Liver phosphatidylcholine

The de novo synthesis of phosphatidylcholine requires choline. In liver, phosphatidylcholine is synthesized and enters the membranes and lipoproteins. The dc novo synthesis of phosphatidylcholine also requires 1,2-diacylglycerol. If there is insufficient choline available, phosphatidylcholine production by the de novo pathway cannot occur. The 1,2-diacylglycerol is then converted to triacylglycerol. which accumulates, as it is not secreted in lipoproteins, by the liver. Therefore, the liver cells fill with triacylglycerol. 

Phosphatidylcholine is the major phospholipid on the surface monolayer of all lipoproteins, including VLDLs. In the liver, phosphatidylcholine is synthesized by two biosynthetic pathways the CDP-choline pathway and the phosphatidylethanolamine A -methyltransferase pathway (Chapter 8). Choline is an essential biosynthetic precursor of phosphatidylcholine via the CDP-choline pathway. When cells or animals are deprived of choline, plasma levels of TG and apo B are markedly reduced and TG accumulates in the liver, resulting in fatty liver. These observations led to the widely held view that the fatty liver caused by choline deficiency is due to inhibition of PC synthesis, which in turn would decrease VLDL secretion. This hypothesis was tested in primary rat hepatocytes cultured in medium lacking choline. Upon removal of choline/methionine from culture medium, the TG content of hepatocytes was increased 6-fold, and the secretion of TG and apo B in VLDL was markedly reduced. The interpretation of these experiments was that hepatic VLDL secretion requires the synthesis of phosphatidylcholine from either the CDP-choline or methylation pathways which require choline or methionine, respectively, as precursors (D.E. Vance, 1988). However, since choline deprivation was induced in a background of methionine insufficiency, it was not clear whether the lack of choline per se, and inhibition of the choline pathway for phosphatidylcholine synthesis, decreased VLDL secretion. More recent experiments have shown, surprisingly, that deficiency of choline in primary mouse hepatocytes does not reduce, but increases, phosphatidylcholine synthesis via the CDP-choline pathway, and does not decrease VLDL secretion (J.E. Vance, 2004). Thus, a deficiency of dietary choline reduces plasma TG and apo B levels by a mechanism that does not involve reduction of phosphatidylcholine synthesis. 

Phosphatidylcholine can also be synthesized by the stepwise methylation of phosphatidylethanolamine. Methyl groups are transferred from 5-adenosyl-L-methionine and this pathway is a minor one in animals (20% of liver phosphatidylcholine synthesis but undetectable in other tissues Bell and Coleman, 1980) and plants (Moore, 1982). In those bacteria which contain phosphatidylcholine, it is made by stepwise methylation of phosphatidylethanolamine (Lennarz, 1970). 

In rat liver, phosphatidylcholine and phosphatidylethanolamine, the major phospholipid components of the mitochondrial membranes, are synthesized in the endoplasmic reticulum and are transferred to the mitochondria through a protein-mediated carrier mechanism. The mitochondria can synthesize phosphatidic acid, phosphatidylglycerol and diphosphatidyl-glycerol from glycerol-3-phosphate and can also convert phosphatidylserine to phosphatidylethanolamine by decarboxylation. The enzymes for phosphatidic acid synthesis are mainly located in the outer membrane. The details of the way in which these phospholipids become incorporated into the inner and outer mitochondrial membranes have yet to be determined. 

Early experiments on phospholipase A used an enzyme from snake venom which released one mole of fatty acid from a diacyl phospholipid. The original studies showed quite clearly that unsaturated fatty acids were released from egg or liver phosphatidylcholines and so it was quite natural to assume that the enzyme was specific for unsaturated acids. When fully saturated or fully unsaturated lipids were the substrates, however, one mole of fatty acid was still released from one mole of phospholipid and it was realized that the enzyme must be specific for one or other of the two positions. Early chemical analyses of the products of phospholipase A hydrolysis seemed to indicate that the enzyme released the fatty acid from the 1-position. When it was discovered that the enzyme also liberates fatty acid from plasmalogen (where it is known quite definitely to be located at the 2-position) the problem was reinvestigated more rigorously. 

Phosphatidylethanolamine synthesis begins with phosphorylation of ethanol-amine to form phosphoethanolamine (Figure 25.19). The next reaction involves transfer of a cytidylyl group from CTP to form CDP-ethanolamine and pyrophosphate. As always, PP, hydrolysis drives this reaction forward. A specific phosphoethanolamine transferase then links phosphoethanolamine to the diacylglycerol backbone. Biosynthesis of phosphatidylcholine is entirely analogous because animals synthesize it directly. All of the choline utilized in this pathway must be acquired from the diet. Yeast, certain bacteria, and animal livers, however, can convert phosphatidylethanolamine to phosphatidylcholine by methylation reactions involving S-adenosylmethionine (see Chapter 26). 

Tijburg LBM, Geelen MJH, van Golde LMG Regulation of the biosynthesis of triacylglycerol, phosphatidylcholine and phos-phatidylethanolamine in the liver. Biochim Biophys Acta 1989 1004 1. 

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. 

Figure 4. Linearity of the metabolism of parathion and benzphetamine by a reconstituted monooxygenase oxidase enzyme system from rabbit liver. The 0.5-mL reaction mixture contained 50 fig of sodium deoxycholate, 15 iig of dilauroyl l-5-phosphatidylcholine, 1.5 units of NADPH-Cytochrome c reductase, 0.5 nmol of Cytochrome P-450, 0.05M Hepes buffer (pH 7.8), 0.015M MgCh, O.lmU EDTA, and 5 X lO M [ethyl- C] parathion or / X 10 M benzphetamine.

Mizuguchi, H., Kudo, N., Ohya, T. Kawashima, Y. (1999) Effects of tiadenol and di-(2-ethyl-hexyl)phthalate on the metabolism of phosphatidylcholine and phosphatidylethanolamine in the liver of rats comparison with clofibric acid. Biochem. Pharmacol, 57, 869-876 Mocchiutti, N.O. Bernal, C.A. (1997) Effects of chronic di(2-ethylhexyl) phthalate intake on the secretion and removal rate of triglyceride-rich lipoproteins in rats. Food chem. Toxicol, 35, 1017-1021... 

Orlando R, Eragasso A, Lampertico M, et al. Pharmacokinetic study of silybin-phosphatidylcholin complex in liver cirrhosis after multiple doses. Med Sci Res 1990 19 827-828. 

Although the sinusoidal and canalicular surfaces of the liver cell are similar, having phosphatidyl ethanolamine and sphingomyelin in the exterior surface, on the contiguous surface of the liver cell, the exterior layer is almost entirely composed of phosphatidylcholine. 

FIGURE 21-29 Summary of the pathways to phosphatidylcholine and phosphatidylethanolamine. Conversion of phosphatidylethanolamine to phosphatidylcholine in mammals takes place only 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. 

Bile consists of a watery mixture of organic and inorganic compounds. Phosphatidylcholine (lecithin, see p. 201) and bile salts (conjugated bile acids) are quantitatively the most important organic components of bile. Bile can either pass directly from the liver where it is synthesized into the duodenum through the common bile duct, or be stored in Ihe gallbladder when not immediately needed for digestion. 

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... 

Pharmaceuticals. Lecithin and especially purified phosphatidylcholine can act as excipients in pharmaceutical (drug) formulation to enhance and control the Unavailability of the active component. Moreover, phosphatidylcholine can be utilized as a diedelic source, as it involved in the cholesterol metabolism and the metabolism of fats in the liver also, it can be utilized as a precursor of brain acetylcholine, as neurotransmiticr. 

Phospholipids are considered to be involved in the transport of triglycerides through die liver, especially during mobilization from adipose tissue, Conditions which could be interpreted as interfering with phosphatidylcholine formation, such as deficiency of choline or its precursors, result in a pronounced increase 111 liver triglycerides. 

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. 

Handa, T., Eguchi, Y., and Miyajima, K. (1994) Effects of cholesterol and cholesteryl oleate on lipolysis and liver uptake oftriglycerides/phosphatidylcholine emulsions in iBIsarm. Res., 11 1283-1287. 

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