Acyl-cholesterol acyltransferase

Although lanosterol may appear similar to cholesterol in structure, another 20 steps are required to convert lanosterol to cholesterol (Figure 25.35). The enzymes responsible for this are all associated with the endoplasmic reticulum. The primary pathway involves 7-dehydroeholesterol as the penultimate intermediate. An alternative pathway, also composed of many steps, produces the intermediate desmosterol. Reduction of the double bond at C-24 yields cholesterol. Cholesterol esters—a principal form of circulating cholesterol—are synthesized by acyl-CoA cholesterol acyltransferases (ACAT) on the cytoplasmic face of the endoplasmic reticulum. 

FIGURE 25.39 Endocytosis and degradation of lipoprotein particles. (ACAT is acyl-CoA cholesterol acyltransferase.)... 

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.

Cholesterol esters are produced by transferring an acyl moiety from acyl-CoA or from phosphatidylcholine onto the cholesterol hydroxyl group. The latter process is catalyzed by phosphatidylcholine cholesterol acyltransferase ... 

L. L. Gallo, S. B. Clark, S. Myers, G. V. Vahouny, Cholesterol Absorption in Rat Intestine Role of Cholesterol Esterase and Acyl Coenzyme A Cholesterol Acyltransferase , J. Lipid Res. 1984, 25, 604-612. 

T. F. Woolf, A. Black, Y. Y. Shum, W. Mcnally, H. Lee, T. Chang, BioDisposion Studies with the Acyl-Coenzyme-A-Cholesterol Acyltransferase Inhibitor 2,2-Dimethyl-V-(2,4,6-Trimethoxyphenyfidodecanamide, CI-976 , Drug Metab. Dispos. 1993, 21, 1112-1118. 

Puglielli, L., Konopka, G., Pack-Chung, E., Ingano, L.A., Berezovska, O., Hyman, B.T., Chang, T.Y., Tanzi, R.E., and Kovacs, D.M., Acyl-coenzyme A cholesterol acyltransferase modulates the generation of the amyloid beta-peptide, Nat. Cell Biol., 3, 905, 2001. 

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). 

ACAT Acyl-CoA cholesterol acyltransferase cAPK Protein kinase A (or cyclic AMP-... 

Cholesterol metabolism. Hydrogenated oil, administered orally to hamsters at a dose of 20% of diet for 4 weeks, induced hypercholesterolemia. Oil feeding had no effect on cholesterol synthesis but markedly inhibited cholesterol esterification in both the liver and the intestine. The diet-induced hypercholesterolemia was strongly correlated with an increase in acyl-CoA/cholesterol acyltransferase activity. The hypercholesterolemia increased aortic uptake of cholesterol and hence acyl-CoA/cholesterol acyltransferase activity " Coconut fat, administered orally to rabbits with partial ileal bypass, produced a significant increase of serum total cholesterol and phospholipids concentrations. The effect on semm lipids of the type of fat was similar in control and partial ileal bypass rabbits A Coconut—a main source of energy for two... 

Cellular uptake and degradation of LDL. AC AT acyl CoA cholesterol acyltransferase. 

Regulation of the LDL receptor gene involves a hormone-response element (HRE, see p. 238).] Third, if the cholesterol is not required immediately for some structural or synthetic purpose, it is esterified by acyl CoA cholesterol acyltransferase (ACAT, AC AT transfers a fatty acid from a fatty acyl CoA derivative to cholesterol, producing a cholesteryl ester that can be stored in the cell (Figure 18.21). The activity of ACAT is enhanced in the presence of increased intracellular cholesterol. 

VLDL in the plasma is converted to LDL—a much smaller, denser particle. Apo CM and apo E are returned to HDLs, but the LDL retains apo B-100, which is recognized by receptors on peripheral tissues and the liver. LDLs undergo receptor-mediated endocytosis, and their contents are degraded in the lysosomes. A deficiency of functional LDL receptors causes type II hyperlipidemia (familial hypercholesterolemia). The endocytosed cholesterol inhibits HMG CoA reductase and decreases synthesis of LDL receptors. Some of it can also be esterified by acyl CoAxholesterol acyltransferase and stored. 

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... 

Isochromophilones VII (190) and VIII (191) from a Penicillium sp. inhibit diacylglycerol acytransferase activity with IC5o values of 20.0 and 127 pM and acyl-CoA cholesterol acyltransferase activity with IC50 values of 24.5 and 47.0, respectively. They also show moderate antimicrobial activity [153]. 

Of the various lipid components of the lipoproteins, only the biosynthesis of cholesteryl esters has not yet been mentioned. Cholesteryl ester is the storage form of cholesterol in cells. It is synthesized from cholesterol and acyl-CoA by acyl-CoA cholesterol acyltransferase (ACAT) (fig. 20.13), which is located on the cytosolic surface of hepatic endoplasmic reticulum. Acylation of the 3 hydroxyl group of cholesterol eliminates the polarity of cholesterol and facilitates the packing of cholesterol as its ester in the core of the lipoprotein or for storage in lipid droplets within cells. 

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

Arai N, Shiomi K, Tomoda H, Tabata N, Yang DJ, Masuma R, Kawakubo T, Omura S (1995) Isochromophilones III VI, Inhibitors of Acyl-CoA Cholesterol Acyltransferase Produced by Penicillium multicolor FO-3216. J Antibiot 48 696... 

Intestinal acyl-CoA cholesterol acyltransferase (ACAT-2, also present in liver), which esterifies free cholesterol with palmitic or oleic acid, is another enzyme that was identified early on as a potential target to inhibit cholesterol absorption because most cholesterol in chylomicrons is esterified before being secreted by enterocytes (6, 14). As for CEL, various inhibitors of this enzyme were also developed and tested with mixed results (10, 15-17). However, the importance of ACAT-2 was later confirmed by studies of gene-knockout mice, which exhibit markedly reduced cholesterol absorption and atherosclerosis when fed Western diet (18). Nonetheless, progress in developing effective ACAT inhibitors has been slow, in part because of concerns about the potential for deleterious systemic effects resulting from inhibition of the more widely expressed ACAT-1 (19). Despite these... 

Clark, S. B. and Tercyak, A. M. (1984) Reduced cholesterol transmucosal transport in rats with inhibited mucosal acyl CoAxholesterol acyltransferase and normal pancreatic function. J. Lipid Res. 25, 148-159. 

Tomoda, H. Kim, Y. K. Nishida, H. Musuma, R. Omura, S. 1994. Pyripy-ropenes, novel inhibitors of acyl-CoA Cholesterol acyltransferase produced by Aspergillus fumigatus. I. Production, isolation, and biological properties. /. Antibiotics, 47,148-153. 

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... 

Figure 7 Process of lipid droplet formation in macrophages and inhibition sites of inhibitors. ACAT (acyl-CoA cholesterol acyltransferase) and ACS (acyl-CoA synthetase).

H Tomoda, H Nishida, YK Kim, R Obata, T Sunazuka, S Omura, J Bordner, M Guadllana, PG Dormer, AB Smith III. Relative and absolute stereochemistry of pyripyropene A, a potent, bioavailable inhibitor of acyl-CoA cholesterol acyltransferase. J Am Chem Soc 116 12097-12098, 1994. 

H Tomoda, H Nishida, R Masuma, J Cao, S Okuda, S Omura. Purpactins, new inhibitors of acyl-CoA cholesterol acyltransferase produced by Penicilliumpurpur-ogenum. I. Production, isolation and physico-chemical and biological properties. J Antibiot 44 136-143, 1991. 

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