Lecithin-cholesterol acyltransferase LCAT

High-density lipoproteins (HDL) have much longer life spans in the body (5 to 6 days) than other lipoproteins. Newly formed HDL contains virtually no cholesterol ester. However, over time, cholesterol esters are accumulated through the action of lecithin cholesterol acyltransferase (LCAT), a 59-kD glycoprotein associated with HDLs. Another associated protein, cholesterol ester transfer protein, transfers some of these esters to VLDL and LDL. Alternatively, HDLs function to return cholesterol and cholesterol esters to the liver. This latter process apparently explains the correlation between high HDL levels and reduced risk of cardiovascular disease. (High LDL levels, on the other hand, are correlated with an increased risk of coronary artery and cardiovascular disease.)... 

Lysolecithin (lysophosphatidylcholine) may be formed by an alternative route that involves lecithin cholesterol acyltransferase (LCAT). This enzyme. 

ApoC-I is expressed mainly in liver but also in lung, skin, testis, spleen, neural retina, and RPE. Its multiple functions include the activation of lecithin cholesterol acyltransferase (LCAT) and the inhibition, among others, of lipoprotein and hepatic lipases that hydrolyze triglycerides in particle cores. Notably, both LCAT and lipoprotein lipases are expressed in RPE and choroid (Li et al., 2006). Moreover ApoC-I has been shown to displace ApoE on the VLDL and LDL and thus hinder their binding and uptake via their corresponding receptors (Li et al., 2006). 

Figure 11.15 The reaction catalysed by lecithin cholesterol acyltransferase (LCAT). LinoLeate is transferred from a phospholipid in the blood to cholesterol to form cholesteryl linoleate, catalysed by LCAT. The cholesterol ester forms the core of HDL, which transfers cholesterol to the liver. Discoidal HDL (i.e. HDL3) is secreted by the liver and collects cholesterol from the peripheral tissues, especially endothellial cells (see Figure 22.10). Cholesterol is then esterified with lin-oleic acid and HDL changes its structure (HDL2) to a more stable form as shown in the lower part of the figure. R is linoleate.

The HDLs also originate in the liver. They return the excess cholesterol formed in the tissues to the liver. While it is being transported, cholesterol is acylated by lecithin cholesterol acyltransferase (LCAT). The cholesterol esters formed are no longer amphipathic and can be transported in the core of the lipoproteins. In addition, HDLs promote chylomicron and VLDL turnover by exchanging lipids and apoproteins with them (see above). 

Phosphatidylcholine-sterol acyltransferase— lecithin-cholesterol acyltransferase (LCAT) ... 

Dobiasova M, Frohlich JJ (1998) Assays of lecithin cholesterol acyltransferase (LCAT) Methods Mol Biol 110 217-230... 

Funke H, Eckardstein A von, Pritchard PH, Albers JJ, Kastelein JJ, Droste C, Assmann G (1991) A molecular defect causing fish eye disease an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity. Proc Natl Acad Sci U S A 88 4855-4859... 

Liver and some intestinal cells export cholesterol into the bloodstream, together with triacylglycerols and phospholipids in the form of VLDL particles, for uptake by other tissues (see Fig. 21-1). Cholesteryl esters are formed in the ER by lecithin cholesterol acyltransferase (LCAT), an enzyme that transfers the central acyl group from phosphatidylcholine to the hydroxyl group of cholesterol.191 1913 This enzyme is also secreted by the liver and acts on free cholesterol in lipoproteins.192 Tissue acyltransferases also form cholesteryl esters from fatty acyl-CoAs.192a... 

Reaction catalyzed by lecithin cholesterol acyltransferase (LCAT). The resulting cholesteryl ester is transferred to VLDL and LDL particles by a lipid transfer protein. 

The apoproteins of HDL are secreted by the liver and intestine. Much of the lipid comes from the surface monolayers of chylomicrons and VLDL during lipolysis. HDL also acquire cholesterol from peripheral tissues in a pathway that protects the cholesterol homeostasis of cells. In this process, free cholesterol is transported from the cell membrane by a transporter protein, ABCA1, acquired by a small particle termed prebeta-1 HDL, and then esterified by lecithin cholesterol acyltransferase (LCAT), leading to the formation of larger HDL species. The cholesteryl esters are transferred to VLDL, IDL, LDL, and chylomicron remnants with the aid of cholesteryl ester transfer protein (CETP). Much of the cholesteryl ester thus transferred is ultimately delivered to the liver by endocytosis of the acceptor lipoproteins. HDL can also deliver cholesteryl esters directly to the liver via a docking receptor (scavenger receptor, SR-BI) that does not endocytose the lipoproteins. 

Once associated with HDL, FC is converted to CE by the action of lecithin-cholesterol acyltransferase (LCAT), which resides on the surface of HDL. This conversion creates a concentration gradient for the further uptake of FC. The newly formed CE enters the core of the HDL because of its highly hydrophobic nature. This process transforms nascent disk-shaped HDL into mature spherical HDL (HDL3). 

Hyperlipidemia (mainly hypercholesterolemia) is a regular part of nephrotic syndrome (K13, W6). Serum levels of cholesterol are often markedly elevated, usually above 10 mmol/L. However, in severely malnourished patients, normal or even decreased serum cholesterol level can be found. Serum levels of triacylglyc-erols fluctuate, from normal values to markedly elevated values (mainly in patients with proteinuria higher than 10 g/24 hr). There is a variable increase in plasma concentrations of very low density lipoproteins (VLDL, they correlate negatively with serum albumin level), intermediate-density lipoproteins (IDL), andLDL however, plasma concentrations of HDL are usually normal (J3). Levels of lipoprotein(a) [Lp(a)j are also increased (W4). Remission of nephrotic syndrome or decrease of proteinuria may result in the decrease of plasma concentrations of Lp(a) (G2). Concentration of free fatty acids in serum is commonly decreased because they are normally bound to albumin and albumin is lost into the urine. The activity of lecithin cholesterol acyltransferase (LCAT) is usually decreased. 

C14. Chung, J., Abano, D., Fless, G., and Scanu, A. M., Purification and properties of lecithin cholesterol acyltransferase (LCAT) from human sera. Circulation 56 (Suppl. Ill), 185 (1977). 

A few words about HDL these lipoproteins are synthesized largely by the liver. They act as ApoE, ApoC, and ApoA traffickers, but in addition, they also serve as a factory for the synthesis of cholesterol esters. HDL may absorb free cholesterol from various peripheral tissues, including arteries. Cholesterol is then converted to a large extent to fatty acyl esters by the action of the enzyme lecithin-cholesterol acyltransferase [LCAT see Equation 19.2)]. LCAT is activated by ApoA-I. Inactive LCAT is a plasma component. 

HDLs gradually accumulate cholesteryl esters, converting nascent HDLs to HDL2 and HDL3. Any free cholesterol present in chylomicron remnants and VLDL remnants (IDLs) can be esterifled through the action of the HDL-associated enzyme, lecithin cholesterol acyltransferase (LCAT). LCAT is synthesised in the liver and so named because it transfers a fatty acid from the C-2 position of lecithin to the C-3-OH of cholesterol, generating a cholesteryl ester and lysolecithin. The activity of LCAT requires interaction with apo-A-I, which is found on the surface of HDLs. 

The liver synthesizes two enzymes involved in intra-plasmic lipid metabolism hepatic triglyceride lipase (HTL) and lecithin-cholesterol-acyltransferase (LCAT). The liver is further involved in the modification of circulatory lipoproteins as the site of synthesis for cholesterol-ester transfer protein (CETP). Free fatty acids are in general potentially toxic to the liver cell. Therefore they are immobilized by being bound to the intrinsic hepatic fatty acid-binding protein (hFABP) in the cytosol. The activity of this protein is stimulated by oestrogens and inhibited by testosterone. Peripheral lipoprotein lipase (LPL), which is required for the regulation of lipid metabolism, is synthesized in the endothelial cells (mainly in the fatty tissue and musculature). 

Kuivenhoven, J., Pritchard, H., Hill, J-, Frohlich, J., Assman, G.,and Kastelein, J. (1997). The molecular pathology of lecithin Cholesterol acyltransferase (LCAT) deficiency syndromes. J. Lipid Res. 38,191-205. 

There are currently no published data regarding EL mass or activity levels in human plasma. Indeed, there has been relatively little study of phosphohpase activity in human plasma. Phospholipase activity increases after administration of heparin [24]. Some of the phospholipase activity in human plasma [25] has been attributed to lecithin-cholesterol acyltransferase (LCAT) [26] and hepatic lipase [27]. In the presence of inflammation, the secretory phospholipase A2 (sPLA2) may account for some of the plasma phosphohpase achvity and is also increased after heparin administration [28]. The contribuhon of endofhehal hpase to plasma phospholipase activity is unknown, but fhe decrease in post-heparin phosphohpase activity in EL knockout mice suggests that EL may contribute substantiaUy to plasma phosphohpase activity in humans. 

Apolipoprotein A-I (ApoA-I) ApoA-I is the major protein component of HDL in plasma. The protein helps to clear cholesterol from arteries and promotes cholesterol efflux form tissues to the liver for excretion. It is a cofactor for lecithin cholesterol acyltransferase (LCAT), which is responsible for the formation of most plasma cholesteryl esters. 

Lipoproteins are often called pseudomicellar because their outer shell is in part composed of amphipathic phospholipid molecules. Unlike simple micelles, lipoproteins contain apolipoproteins, or apoproteins, in their outer shell and a hydrophobic core of triacylglycerol and cholesteryl esters. Unesterified, or free, cholesterol, which contains a polar group, can be found as a surface component and in the region between the core and surface (Figure 20-1). Most lipoproteins are spherical. However, newly secreted high-density lipoproteins (HDLs) from the liver or intestine are discoidal and require the action of lecithin-cholesterol acyltransferase (LCAT) in plasma to expand their core of neutral lipid and become spherical. The hydrophobic core of the low-density lipoprotein (LDL) molecule may contain two concentric layers one of triacylglycerol and another of cholesteryl ester. 

HDL High-density lipoprotein synthesized in the liver, the HDL serves as a source of apoUpoproteins for other lipoproteins, as the site of action for the conversion of cholesterol to cholesterol ester in the plasma by the enzyme lecithin-cholesterol acyltransferase (LCAT), and delivers cholesterol esters derived from peripheral membranes to the liver. It is commonly called the good cholesterol. ... 

Reaction Catalyzed by Lecithin Cholesterol Acyltransferase (LCAT). 

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