LCAT acyltransferase

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. 

HDL is synthesized and secreted from both liver and intestine (Figure 25—5). However, apo C and apo E are synthesized in the liver and transferred from fiver HDL to intestinal HDL when the latter enters the plasma. A major function of HDL is to act as a repository for the apo C and apo E required in the metabohsm of chylomicrons and VLDL. Nascent HDL consists of discoid phosphohpid bilayers containing apo A and free cholesterol. These hpoproteins are similar to the particles found in the plasma of patients with a deficiency of the plasma enzyme lecithimcholesterol acyltransferase (LCAT) and in the plasma of patients with obstructive jaundice. LCAT—and the LCAT activator apo A-I— bind to the disk, and the surface phosphohpid and free cholesterol are converted into cholesteryl esters and... 

Figure 25-5. Metabolism of high-density lipoprotein (HDL) in reverse cholesteroi transport. (LCAT, lecithinxholesterol acyltransferase C, cholesterol CE, cholesteryl ester PL, phospholipid A-l, apolipoprotein A-l SR-Bl, scavenger receptor B1 ABC-1, ATP binding cassette transporter 1.) Prep-HDL, HDLj, HDL3—see Table 25-1. Surplus surface constituents from the action of lipoprotein lipase on chylomicrons and VLDL are another source of preP-HDL. Hepatic lipase activity is increased by androgens and decreased by estrogens, which may account for higher concentrations of plasma HDLj in women.

Figure 26-5. Factors affecting cholesterol balance at the cellular level. Reverse cholesterol transport may be initiated by pre 3 HDL binding to the ABC-1 transporter protein via apo A-l. Cholesterol is then moved out of the cell via the transporter, lipidating the HDL, and the larger particles then dissociate from the ABC-1 molecule. (C, cholesterol CE, cholesteryl ester PL, phospholipid ACAT, acyl-CoA cholesterol acyltransferase LCAT, lecithinicholesterol acyltransferase A-l, apolipoprotein A-l LDL, low-density lipoprotein VLDL, very low density lipoprotein.) LDL and HDL are not shown to scale.

Familial lecithimcholesterol acyltransferase (LCAT) deficiency Absence of LCAT leads to block in reverse cholesterol transport. HDL remains as nascent disks incapable of taking up and esterifying cholesterol. Plasma concentrations of cholesteryl esters and lysolecithin are low. Present is an abnormal LDL fraction, lipoprotein X, found also in patients with cholestasis. VLDL is abnormal ( 3-VLDL). 

FIGURE 9. Endogenous lipoprotein metabolism. In liver cells, cholesterol and triglycerides are packaged into VLDL particles and exported into blood where VLDL is converted to IDL. Intermediate-density lipoprotein can be either cleared by hepatic LDL receptors or further metabolized to LDL. LDL can be cleared by hepatic LDL receptors or can enter the arterial wall, contributing to atherosclerosis. Acetyl CoA, acetyl coenzyme A Apo, apolipoprotein C, cholesterol CE, cholesterol ester FA, fatty acid HL, hepatic lipase HMG CoA, 3-hydroxy-3-methyglutaryl coenzyme A IDL, intermediate-density lipoprotein LCAT, lecithin-cholesterol acyltransferase LDL, low-density lipoprotein LPL, lipoprotein lipase VLDL, very low-density lipoprotein. 

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). 

LCAT, lecithin cholesterol acyltransferase CETP, cholesterol ester transfer protein SR-61, scavenger receptor-BI... 

ICAT (or PCAT, phosphatidylcholine-cholesterol acyltransferase) is an enzyme in the blood that is activated by apoA-1 on HDL. LCAT adds a fatty add to cholesterol, producing cholesterol esters, which dissolve in the core of the HDL, allowing HDL to transport cholesterol from the periphery to the liver. This process of reverse cholesterol transport is shown in Figure 1-15-7. 

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) ... 

Rare genetic disorders, including Tangier disease and LCAT (lecithin cholesterol acyltransferase) deficiency, are associated with extremely low levels of HDL. Familial hypoalphalipoproteinemia is a more common disorder with levels of HDL cholesterol usually below 35 mg/dL in men and 45 mg/dL in women. These patients tend to have premature atherosclerosis, and the low HDL may be the only identified risk factor. Management should include special attention to avoidance or treatment of other risk factors. Niacin increases HDL in many of these patients. Reductase inhibitors and fibric acid derivatives exert lesser effects. 

Fig. 5.2.1 The major metabolic pathways of the lipoprotein metabolism are shown. Chylomicrons (Chylo) are secreted from the intestine and are metabolized by lipoprotein lipase (LPL) before the remnants are taken up by the liver. The liver secretes very-low-density lipoproteins (VLDL) to distribute lipids to the periphery. These VLDL are hydrolyzed by LPL and hepatic lipase (HL) to result in intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL), respectively, which then is cleared from the blood by the LDL receptor (LDLR). The liver and the intestine secrete apolipoprotein AI, which forms pre-jS-high-density lipoproteins (pre-jl-HDL) in blood. These pre-/ -HDL accept phospholipids and cholesterol from hepatic and peripheral cells through the activity of the ATP binding cassette transporter Al. Subsequent cholesterol esterification by lecithinxholesterol acyltransferase (LCAT) and transfer of phospholipids by phospholipid transfer protein (PLTP) transform the nascent discoidal high-density lipoproteins (HDL disc) into a spherical particle and increase the size to HDL2. For the elimination of cholesterol from HDL, two possible pathways exist (1) direct hepatic uptake of lipids through scavenger receptor B1 (SR-BI) and HL, and (2) cholesteryl ester transfer protein (CfiTP)-mediated transfer of cholesterol-esters from HDL2 to chylomicrons, and VLDL and hepatic uptake of the lipids via the LDLR pathway...

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... 

Kuivenhoven JA, Pritchard H, Hill J, Frohlich J, Assmann G, Kastelein J (1997) The molecular pathology of lecith in cholesterol acyltransferase (LCAT) deficiency syndromes. J Lipid Res 38 191-205... 

Esterification of cholesterol When cholesterol is taken up by HDL, it is immediately esterified by the plasma enzyme phos-phatidylcholine cholesterol acyltransferase (PCAT, also known as LCAT, in which "L" stands for lecithin). This enzyme is synthesized by the liver. PCAT binds to nascent HDLs, and is activated by apo A-l. PCAT transfers the fatty acid from carbon 2 of phosphatidyl-... 

Figure 21-1 Movement of triacylglycerols from liver and intestine to body cells and lipid carriers of blood. VLDL very low density lipoprotein which contains triacylglycerols, phospholipids, cholesterol, and apolipoproteins B, and C. IDL intermediate density lipoproteins found in human plasma. LDL low density lipoproteins which have lost most of their triacylglycerols. ApoB-100, etc., are apolipoproteins listed in Table 21-2. LCAT, lecithin cholesterol acyltransferase CETP, cholesteryl ester transfer protein (see Chapter 22).

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... 

Unlike fatty acids, cholesterol is not degraded to yield energy. Instead excess cholesterol is removed from tissues by HDL for delivery to the liver from which it is excreted in the form of bile salts into the intestine. The transfer of cholesterol from extrahepatic tissues to the liver is called reverse cholesterol transport. When HDL is secreted into the plasma from the liver, it has a discoidal shape and is almost devoid of cholesteryl ester. These newly formed HDL particles are good acceptors for cholesterol in the plasma membranes of cells and are converted into spherical particles by the accumulation of cholesteryl ester. The cholesteryl ester is derived from a reaction between cholesterol and phosphatidylcholine on the surface of the HDL particle catalyzed by lecithimcholesterol acyltransferase (LCAT) (fig. 20.17). LCAT is associated with FIDL in plasma and is activated by apoprotein A-I, a component of HDL (see table 20.3). Associated with the LCAT-HDL complex is cholesteryl ester transfer protein, which catalyzes the transfer of cholesteryl esters from HDL to VLDL or LDL. In the steady state, cholesteryl esters that are synthesized by LCAT are transferred to LDL and VLDL and are catabolized as noted earlier. The HDL particles themselves turn over, but how they are degraded is not firmly established. 

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. 

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