Cholesteryl ester transferase

Cholesteryl ester transferase Marker Statins Atherosclerosis Efficacy... 

Much of the cholesterol synthesis in vertebrates takes place in the liver. A small fraction of the cholesterol made there is incorporated into the membranes of he-patocytes, but most of it is exported in one of three forms biliary cholesterol, bile acids, or cholesteryl esters. Bile acids and their salts are relatively hydrophilic cholesterol derivatives that are synthesized in the liver and aid in lipid digestion (see Fig. 17-1). Cholesteryl esters are formed in the liver through the action of acyl-CoA-cholesterol acyl transferase (ACAT). This enzyme catalyzes the transfer of a fatty acid from coenzyme A to the hydroxyl group of cholesterol (Fig. 21-38), converting the cholesterol to a more hydrophobic form. Cholesteryl esters are transported in secreted lipoprotein particles to other tissues that use cholesterol, or they are stored in the liver. 

The fourth major lipoprotein type, high-density lipoprotein (HDL), originates in the liver and small intestine as small, protein-rich particles that contain relatively little cholesterol and no cholesteryl esters (Fig. 21-40). HDLs contain apoA-I, apoC-I, apoC-II, and other apolipoproteins (Table 21-3), as well as the enzyme lecithin-cholesterol acyl transferase (LCAT), which catalyzes the formation of cholesteryl esters from lecithin (phosphatidylcholine) and cholesterol (Fig. 21-41). LCAT on the surface of nascent (newly forming) HDL particles converts the cholesterol and phosphatidylcholine of chylomicron and VLDL remnants to cholesteryl esters, which begin to form a core, transforming the disk-shaped nascent HDL to a mature, spherical HDL particle. This cholesterol-rich lipoprotein then returns to the liver, where the cholesterol is unloaded some of this cholesterol is converted to bile salts. 

FIGURE 21-41 Reaction catalyzed by lecithin-cholesterol acyl transferase (LCAT). This enzyme is present on the surface of HDL and is stimulated by the HDL component apoA-I. Cholesteryl esters accumulate within nascent HDLs, converting them to mature HDLs. 

Cholesteryl esters that are internalized via the LDL receptor are hydrolyzed to produce cholesterol and an acyl chain. Cholesterol, in (urn, activates the enzyme acyl-CoA cholesterol acyl-transferase (ACAT) which re-esterifies cholesterol. In an apparently futile cycle, the cholesteryl esters are hydrolyzed by cholesteryl ester hydrolase. The cholesterol moiety has several fates it may leave the cell and bind to an acceptor such as high-density lipoprotein (HDL), it may be converted to steroid hormones, or it may be reesterified by ACAT. When the cellular cholesterol concentration falls, the activity of HMG-CoA reductase is increased, as is the number of LDL receptors, which results in an increase of cellular cholesterol, due both to de novo synthesis and to the uptake of cholesterol-rich lipoproteins in the circulation. An increase in cellular cholesterol results in the rapid decline in the mRNA levels for both HMG-CoA reductase and the LDL receptor. This coordinated regulation is brought about by the presence of an eight nucleotide sequence on the genes which code for both proteins this is termed the sterol regulatory element-1. 

The level of intracellular cholesterol is regulated through cholesterol-induced suppression of LDL-receptor synthesis and cholesterol-induced inhibition of cholesterol synthesis. The increased level of intracellular cholesterol that results from LDL uptake has the additional effect of activating acyl-CoA cholesteryl acyl transferase (ACAT) (see below), thereby allowing the storage of excess cholesterol within cells. However, the effect of cholesterol-induced suppression of LDL-receptor synthesis is a decrease in the rate at which LDLs and IDLs are removed from the serum. This can lead to excess circulating levels of cholesterol and cholesteryl esters when the dietary intake of fat and cholesterol is excessive. Excess cholesterol tends to be deposited in the skin and tendons and within the arteries, which can lead to atherosclerosis. 

I he average daily intake of total dietary cholesterol is 400-500 mg. Cholesterol also enters the gastrointestinal tract via the bile. Between fiOO and 1200 mg of free cholesterol is secreted in the bile per day. By weight, bile consists of 92% water, 6% bile salts, 0,3% cholesterol, and small amounts of bilirubin, fatty acids, phosphatidylcholine, and sails. The cholesteryl esters of the diet are hydmlyzed to free cholesterol and a fatty add by pancreatic cholesterol esterase. After entry into the enterocyte, the free cholesterol is nmverted back to cholesteryl esters by acyl CoA cholesterol acyl transferase. Some evidence suggests that the absorption of dietary cholesterol (from the bile salt micelles) is mediated by a membrane-bound transport protein of the brush border (1 humhofer and Hauser, 1990),... 

In the liver, cholesterol has three major fates conversion to bile acids, secretion into the blocKlstream (packaged in lipoproteins), and insertion into the plasma membrane. Conversion of cholesterol to cholic acid, one of the bile acids, requires about 10 enzymes. The rate of bile synthesis is regulated by the first enzyme of the pathway, cholesterol la-hydioxylase, one of the cytochrome P450 enzymes (see the section on Iron in Chapter 10), Cholesterol, mainly in the form of cholesteryl esters, is exported to other organs, after packaging in particles called very-low-density lipoproteins. Synthesis of cholesteryl esters is catalyzed by acyl CoA cho-Jesteroi acy(transferase, a membranc bound enzyme of the ER, Free cholesterol is used in membrane synthesis, where it appears as part of the walls of vesicles in the cytoplasm. These vesicles travel to the plasma membrane, where subsequent fusion results in incorporation of their cholesterol and phospholipids into the plasma membrane. 

An increase in 18 1 in liver cells results in an increased availability of this fatty acid to acyl-CoAicholestero acyl transferase (ACAT). ACAT is the enzyme that catalyzes the attachment of free fatty acids to cholesterol, creating cholesteryl esters. 

FIGURE 9.1 Simplified overview of lipid and lipoprotein metabolism with some key enzymes numbered (1) cholesteryl ester transfer protein (CETP), (2) hepatic triglyceride lipase, (3) lecithin cholesterol acyl transferase (LCAT), and (4) lipoprotein lipase. 

Cholesterol is synthesised from glucose by the liver (Chapter 38). Some of the cholesterol is esterifled with fatty acids in a reaction catalysed by acyl CoA-cholesterol-acyl transferase (ACAT) to form cholesteryl ester (Fig. 39.2). This is hydrophobic and with its hydro-phobic associate, the triacylglycerols, is stored in the core of the nascent VLDL particles. The nascent VLDLs leave the Ever via the hepatic vein and progress to the periphery. In the peripheral capillaries, lipoprotein lipase removes much of the triacylglycerol content by... 

Dietary cholesterol is absorbed by intestinal ABC cholesterol transporter (Chapter 41). Once inside the cell, cholesterol is esterified by acyl CoA-cholesterol-acyl transferase (ACAT) to form the hydro-phobic cholesteryl ester. This reaction facilitates and maximises absorption of cholesterol, which is probably an advantage to people deprived of cholesterol-rich food such as meat. Unfortunately, efficient absorption of cholesterol is not an advantage to the affluent. However, margarines enriched with plant sterols have been used to inhibit cholesterol absorption in an attempt to lower blood cholesterol. Research is under way to develop ACAT inhibitors that potentially are cholesterol-lowering drugs. Ezetimibe is a new drug that inhibits cholesterol absorption by inhibition of the intestinal cholesterol-transporter protein NPCILI (Niemann-Pick Cl-like protein 1). 

More than 80% of the cholesteryl esters (CE) found in human plasma derive from the reaction of lecithin cholesterol acyl transferase (LCAT). Since the content of CE in plasma high positively correlates with the incidence of atherosclerosis and myocardial infarction, there has been in the past and still is great interest in investigation of the enzymes involved in lipoprotein metabolism. This overview summarizes some general features, with particular emphasis on investigations carried out in our laboratory (a) the substrates of LCAT in plasma (b), the influence of LCAT on the Upoprotein spectrum (c) the distribution of formed CE after the action of LCAT (d) the impact of cholesteryl ester transfer/exchange protein (CETP) on Upoprotein metabolism. 

S),25-epiminolanosterol (116) was a potent noncompetitive inhibitor (Kj = 3.0 nM) of the 5-adenosyl-L-methi(Miine-C-24 Me transferase from sunflower embryos [127]. Cholesteryl ester of l-aziridine acetic acid (117) showed excellent inhibition of a dimethyl-benzanthrene induced and transplantable mammary adenocarcinoma [128]. 

Acyl-CoA cholesterol acyl transferase (ACAT) catalyzes the intracellular formation of cholesteryl esters (CE) in all mammalian cells. It has been implicated as a key enzyme involved in cholesterol absorption, very low density lipoprotein secretion, and the formation of lipid-laden macrophages. The accumulation of CE in macrophage-derived foam cells is characteristic of the early step in the development of atherosclerosis. ACAT inhibitors reduced TC levels without affecting HDL-C. This can be attributed to decreased intestinal cholesterol absorption based on binding to bile acid (Turley SD. and Herndon MW. 1994)... 

Ezetimibe (Fig. 12.3) is a drug that works by reduction of blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. As indicated above, cholesterol in the body is derived from dietary sources or is synthesised in the body. Acyl Coenzyme A Cholesterol A Transferase (ACAT) is a membrane protein that catalyses the synthesis of cholesteryl esters from cholesterol. Inhibition of ACAT has therefore been... 

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