Plasma lipoproteins cholesterol esters, formation

The initial steps of reverse cholesterol transport involve export of cholesterol from peripheral cells to plasma lipoproteins for subsequent delivery to the liver. In vivo, HDL or its apolipoproteins act as acceptors of cholesterol from peripheral cells, carrying it to the liver for degradation. When cholesterol acceptors such as HDL are present, cholesterol efflux from macrophages is accelerated, which prevents foam cell formation. To produce this efflux, neutral cholesteryl ester hydrolase catalyzes intracellular hydrolysis of cholesteryl esters into free cholesterol in the lysosome (Avart et al. 1999). 

Cholesterol and triglycerides, as the major plasma hpids, are essential substrates for cell membrane formation and hormone synthesis and provide a source of free fatty acids. Hyperlipidemia is defined as an elevation of one or more of cholesterol, cholesterol esters, phospholipids, or triglycerides. Lipids, being water immiscible, are not present in free form in the plasma but rather circulate as hpoproteins. Hyperlipoproteinemia describes an increased concentration of the lipoprotein macromolecules that transport lipids in the plasma. The density of plasma lipoproteins is determined by their relative content of protein and lipid. Density, composition, size, and electrophoretic mobility divide lipoproteins into four classes (Table 21-1). 

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]. 

To appreciate the metabohc role of plasma lipoprotein CE, it is important to realize that these esters are formed both within cells and in blood plasma, that two different cholesterol-esterifying mechanisms are involved, and that the formation... 

The esterification of cholesterol in animals has attracted considerable research because of the possible involvement of cholesterol and its ester in various disease states (cf. Glomset and Norum, 1973, and Sections 12.1, 12.3 and 12.6). Cholesterol esters are formed by the action of lecithin cholesterol acyltransferase (LCAT, EC 2.3.1.43) which is particularly active in plasma (cf. Sabine, 1977, for a review of cholesterol metabolism). The reaction involves transfer of a fatty acid from position 2 of lecithin (phosphatidylcholine) to the 3-hydroxyl group of cholesterol with the formation of monoacyl-phosphatidylcholine. Although LCAT esterifies plasma cholesterol solely at the interface of high-density lipoprotein and very-low-density lipoprotein, the cholesterol esters are transferred to other lipoproteins by a particular transport protein (CETP cholesteryl ester transfer protein). Cholesteryl esters, in contrast to free cholesterol, are taken up by cells mostly via specific receptor pathways (Brown et aL, 1981), are hydrolysed by lysosomal enzymes and eventually re-esterified and stored within cells. LCAT may also participate in the movement of cholesterol out of cells by esterifying excess cholesterol in the intravascular circulation (cf. Marcel, 1982). 

Phosphaddylchotine-slerol acyitransferase (EC 2.3.1.43). Plasma cholesterol and triacylglycerols increased. Lysophosphatidylcholine and cholesterol esters decreased. Turbid or milky plasma. Multiple lipoprotein abnormalities. Comeal opacities. Normochromic anemia and proteinuria, due to renal damage. Therapy by enzyme replacement. [The enzyme catalyses formation of cholesterol esters by tranter of an unsaturated fatty acid from position 2 of lecithin to the 3-OH of cholesterol]... 

One interesting property of FED plasma is its poor capacity to activate cholesterol esterification [6]. Specifically it will not activate the formation of cholesterol esters in HDL, but it will do so in other lipoproteins. FED plasma lacks, therefore, a-HDL lecithin cholesterol acyltransferase (LCAT), although p-LCAT is present in normal amounts. 

Ashidate K, Kawamura M, Mimura D, Tohda Fi, Miyazaki S, Teramoto T, Hirata Y, Yamamoto Y (2005) Gentisic acid, an aspirin metabolite, inhibits oxidation of low-density lipoprotein and the formation of cholesterol ester hydroperoxides in human plasma. Fur J Pharmacol 513 173... 

An enzyme which catalyses the formation of cholesterol esters by the transfer of fatty acids from lecithin to the cholesterol of plasma lipoproteins (especially high density lipoproteins). A rare inborn error occurs in which there is a deficiency of this enzyme. Patients with this condition have high plasma levels of un-esterified cholesterol. 

Lecithin cholesterol acyltransferase, LCAT, is the second enzyme of major importance in the enzymic phase of lipoprotein metabolism. Cholesteryl ester formation by this enzyme significantly changes the dynamics of the plasma cholesterol pool. Unlike the spontaneous rapid equilibration of cholesterol between lipoproteins. 

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. 

Third, acyl-CoA cholesterol acyltransferase (ACAT) [EC 2.3.1.26], an enzyme that works after the formation of cholesterol, was considered a unique target of inhibition [32], ACAT catalyzes the synthesis of cholesteiyl esters from cholesterol and long-chain fatty acyl-CoA. ACAT plays important roles in the body, for example, in the absorption of dietary cholesterol from the intestines, production of lipoprotein in liver and formation of foam cells from macrophages in arterial walls. Therefore, ACAT inhibition is expected not only to lower plasma cholesterol levels but also to have a direct effect at the arterial wall. A number of synthetic ACAT inhibitors such as ureas, imidazoles, and acyl amides have been developed [33], Several groups have searched for novel ACAT inhibitors... 

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. 

HDLs are secreted in nascent form by hepatocytes and en-terocytes (Figure 20-7). Loss of surface components, including phospholipids, free cholesterol, and protein from chylomicrons and VLDL as they are acted on by lipoprotein lipase, may also contribute to formation of HDL in plasma. Discoidal, nascent HDL is converted to spherical, mature HDL by acquiring free cholesterol from cell membranes or other lipoproteins. This function of HDL in peripheral cholesterol removal may underlie the strong inverse relationship between plasma HDL levels and incidence of coronary heart disease. After esterification of HDL surface cholesterol by LCAT, which is activated by apo A-I, HDL sequesters the cholesteryl ester in its hydrophobic core. This action increases the gradient of free cholesterol between the cellular plasma membrane and HDL particles. Cholesteryl esters are also transferred from HDL to VLDL and LDL via apo D, the cholesteryl ester transfer protein (Figure 20-8). 

This reaction is responsible for formation of most of the cholesteryl ester in plasma. The preferred substrate is phosphatidylcholine, which contains an unsaturated fatty acid residue on the 2-carbon of the glycerol moiety. HDL and LDL are the major sources of the phosphatidylcholine and cholesterol. Apo A-I, which is a part of HDL, is a powerful activator of LCAT. Apo C-I has also been implicated as an activator of this enzyme however, activation may depend on the nature of the phospholipid substrate. LCAT is synthesized in the liver. The plasma level of LCAT is higher in males than in females. The enzyme converts excess free cholesterol to cholesteryl ester with the simultaneous conversion of lecithin to lysolecithin. The products are subsequently removed from circulation. Thus, LCAT plays a significant role in the removal of cholesterol and lecithin from the circulation, similar to the role of lipoprotein lipase in the removal of triacylglycerol contained in chylomicrons and VLDL. Since LCAT regulates the levels of free cholesterol, cholesteryl esters, and phosphatidylcholine in plasma, it may play an important role in maintaining normal membrane structure and fluidity in peripheral tissue cells. 

The metabolism of HDL involves several different enzymes and transfer proteins but is not completely understood [7]. The major apolipoprotein of HDL is apoA-I. The liver and intestine are the sources of apoA-I, which interacts with peripheral cells to remove excess cellular cholesterol via the ATP-binding cassette protein A1 (ABCAl). Unesterified cholesterol associated with nascent HDL is a substrate for the plasma enzyme lecithin cholesterol acyltransferase (LCAT), resulting in the formation of cholesteryl ester and enlargement of the HDL particle. Genetic defects in apoA-I, ABCAl and LCAT can cause low levels of HDL, termed hypoalphalipopro-teinemia. HDL cholesteryl ester is transferred to apoB-containing lipoproteins (such as LDL) by the cholesteryl ester transfer protein (CETP) and can be returned to the liver via the LDL receptor. HDL may also deliver some cholesterol directly to the liver via the scavenger receptor class BI (SR-BI). The removal of excess cholesterol from peripheral cells and delivery to the liver for excretion in the bile is a process that has been termed reverse cholesterol transport . 

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