular X-ray contrast agents have been encapsulated into liposomes using different lipids and methods of preparation. Table 1 gives a short and intentionally incomplete overview of some of the approaches. The first liposomal contrast agent preparation that was tested in humans contained diatrizoate [48]. The injected dose was up to 0.5 ml kg k The preparation was effective even in plain radiography where lesions down to 0.8-1.0 cm could be detected in patients. However, adverse events such as fever and hyperthermia, which occurred in 30% of the patients, limited further use. We have incorporated iopromide into MLVs that were prepared from phosphatidyl choline (PC), cholesterol and stearic acid at a molar ratio of 4 5 1 using the ethanol-evaporation technique [44]. The liposomes can be stored freeze-dried and they are reconstituted before use by... 

Similarly, apolipoprotein E expression increases in neurotoxicity mediated by KA (Table 6.3) (Boschert et al., 1999). Apolipoprotein E is a major lipoprotein in the brain. It is involved in the transport, distribution, and other aspects of cholesterol homeostasis. Apolipoprotein E also plays a dominant role in the mobilization and redistribution of brain lipids in repair, growth, and maintenance of nerve cells (Mahley, 1988). The secretion of apolipoproteins E and D may be differentially regulated in cultured astrocytes. In cell culture systems this depends upon the extracellular lipid milieu (Patel et al., 1995). During neurotoxicity mediated by KA, apolipoprotein E levels increase moderately in astrocytes and apolipoprotein E mRNA increases very strongly in clusters of CA1 and CA3 pyramidal neurons. Based on hybridization in situ and immunohistochemical studies, expression of apolipoprotein E in neurons may be a part of a rescue program to counteract neurodegeneration mediated by KA (Boschert et al., 1999). 

Macrophages and cytokines can also influence lipoprotein metabolism [139], Grove et al. indicated that macrophages can secrete several proteins, including 27-oxygenated metabolites of cholesterol, that upregulate LDL receptors in HepG2 cells [140], This mechanism was compared with the classical HDL-dependent reverse cholesterol transport. With albumin as extracellular acceptor, the major secreted product was 3-/3-hydroxy-5-cholestenoic acid with HDL as acceptor, 27-hydroxycholesterol was the major secreted product [140, 141]. 

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