Cholesterol esters metabolic role

Thioesters play a paramount biochemical role in the metabolism of fatty acids and lipids. Indeed, fatty acyl-coenzyme A thioesters are pivotal in fatty acid anabolism and catabolism, in protein acylation, and in the synthesis of triacylglycerols, phospholipids and cholesterol esters [145], It is in these reactions that the peculiar reactivity of thioesters is of such significance. Many hydrolases, and mainly mitochondrial thiolester hydrolases (EC 3.1.2), are able to cleave thioesters. In addition, cholinesterases and carboxylesterases show some activity, but this is not a constant property of these enzymes since, for example, carboxylesterases from human monocytes were found to be inactive toward some endogenous thioesters [35] [146], In contrast, allococaine benzoyl thioester was found to be a good substrate of pig liver esterase, human and mouse butyrylcholinesterase, and mouse acetylcholinesterase [147],... 

The primary developmental mechanism of the atherosclerotic process is not completely understood. It seems likely that the development of atherosclerosis is preceded by metabolic abnormalities of the synthesis, transport, and utilization of lipids. Lipids such as triglycerides and cholesterol esters are circulated in the blood in the form of particles (lipoproteins) wrapped in hydrophilic membranes that are synthesized from phospholipids and free cholesterol. Cholesterol is transported by particles of various sizes synthesized from triglycerides, cholesterol esters, and phospholipids, each of which plays a very specific role. 

Desmosterol and cholesterol esters disappear from the brain as mye-lination proceeds and none at all is found in healthy adult nervous tissue (Adams and Davison, 1959 Fumagalli and Paoletti, 1963). This supports the idea that both substances have an important role in sterol synthesis and metabolism during development, differentiation, and myelination in... 

Lipoproteins are complexes of lipids and proteins [43]. They play important roles in the transport and metabolism of lipids such as triglycerides, free cholesterol, cholesterol esters and phospholipids [44]. There are four major types of lipoproteins, including chylomicrons (CM), very low density lipoproteins (VLDL), low density lipoproteins (LDL) and high density lipoproteins (HDL) [45]. Different types of lipoproteins vary in sizes, lipid, and protein compositions and functions (Table 1) [46]. 

Lipid removal may be a critical factor in plaque formation and the location of lecithin-cholesterol trans-acylase in the arterial wall could play an important role since cholesterol is rapidly exchanged" with the blood while cholesterol ester is not. Kuo in an editorial cites the evidence for the theory that a dlsturbemce in carbohydrate metabolism can be responsible for atherosclerosis and should be included as one of the primary risk factors in coronary heart disease. In this regard, Clements and coworkers have shown the presence in aorta of aldose reductase, an enzyme which they feel provides a mechanism for the alteration of arterial metabolism by hyperglycemia. Another approach to molecular interactions was described by Levy and Day who concluded from their results that the low density lipoproteins are uniquely polycationic at the surface and that these ions react with the internal arterial macromolecular polyanions. 

The role of linoleate in cholesterol deposition and transport is not entirely clear. Kelsey and Longenecker (1941) proved that 62% of the plasma cholesterol of cattle occurred in combination with linoleate. It is only natural to postulate that, in the absence of EFA, cholesterol is deposited in the liver, because there is insufficient linoleate available to transport it to other tissues for metabolism and excretion. However, it has been shown that, in such conditions, the increased cholesterol is deposited in the liver as an ester. The cholesterol esters in the liver of rats have been proved to consist almost entirely of those of saturated and oleic acids only approximately 10% of the cholesterol occurs in combination with linoleic acid, irrespective of whether or not the diet contains EFA (Achaya et al., 1954a). It would thus appear that Unoleic acid is of prime importance in the control of the distribution and deposition of cholesterol in the rat. Whether or not the same situation obtains in the case of man is a moot question. 

The role of the liver in the metabolism of chylomicron cholesterol ester is even more extensive than in the metabolism of triglycerides, as only about 20% of the chylomicron triglyceride (Ontko and Zil-versmit, 1967), but more than 70% of the cholesterol ester is taken up by the liver (Quarfordt and Goodman, 1967). 

The liver plays a decisive role in the cholesterol metabolism. The liver accounts for 90% of the overall endogenic cholesterol and its esters the liver is also impli-cated in the biliary secretion of cholesterol and in the distribution of cholesterol among other organs, since the liver is responsible for the synthesis of apoproteins for pre-p-lipoproteins, a-lipoproteins, and P-lipoproteins which transport the secreted cholesterol in the blood. In part, cholesterol is decomposed by intestinal micro-flora however, its major part is reduced to coprostanol and cholestanol which, together with a small amount of nonconverted cholesterol, are excreted in the feces. 

The search for intestinal cholesterol transporters extended for many years, beginning with a debate about whether or not it was even a protein-facilitated process (4, 5). The pancreatic enzyme carboxyl ester lipase (CEL, also called cholesterol esterase) was believed to be important to this process (6,7) and several companies devoted considerable resources to the development and testing of compounds to inhibit CEL, with mixed results (8-10). These efforts were abandoned in the mid-1990s, however, after studies with gene-knockout mice demonstrated that the enzyme was important only for absorption of cholesteryl ester (11, 12), which is a minor component of dietary cholesterol and is present at very low levels in bile. Interestingly, CEL is also found in liver where it has been shown to affect HDL metabolism (13). Thus, it may ultimately play an important role in cholesterol metabolism and may yet prove to be a useful drug target for CVD treatment (Camarota and Howies, unpublished). 

Lecithin-cholesterol acyltransferase is a water-soluble plasma enzyme that plays an important role in the metabolism of HDLs by catalyzing the formation of cholesteryl esters on HDLs through the transfer of fatty acids from the sn-2 position of phosphatidylcholine to cholesterol (Jonas, 1986). ApoA-1 is the major cofactor of LCAT in HDLs and reconstituted lipoproteins (Fielding et ai, 1972). Many laboratories have used techniques such as synthetic peptide analogs (Anantharamaiah et ai, 1990a Anantharamaiah, 1986), monoclonal antibodies (Banka et al., 1990), and recombinant HDL particles (Jonas and Kranovich, 1978) to attempt to identify the major LCAT-activating region of apoA-I. 

Abnormal lipoproteins are produced under various metabolic conditions. P-VLDL, a triglyceride-depleted, cholesterol-enriched form of VLDL, accumulates in the plasma of cholesterol-fed animals [13,14] or of humans with type III hyperlipoproteinemia [15]. In patients with this disease, the accumulation of j8-VLDL is believed to be due to incomplete clearance of chylomicron remnants by the liver. Slow turnover of remnants allows them to accumulate cholesteryl esters and thus to evolve into j8-VLDL particles [16,17]. -VLDL (density <1.006 g/ml, j8-electro-phoretic mobility) contain both apo-B and apo-E and may play a significant role in the formation of atherosclerotic foam cells [18]. 

Lipoproteins are macromolecular assemblies that contain proteins and lipids, including free and esterified cholesterol, triglycerides, and phospholipids. The protein components, known as apoUpoprotems, provide structural stability to the lipoproteins, and also may function as ligands in hpoprotein-receptor interactions or as cofactors in enzymatic processes that regulate lipoprotein metabolism. In aU Upoprotems, the most water-insoluble lipids (cholesteryl esters and triglycerides) are core components, and the more polar, water-soluble components (apoproteins, phospholipids, and unesterified cholesterol) are located on the surface. The major classes of lipoproteins and their properties are presented in Table 35-1. Table 35-2 describes apoproteins that have well-defined roles in plasma lipoprotein metabolism. 

Although cholesteryl esters (CEs) play an important role in cholesterol metabolism, there are few reports on CE analysis by MS. The behavior of cholesteryl esters in ESI is very similar to that of TAGs, and thus NH4 [124,125] and Ag+ adducts [126] have been used for their analysis. Fragmentation of the adduct ions produces a characteristic ion of miz 369.35 corresponding to [cholesterol-HjO]. Other steryl esters behave similarly (e.g., estrone esters [127]). With APPI, the [M-l-H-H20]+ ions are the most prominent ones [121]. 

An inherited lack of, or deficiency in, cell surface receptors for low density lipoproteins results in a condition, familial hypercholesterolaemia, in which blood cholesterol concentrations are rather high. This condition, if untreated, leads to severe vascular disease and death from ischaemic heart disease. Lipids are involved in several ways. First, one of the characteristics of developing atherosclerotic plaques is an accumulation of lipids, particularly cholesteryl esters, which are derived from plasma lipoproteins secondly, lipids are involved (because of their role as precursors of eicosanoids) in the formation of thrombi which may block arteries and cause ischaemia. Another risk factor for ischaemic heart disease that involves lipid metabolism is obesity, characterized by an excessive accumulation of adipose tissue. In particular, upper body obesity is also associated with Type II diabetes and hyperinsulinaemia. Hyperlipoproteinaemia is secondary to obesity and diabetes mellitus and if these conditions are treated, blood lipid concentrations return to normal. 

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