Cholesteryl ester hydrolase

S. Wee, W. M. Grogan, Testicular Temperature-Labile Cholesteryl Ester Hydrolase , J. Biol. Chem. 1993, 268, 8158-8163. 

This is a broad class of enzymes that catalyze the hydrolysis of esters some of these enzymes are quite specific. See also Cholesteryl Ester Hydrolase specific esterase... 

CHOLESTERYL ESTER HYDROLASE OHOLINE AOETYLTRANSFERASE OHOLINE DEHYDROGENASE OHOLINE KINASE OHOLINE OXIDASE Oholine phosphatase,... 

CHOLESTERYL ESTER HYDROLASE ESTER HYDROLYSIS MECHANISMS ETA (7,)... 

Krause, B. R., Sliskovic, D. R., Anderson, M., and Homan, R. (1998) Lipid-lowering effects ofWAY-121,898, an inhibitor of pancreatic cholesteryl ester hydrolase. Lipids 33, 489-498. 

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. 

Defect in lysosomal cholesteryl ester hydrolase affects metabolism of LDLs... 

R.A. Anderson and G.N. Sando, Cloning and expression of cDNA encoding human lysosomal acid lipase/cholesteryl-ester hydrolase. Similarities to gastric and lingual lipases, J. Biol. Chem., 1991, 266, 22479-22484. 

Modified LDL taken up by the cell are delivered to the endolysosome pathway, where enzymes hydrolyze cholesteryl esters to free cholesterol and fatty acids. The levels of free cholesterol and cholesteryl esters are regulated with the help of neutral cholesteryl ester hydrolase, which converts cholesteryl ester to free cholesterol. After cholesterol leaves the lysosome, it is transported to the ER and to the plasma membrane by means of an intermediate step through the Golgi apparatus. Recycling compartments, especially multivesicular endosomes, harbor most of the cholesterol in the endocytic pathway. The intra-endosomal membranes of multivesicular late endosomes that are enriched in the phospholipids lyso-bisphosphatidic acid/bismonoacylglycerophosphate serve as important regulators of cholesterol transport (Kobayashi et al. 1999 Ikonen 2008). Lysobisphosphatidic acid is structurally... 

The initial steps of reverse cholesterol transport involve export of cholesterol from peripheral cells to plasma lipoproteins for subsequent delivery to the liver. In vivo, HDL or its apolipoproteins act as acceptors of cholesterol from peripheral cells, carrying it to the liver for degradation. When cholesterol acceptors such as HDL are present, cholesterol efflux from macrophages is accelerated, which prevents foam cell formation. To produce this efflux, neutral cholesteryl ester hydrolase catalyzes intracellular hydrolysis of cholesteryl esters into free cholesterol in the lysosome (Avart et al. 1999). 

Prophospholipase, activated to phospholipase Cholesteryl ester hydrolase Lipase and procolipase, converted to colipase Amylase Ribonuclease Deoxyribonuclease... 

However, in addition to this receptor-mediated LDL uptake, cells can also internalize LDL by a bulk-phase pinocytosis which does not require specific cell-surface binding. In this situation LDL is taken up at a rate proportional to the environmental concentration. At low extracellular LDL concentrations the bulk process is insignificant when compared to the receptor mediated uptake. However at elevated LDL concentrations although receptor-mediated uptake becomes rapidly saturated, bulk phase pinocytosis increases in rate proportionately to the overall LDL concentration. The smooth muscle cells in the normal atherosclerotic lesion accumulate lipid by this receptor-independent process which is not subject to feedback control. In addition to this a relative deficiency of lysosomal cholesteryl ester hydrolase activity in the presence of overwhelming concentrations of substrate may also contribute to the aggrevated situation. 

The anatomic sites (subcellularly) and the details of the enzymatic processes involved in the hydrolysis of chylomicron cholesteryl esters newly taken up by the liver have not been fully defined. It is clear that one of the major processes consists of receptor-mediated endocytosis of chylomicron remnants, followed by hydrolysis of cholesteryl esters and other remnant components within lysosomes. In rare genetic diseases characterized by lysosomal acid lipase deficiency (Wol-man s disease and cholesteryl ester storage disease), cholesteryl esters accumulate in liver cells and in other tissues as well [see Assmann and Frederickson (1983) for review and references]. An acid cholesteryl ester hydrolase from rat liver lysosomes has been partially purified and characterized (Brown and Sgoutas, 1980 Van Berkel etal., 1980). Enzymatic activity was found in preparations of both parenchymal and nonparenchymal liver cells (Van Berkel et al., 1980). Hydrolysis of chylomicron cholesteryl esters taken up by isolated rat hepatocytes was inhibited by chloroquine (Florin and Nilsson, 1977), an agent which inhibits the action of acid hydrolases in lysosomes. Finally, there is also evidence that the rate of cholesteryl ester hydrolysis may be limited by the rate at which internalized remnant particles are moved to the presumably lysosomal site of hydrolysis (Nilsson, 1977 Florin and Nilsson, 1977 Cooper and Yu, 1978). 

On the other hand, there are other processes that may participate as well, to some extent, in the initial metabolism and hydrolysis of chylomicron cholesteryl esters in the liver. Liver homogenates and homogenate fractions display cholesteryl ester hydrolase activity at neutral pH, and the enzyme(s) responsible for such activity have been partially purified and characterized (Deykin and Goodman, 1962 Stein et al., 1969 Tuhackova et al., 1980). It is possible that some uptake of cholesteryl esters can occur without uptake of the entire remnant particle [see, e.g., Chajek-Shaul et al. (I981a,b) for such evidence in other tissues]. It is also possible that dissociation of the constituents of the remnant can occur to some extent, permitting cholesteryl ester hydrolysis to take place before remnants are delivered to lysosomes. The extent to which these alternative processes might occur in normal physiology is not known. 

Preliminary experiments were conducted to see if cyclic AMP-mediated protein phosphorylation mechanisms might be involved in the variation (and regulation) of enzyme activity, as had been reported for lipase and cholesteryl ester hydrolase in other tissues (Khoo et al., 1976 Pittman-and Steinberg, 1977). These experiments did not provide evidence for the involvement of such mechanisms in the observed interanimal variation of RPH activity. This variation, additionally, was not related to the age of the animals, time of day of death, order of animal kill, or strain of rat. At present, an explanation for the observed... 

Further reading Fredrickson, D.S. and Ferrans, V.J. (1978). Acid cholesteryl ester hydrolase deficiency. (Wolman s disease and cholesteryl ester storage disease). In Stanbury, J.B., Wyngaarden, J.B. and Fredrickson, D.S. (eds.) The Metabolic Basis of Inherited Disease. 4th Edn., p. 670. (New York McGraw-Hill)... 

Gad MZ, Harrison EH (1991) Neutral and acid retinyl ester hydrolases associated with rat liver microsomes relationships to microsomal cholesteryl ester hydrolases. J Lipid Res 32 685-694... 

Phospholipase A2 (section 7.2) hydrolyses the fatty acid in position 2 of phospholipids, the most abundant being phosphatidylcholine. The enzyme is present as an inactive proenzyme in pancreatic juice and is activated by the tryptic hydrolysis of a heptapeptide from the N-terminus. The major digestion products that accumulate in intestinal contents are lysophospholipids. Any cholesteryl ester entering the small intestine is hydrolysed by a pancreatic cholesteryl ester hydrolase. 

Inside the cell, cholesteryl esters are hydrolysed by cholesteryl ester hydrolase. Incorporation of cholesterol into the endoplasmic reticulum membranes serves to inhibit hydroxymethylglutaryl-CoA reductase, the rate limiting enzyme in cholesterol biosynthesis (section 7.5). Thereby, an abundant supply of cholesterol in the plasma is able to suppress its own endogenous biosynthesis and ensure that excessive amounts do not accumulate. The importance of this pathway for cholesterol homeostasis... 

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