Phosphatidylcholine cholesterol acyltransferase

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 ... 

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. 

Phosphatidylcholine-sterol acyltransferase— lecithin-cholesterol acyltransferase (LCAT) ... 

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... 

M32. Matz, C. E., and Jonas, A., Reaction of human lecithin cholesterol acyltransferase with synthetic micellar complexes of apolipoprotein A-I, phosphatidylcholine and cholesterol. ]. Biol. Chem. 257, 4541-4546 (1982). 

Cholesterylesters arise from the activity of acyl-CoA cholesterol acyltransferase, which catalyzes the formation of the esters from acyl-CoA, and also from the activity of lecithin cholesterol acyltransferase, which catalyzes the formation of the ester from phosphatidylcholine. 

Lecithin-cholesterol acyltransferase is a water-soluble plasma enzyme that plays an important role in the metabolism of HDLs by catalyzing the formation of cholesteryl esters on HDLs through the transfer of fatty acids from the sn-2 position of phosphatidylcholine to cholesterol (Jonas, 1986). ApoA-1 is the major cofactor of LCAT in HDLs and reconstituted lipoproteins (Fielding et ai, 1972). Many laboratories have used techniques such as synthetic peptide analogs (Anantharamaiah et ai, 1990a Anantharamaiah, 1986), monoclonal antibodies (Banka et al., 1990), and recombinant HDL particles (Jonas and Kranovich, 1978) to attempt to identify the major LCAT-activating region of apoA-I. 

A phospholipid monolayer in the surface is consistent with the current model that LD are formed by TAG deposition between the two leaflets of the ER membrane and may remain connected to it [144, 145 see below]. Distribution of acyl-CoA cholesterol acyltransferase-1, a major enzyme that synthesizes cholesterylester, in the entire ER [148] seems to indicate that LD may bud anywhere along the membrane. However, Cap-LC/ESI mass spectrometry showed that FA moieties of phosphatidylcholine and lyso-phosphatidylchohne in LD are distinct from those in the rough ER [149]. The results do rule out the generation of the LD surface generated from the ER membrane but indicate that the former is a highly differentiated domain. Mature LD might be independent of the ER. Alternatively, the LD may be connected to the ER, but some molecular mechanism may demarcate the LD surface from the bulk ER membrane as postulated for other ER domains [150]. Whatever is true, TAG synthesized in wide areas of the ER do not deposit indiscriminately but are concentrated to loci specialized to make LD. ADRP or other LD-associated proteins may be involved (see below). 

Parks JS, Thuren TY, Schmitt JD. Inhibition of lecithin cholesterol acyltransferase activity by synthetic phosphatidylcholine species containing eicosapentaenoic acid or docosahexaenoic acid in the sn-2 position. J Lipid Res 1992 33 879-887. 

Cholesterol esters are synthesized in plasma from cholesterol and an acyl chain on phosphatidylcholine via a reaction catalyzed by lecithin cholesterol acyltransferase (LCAT). Another mechanism for making cholesterol esters is via the enzymatic reaction catalyzed by ACAT. 

There are two pieces of evidence in the literature that support the prediction that the cholesterol content of tissue membranes of children with SCD is increased relative to children without this hematological disease, and both are related to the phenomenon of reverse cholesterol transport, which allows the liver to eliminate excess cholesterol in peripheral tissues. Central to the reverse cholesterol transport is the efflux of cholesterol from the membranes followed by the lecithin-cholesterol acyltransferase-catalyzed acylation of that cholesterol with a fatty acid from phosphatidylcholine. This reaction is activated by high density lipoprotein (HDL) and is favored by n-3 PUFA in the HDL particles. The cholesterol esters are finally delivered to the liver bound to low density lipoprotein or by very low density Hpoproteins. 

The esterification of cholesterol in animals has attracted considerable research because of the possible involvement of cholesterol and its ester in various disease states (cf. Glomset and Norum, 1973, and Sections 12.1, 12.3 and 12.6). Cholesterol esters are formed by the action of lecithin cholesterol acyltransferase (LCAT, EC 2.3.1.43) which is particularly active in plasma (cf. Sabine, 1977, for a review of cholesterol metabolism). The reaction involves transfer of a fatty acid from position 2 of lecithin (phosphatidylcholine) to the 3-hydroxyl group of cholesterol with the formation of monoacyl-phosphatidylcholine. Although LCAT esterifies plasma cholesterol solely at the interface of high-density lipoprotein and very-low-density lipoprotein, the cholesterol esters are transferred to other lipoproteins by a particular transport protein (CETP cholesteryl ester transfer protein). Cholesteryl esters, in contrast to free cholesterol, are taken up by cells mostly via specific receptor pathways (Brown et aL, 1981), are hydrolysed by lysosomal enzymes and eventually re-esterified and stored within cells. LCAT may also participate in the movement of cholesterol out of cells by esterifying excess cholesterol in the intravascular circulation (cf. Marcel, 1982). 

Abbreviations are VLDL, very low density lipoproteins IDL, intermediate density lipoproteins LDL, low density lipoproteins HDL, high density lipoproteins HDL and HDL, subclasses of HDL that have densities of 1.063-1.125 and 1.125-1.120 respectively DNS, dimethylaminonaphthyl LCAT, lecithin cholesterol acyltransferase DMPC, dimyristoylphosphatidylcholine PPOPC, l-palmitoyl-2-palmitoleoyl phosphatidylcholine GdmCl, guanidium chloride LAP, lipid associating peptide and PNA, 9(3 -pyrenyl)nonanoic acid. 

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. 

The average daily intake of total dietary cholesterol is 400-500 mg. Cholesterol also enters the gastrointestinal tract via the bile. Between 800 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 amoimts of bilirubin, fatty acids, phosphatidylcholine, and salts. The cholesteryl esters of the diet are hydrolyzed to free cholesterol and a fatty acid by pancreatic cholesterol esterase. After entry into the enterocyte, the free cholesterol is converted back to cholesteryl esters by acyl CoAxholesterol acyltransferase. 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 (Thumhofer and Hauser, 1990). 

Apo Al, like apo B, is secreted mainly from liver and intestinal cells. Unlike apo B, however, apo Al is secreted in lipid-free or lipid-poor from. The cholesterol and phospholipids that are transferred to HDLs move down concentration gradients driven by the plasma enzyme lecithinxholesterol acyltransferase (LCAT). LCAT, which is bound to HDL, converts cholesterol and phosphatidylcholine to insoluble CE and lysophos-phatidylcholine (Section 3.4), which is soluble and is transferred to albumin in the plasma. Cholesterol has a small but significant solubility and, as a result, can be transferred spontaneously from cell and lipoprotein surfaces to apo Al. Cholesterol may also be transferred as a result of molecular collision between lipoprotein particles. The LCAT reaction consumes equal amounts of cholesterol and phospholipids, but the rate at which phospholipids are transferred spontaneously between cells and lipoproteins is much lower... 

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