Esters cholesteryl, synthesis

Lipemic activity. Cigarette smoke extract, in macrophages with LDL culture at a dose of 100 Xg/mL, stimulated cholesteryl oleate synthesis approximately equal to 12.5-fold. Enhancement in cholesteryl ester synthesis was dependent on the concentration of smoke-modified LDL and exhibited saturation kinetics. There was extensive fragmentation of apo B. This LDL modification depended on the incubation time and concentration of the smoke extract. Superoxide dismutase inhibited LDL modification by 52%, suggesting that superoxide anion is involved. The results indicated that smoke extract alters LDL into a form recognized and incorporated by macrophages . En-... 

Cholesterol and cholesteryl ester synthesis acetyl-CoA----> cholesterol----> cholesteryl esters... 

Biosynthesis of cholesteryl esters. The acyl-CoA cholesterol acyltransferase involved in cholesteryl ester synthesis is located on the cytosolic surface of liver endoplasmic reticulum. 

Yotsumoto, H., Yanagita, T., Yamamoto, K., Ogawa, Y., Cha, J.Y., and Mori, Y. 1997. Inhibitory effects of oren-gedoku-toand its components on cholesteryl ester synthesis in cultured human hepatocyte HepG2 cells evidence from the cultured HepG2 cells and in vitro assay of ACAT. Planta Med. 63, 141-145. 

Mahley, R. W., Innerarity, T. L., Brown, M. S., Ho, W. K., and Goldstein, J. L., 1980, Cholesteryl ester synthesis in macrophages Stimulation by P-very low density lipoproteins from cholesterol-fed animals of several species, /. Lipid Res. 21 970. 

LDL (apo B-lOO, E) receptors occur on the cell surface in pits that are coated on the cytosolic side of the cell membrane with a protein called clathrin. The glycoprotein receptor spans the membrane, the B-lOO binding region being at the exposed amino terminal end. After binding, LDL is taken up intact by endocytosis. The apoprotein and cholesteryl ester are then hydrolyzed in the lysosomes, and cholesterol is translocated into the cell. The receptors are recycled to the cell surface. This influx of cholesterol inhibits in a coordinated manner HMG-CoA synthase, HMG-CoA reductase, and, therefore, cholesterol synthesis stimulates ACAT activ-... 

Chatterjee, S., 1994, Neutral sphingomyehnase achon stimulates signal transduction of tumor necrosis factor-alpha in the synthesis of cholesteryl esters in human fibroblasts. /. Biol. Chem. 269 879-882... 

One role of high density lipoprotein (HDL) is to collect unesterified cholesterol from cells, including endothelial cells of the artery walls, and return it to the liver where it can not only inhibit cholesterol synthesis but also provide the precursor for bile acid formation. The process is known as reverse cholesterol transfer and its overall effect is to lower the amount of cholesterol in cells and in the blood. Even an excessive intracellular level of cholesterol can be lowered by this reverse transfer process (Figure 22.10). Unfortunately, the level of HDL in the subendothelial space of the arteries is very low, so that this safety valve is not available and all the cholesterol in this space is taken up by the macrophage to form cholesteryl ester. This is then locked within the macrophage (i.e. not available to HDL) and causes damage and then death of the cells, as described above. 

LDL is catabolized chiefly in hepatocytes and other cells by receptor-mediated endocytosis. Cholesteryl esters from LDL are hydrolyzed, yielding free cholesterol for the synthesis of cell membranes. Cells also obtain cholesterol by synthesis via a pathway involving the formation of mevalonic acid by HMG-CoA reductase. Production of this enzyme and of LDL receptors is transcriptionally regulated by the content of cholesterol in the cell. Normally, about 70% of LDL is removed from plasma by hepatocytes. Even more cholesterol is delivered to the liver via IDL and chylomicrons. Unlike other cells,... 

LCAT catalyzes the transfer of a preferentially unesterified fatty acid from the sn-2 position of phosphatidylcholine to the 3/i-hydroxy group of cholesterol, and thereby produces lysophosphatidylcholine and a cholesteryl ester [50]. Depending on the mutation in the LCAT gene, homozygous or compound heterozygous patients present with one of two clinical phenotypes, classical LCAT deficiency or fish-eye disease [58, 85]. Classical LCAT deficiency is caused by a broad spectrum of missense and non-sense mutations that interfere with the synthesis or secretion or affect the catalytic activity of LCAT [10]. Fish-eye disease is caused by a limited number of missense point mutations that alter the surface polarity, and thereby interfere with the binding of the enzyme to apoA-I containing lipoproteins [77]). 

FIGURE 21-38 Synthesis of cholesteryl esters. Esterification converts cholesterol to an even more hydrophobic form for storage and transport. 

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. 

Postulated scheme for the synthesis, assembly, and secretion of VLDL by a hepatocyte (liver cell). (1) Synthesis The apoproteins, phospholipid, triacylglycerol, cholesterol, and cholesteryl esters are synthesized in the endoplasmic reticulum. (2) Assembly These components are assembled into a prelipoprotein particle in the lumen of the endoplasmic reticulum. (3) Processing The particle moves to the Golgi apparatus, where modification of the apoproteins occurs. 

Paulsen, H., Antons, S., Brandes, A., et al. (1999) Stereoselective Mukaiyama-Michael/Michael/Aldol domino cyclization as the key step in the synthesis of penta-substituted arenes an efficient access to highly active inhibitors of cholesteryl ester transfer protein (CETP). Angew. Chem. Int. Ed. 38, 3373-3375. 

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 properties of 7a-hydroxylase from pigeon liver microsomes305 and from rat liver306,307 have been further described, and new assay methods are available.308,309 Free cholesterol, rather than a cholesteryl ester, was the preferred substrate for the enzyme from rat liver microsomes,310 and the substrate pool for the hydroxylase was about one third of the total amount of cholesterol present in the microsomal preparation.309 Cholesterol 7a-hydroxylase activity is more sensitive to thyroid function than are the activities of the enzymes responsible for cholesterol synthesis,311 and (22f )-22-aminocholesterol, although having no effect on serum or liver cholesterol levels in rats, drastically reduced 7a-hydroxylase activity.312... 

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. 

ACAT transfers amino-acyl groups from one molecule to another. ACAT is an important enzyme in bile acid synthesis, and catalyses the intracellular esterification of cholesterol and formation of cholesteryl esters. ACAT-mediated esterification of cholesterol limits its solubility in the cell membrane and thus promotes accumulation of cholesterol ester in the fat droplets within the cytoplasm this process is important in preventing the toxic accumulation of free cholesterol that would otherwise damage ceU-membrane structure and function. Most of the cholesterol absorbed during intestinal transport undergoes ACAT-mediated esterification before incorporation into chylomicrons. In the liver, ACAT-mediated esterification of cholesterol is involved in the production and release of apo-B-containing lipoproteins. 

---