Liver choline deficiency

Although there is significant capacity for biosynthesis of the choline moiety in the liver, choline deficiency can occur in humans. Male adults deprived of dietary choline become depleted of choline in their tissues and develop liver and muscle damage. Premenopausal women may not be sensitive to dietary choline deficiency (unpublished data). No experiments have been conducted to determine if this occurs in similarly deprived pregnant women, infants, and children. 

Yoshiji, H., Nakae, D., Mizumoto, Y., Horiguchi, K., Tamura, K., Denda, A., Tsujii, T. and Konishi, Y. (1992). Inhibitory effect of dietary iron deficiency on inductions of putative preneoplastic lesions as well as 8-hydroxydeoxyguanosine in DNA and lipid peroxidation in the livers of rats caused by exposure to a choline-deficient L-amino acid defined diet. Carcinogenesis 13, 1227-1233. 

A minor pathway to synthesize PC, which is mainly active in liver cells, utilizes the enzyme phosphatidylethanolamine-A-methyltransferase (PEMT), which converts phosphatidylethanolamine (PE) to PC by the subsequent transfer of three methyl groups from S-adenosylmethionine (Vance et al, 1997). The PEMT pathway, which links PE synthesis to PC, was found to be critical for PC homeostasis in the Uver dining choline deficiency (Walkey et al, 1997). 

Orotic acid added to rat diet also provokes an. excessive biosynthesis of porphyrins in liver, erythrocytes and bone marrow. Administration of adenine monophosphate (AMP) counteracted this effect of orotic acid intoxication [165]. Haemorrhagic renal necrosis in rats, caused by choline deficiency, can be relieved by orotic acid [166], Simultaneous supplementation of the diet with adenine does not influence the protective effect of orotic acid. It has been suggested that orotic acid may lower the body requirement for choline through a metabolic interaction—orotic acid may stimulate the cytidine phosphate choline pathway of lecthin biosynthesis [166]. 

Pomfret, E.A., daCosta, K.A. Zeisel, S.H. (1990) Effects of choline deficiency and methotrexate treatment upon rat liver. J. Nutr. Biochem., 1, 533-541... 

Choline deficiency developed in a 41-year-old woman with advanced cervical cancer who underwent prolonged parenteral nutrition (915). Her liver function tests became abnormal and she became jaundiced and complained of nausea and vomiting. The serum choline concentration was 5.77 mmol/1 and there was histological evidence of hepatic steatosis. There was steady improvement with oral choline supplementation, 3 g/ day, and with oral glutamine 15 g/day. There was a 45% improvement in serum choline concentration over baseline. 

Hager L. Choline deficiency and TPN associated liver dysfunction a case report. Nutrition 1998 14(l) 60-2. 

M.I.R. (1985) Interactions of Barbiturates and a Choline Deficient Diet in Promotion of Liver Carcinogenesis. This Volume. 

We have been investigating a few selected aspects of the mechanism of liver tumor promotion by a diet devoid of choline, a choline deficient (CD) diet. The diet is an effective promoter of the emergence of early presumptive preneoplastic foci of Y-glutamyltranspeptidase (GGT)-positive hepatocytes as well as of the progression of GGT-positive foci to hepatomas (3 4). A CD diet with a high fat content (14%) exerted a stronger promoting action than a CD diet with a low fat content (5%) (5). 

Barbiturates, Choline-Deficient Diet, and Liver Cancer 329... 

Figure 1. Conjugated diene absorption in rat liver 2 days after feeding choline-deficient (CD), choline-supplemented (CS), choline-deficient with corn oil (CDCO) or choline-supplemented with corn oil (CS-CO) diets. The. difference spectrum (inset) is obtained by subtracting the mean values of the control spectra from the mean values of the experimental spectra.

DEHP effects on the peroxisomal system of the liver appeared to be increased in rats kept on a choline deficient diet (Perera et al. 1986). This conclusion was based on an increase in the conjugated dienes in the microsomes of choline-deficient animals exposed to 500 mg/kg DEHP for 4 weeks. Conjugated dienes are indicators of free radical oxygen modification of cellular lipids. 

Methionine is intimately related to lipid metabolism in the liver. Methionine deficiency is one of the causes of the fatty liver syndrome. Lack of methionine prevents the methylation of phosphatidylethanolamine to phosphatidylcholine, resulting in an ability by the liver to build and export very low density lipoprotein. The syndrome can be treated by the administration of choline, and for this reason, choline has often been referred to as the lipotropic factor. 

In many animals, dietary deprivation of choline leads to liver dysfunction and growth retardation, and some patients maintained on choline-free total parenteral nutrition develop liver damage that resolves when choline is provided, suggesting that endogenous synthesis may be inadequate to meet requirements (Zeisel, 2000). There is inadequate information to permit the setting of reference intakes, but the Acceptable Intake for adults is 550 mg (for men) or 425 mg (for women) per day (Institute of Medicine, 1998). In experimental animals choline deficiency is exacerbated by deficiency of methionine, folic acid, or vitamin B12, which impairs the capacity for de novo synthesis. 

Liver health. As noted above, a biomarker of choline deficiency is elevated serum ALT levels, which is an indication of liver damage. One of the many functions of the liver is its role in fat metabolism. Without PC, the liver is unable to synthesize lipoproteins. Of particular importance in liver is the synthesis of very low-density lipoproteins (VLDL). With diminished VLDL production, the liver is not able to export lipid. This results in an accumulation of fat in the liver. Lipid accumulation in the liver leads to various stages of liver disease such as liver cell death, fibrosis, cirrhosis, and liver cancer (248-250). The role of choline in liver disease was underscored in the early 1990s when it was determined that patients on extended total parental nutrition (TPN) treatment developed fatty livers (251). At that time, TPN formulas did not include choline. Adding choline (in the form of lecithin) to TPN formulas reversed fatty buildup in these patients, and a... 

Other studies in animal models show that a choline-deficient diet promotes liver carcinogenesis (256-261). In fact, choline is the only known nutrient for which deficiency is directly linked to liver cancer in the absence of any known carcinogen (262, 263). Choline deficiency is therefore considered to have both cancer initiating and cancer promoting activities. 

Sakaida, I., Matsumura, Y., Akiyama, S., Hayashi, K., Ishige, A., Okita, K. Herbal medicine Sho-saiko-to (TJ-9) prevents liver fibrosis and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. J. Hepatol. 1998 28 298-306... 

The effects of choline deficiency can be demonstrated easily using animals. One of the earliest is a fatty liver. Feeding rats a choline-free diet for 1 day doubles the fat (triglyceride) content of their livers. Rats that survive the continued consumption of such diets can accumulate over 50 times the normal level of hepatic fat. This condition results from impairment of the normal secretion of fatthin shell of phospholipid and protein. 

One explanation of these results is that choline deficiency causes production of lipoproteins with abnormal structures, which results in an inability of the liver to export TGs to the bloodstream. Another theory is that choline deficiency produces defects in the structure of the endoplasmic reticulum, the network of tubules used for the synthesis of proteins and protein complexes destined for secretion from the cell. The membrane walls of the ER consist of phospholipids. Because all membranes contain phosphatidylcholine, a choline deficiency might be expected to result in defects in all membranes of the body, including those of the ER,... 

Choline deficiency produces renal as well as hepatic damage- This damage takes the form of degeneration of the renal tubules and bleeding, which may lead to death of the animal within 1 week of feeding the diet (Keith and Tryphonas, 1978). Under certain conditions, the liver and kidneys develop scar tissue. Cbxho-sEs is a term used to describe the conversion of normal tissues to scarlike fibrous tissues. 

Yao, Z., Jamil, H., and Vance, D. E. (1990), Choline deficiency causes translocation of CTP phosphocholjne cytidyltiansferase from cytosol to endoplasmic reticulum in rat liver- /. Eitjf. Cfretti. 265,4326-4331. 

Fatty acid synthetase, 183 Fatty acid transport, 215-216,12D, 777-774 Falty liver, 293 alcoholism, 250-251 choline deficiency, 3l7 Fatty streak, 360, 636 Fecal blood test, 84 Feedback inhibition, 256 Feeding center, brain, 103-104 Fenton reaction, 627.635,903 Fermentative metabolism, 159,181-182, 233-243... 

Lombardi and colleagues (1968) studied the uptake of fatty acids by the liver, packaging as TGs in lipoproteins, and release back into the bloodstream of fatty acids in choline-sufficient and choline-deficient rats. This study involved injection of a radioactive fatty add (tagged with K ) into a blood vessel. After a 30-minute waiting period, the lipoproteins of the plasma were analyzed. The appearance of radioactivity in the lipoproteins was impaired in the deficient rats. This experiment is illustrated in Figure 6.8. Additional material on the lipoproteins is presented later in this chapter. 

FIGURE 6.8 Packaging of fatty acids by the liver. (1) The radioactive fatty acid is injected into a vein and enters the cells of the liver. Most of the cells of the liver manufacture lipoproteins (circles). (2) Fatty acids in the Uver, including the injected radioactive fatty acid, are converted to triglycerides and packaged into the lipoproteins. (3) Lipoproteins are secreted continuously by the liver into the bloodstream. Most of the lipoproteins in the blood have been in the circulatory system for several hours. Blood sample removal after various time periods following injection of the radioactive tracer facilitates generating a minute-by-minute picture of the secretory processes, both in normal animals and in those that are choline deficient. 

Synthesis of phosphatidylcholine. The rate-limiting reaction is that catalyzed by cytidylyltransferase (reaction 2) which appears to be active only when attached to the endoplasmic reticulum, although it is also found free in the cytosol. Cytidylyltransferase is inactivated by a cAMP-dependent protein kinase and activated by a phosphatase. Translocation to the endoplasmic reticulum can be stimulated by substrates such as fatty acyl Coenzyme A (CoA). Choline deficiency can result in deposition of triacylglycerol in liver and reduced phospholipid synthesis. Enzymes (1) choline kinase ... 

Rats fed a choline-deficient diet rapidly develop a fatty liver. It was of interest to investigate whether rats fed such a choline-deficient diet would respond to treatment with L-tryptophan. Rats fed the control (choline-supplemented) diet but not the choline-deficient diet for 1 week and tube-fed L-tryptophan 10 min before being killed revealed enhanced labeled hepatic nuclear RNA release in vitro.174 When rats were fed elevated L-tryptophan (2%) in the diets (choline-deficient (CD) or choline-supplemented (CS)) for 1 week, labeled hepatic nuclear RNA release was increased with the CS + tryptophan diet but not with the CS + tryptophan diet groups. 3H-tryptophan binding to hepatic nuclei in vitro revealed no change in the CS + tryptophan group,... 

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