Methionine fatty liver

Orotic acid in the diet (usually at a concentration of 1 per cent) can induce a deficiency of adenine and pyridine nucleotides in rat liver (but not in mouse or chick liver). The consequence is to inhibit secretion of lipoprotein into the blood, followed by the depression of plasma lipids, then in the accumulation of triglycerides and cholesterol in the liver (fatty liver) [141 — 161], This effect is not prevented by folic acid, vitamin B12, choline, methionine or inositol [141, 144], but can be prevented or rapidly reversed by the addition of a small amount of adenine to the diets [146, 147, 149, 152, 162]. The action of orotic acid can also be inhibited by calcium lactate in combination with lactose [163]. It was originally believed that the adenine deficiency produced by orotic acid was caused by an inhibition of the reaction of PRPP with glutamine in the de novo purine synthesis, since large amounts of PRPP are utilized for the conversion of orotic acid to uridine-5 -phosphate. However, incorporation studies of glycine-1- C in livers of orotic acid-fed rats revealed that the inhibition is caused rather by a depletion of the PRPP available for reaction with glutamine than by an effect on the condensation itself [160]. 

Ethionine is a hepatotoxic analogue of methionine causing fatty liver (accumulation of triglycerides). Chronic exposure causes cirrhosis, bile duct proliferation, and heptatocellular carcinoma. It forms S-adenosyl ethionine, which traps adenosyl leading to ATP depletion, which reduces triglyceride export from the liver. It also leads to ethylated bases in DNA. 

Controversy has attended both of these claims, but it has been established that wit/o-inositol does have lipotropic activity when it is added to a fat-free diet which is low in other lipotropic agents (for example, choline, or methionine).116 Even here, the inositol does not completely prevent the development of a fatty liver this effect can be produced with choline, with which wq/o-inositol has a supplementary effect. The fatty livers produced (in rats) by the diet mentioned are characteristically high in cholesterol esters. The designation biotin fatty liver for this condition is a misnomer.117... 

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. 

Ethionine is a hepatotoxic analogue of the amino acid methionine (figure 7,4 E). Ethionine is an antimetabolite which has similar chemical and physical properties to the naturally occurring amino acid. After acute doses ethionine causes fatty liver but prolonged administration results in liver cirrhosis and hepatic carcinoma. Some of the toxic effects may be reversed by the administration of methionine. The effects may be produced in a variety of species, athough there are differences in response. The rat also shows a sex difference in susceptibility, the female animal showing the toxic response rather than the... 

A second lipothrophic factor is betaine, which is effective because the transfer of at least one of its methyl groups to homocysteine is very efficient and can replenish methionine for choline formation. In the absence of sufficient lipotrophic factors, a fatty liver develops, and there is insufficient movement of fats either ingested or synthesized in the liver to the adipose tissue. As fats enter or are synthesized in the liver, they are repackaged or packaged as VLDLs to be moved out for transport from the blood to adipose tissue. The VLDLs contain protein, triacylglycerol, cholesterol, cholesterol esters, and phospholipids, especially phosphatidylcholine (lecithin). If one has either a protein deficiency or a lipotrophic factor deficiency, the movement of triacylglycerol s from the liver to adipose is ineffective and a fatty liver can develop. Choline can be present in the diet and need not be synthesized de novo. Phospholipid synthesis has been discussed previously (Chapter 15). 

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. 

Methionine prevents fatty liver and possibly also cirrhosis due to its capability to form choline through transmethylation (Richmond 1986). Taurine is used in the treatment of hepatic disorders (Kendler 1989, Birdsall 1998). 

Lipotropic substances compounds directly or indirectly involved in fat metabolism, which can prevent or correct fatty degeneration of the liver. They serve as substrates of phosphatide biosynthesis, or contribute (e.g. by methylation) to the synthesis of these substrates. Thus choline and any substance capable of contributing methyl groups for choline synthesis (e.g. methionine) are L.s. Liver is the major site of synthesis of plasma phosphoglycerides when the availability of choline is restricted, the rate of phosphatidylcholine synthesis decreases, and the rate of removal of fatty acids from the liver falls below normal. If the rate of supply of fatty acids (free and esterified) to the liver remains normal, the resulting accumulation of fat gives rise to the condition of fatty liver, or fatty degeneration of the liver. 

Choline Green foods, cereals, methionine Component of lecithin Poor growth, fatty liver, perosis... 

Fatty livers are also formed, in the presence of adequate choline, by diets deficient in amino acids other than methionine. This has been shown for threonine (SiNGAL et al. 1954) lysine and tryptophan (Vennart et al. 1958). Threonine deficiency, like choline deficiency, also leads to an increased synthesis of fatty acid from acetate (Yoshida and Harper 1960). An increase in synthesis has also been observed when cystine is added to a low protein diet. The relative importance of these effects for the formation of fatty livers is still uncertain. 

Cirrhosis of the liver in man is often found in chronic alcoholism and is probably due to dietary deficiency. In active fatty alcoholic cirrhosis, choline administration has been shown to lead to a decrease in liver fat. An increase in the rate of phospholipid turnover, following administration of 10 g. of choline or methionine, has been demonstrated in patients with cirrhosis who had evidence of fatty infiltration of the liver as shown by biopsy. In animals, vitamin B12 and folic acid are intimately related to choline and methionine metabolism and are important in the prevention of fatty livers under certain conditions. Whether these vitamins are related to accumulation of fat in the liver and cirrhosis in man remains to be ascertained. The value of high protein diets in the prevention and treatment of experimental dietary cirrhosis in animals is well established there is much evidence that such is also true in man (see also p. 521). 

Choline has been used in the therapy of liver disease in man, either alone or in conjunction with methionine and a diet high in protein and carbohydrate. The value of choline in the treatment of fatty livers and cirrhosis has not been determined with accuracy, since long-term human experiments are difficult to control and, in most instances, multiple therapy has been prescribed. It has been shown that administration of a single 10-g. dose of choline increases the rate of phospholipid turnover in subjects in whom fatty infiltration of the liver was observed on initial biopsy. When fat disappeared from the liver, this effect could not be demonstrated. In patients with active fatty alcoholic cirrhosis, choline administration brought about a moderate reduction in liver fat as shown histologically in biopsy specimens. Provision of adequate protein in the diet was followed by much greater improvement in the liver cell. 

In animals, choline, methionine, vitamin B12, and folic acid have been shown to be interrelated in the prevention of fatty livers under certain dietary conditions. Whether this is true in man is unknown. In patients... 

The question therefore arose about the fate of the methyl group from methionine. When minimal amounts of methionine were used to supplement the diet of rats given homocysteine as their main source of sulfur, the rats did not usually thrive, and at death had fatty accumulations in their livers. Best and his co-workers had earlier reported the efficacy of choline as a lipotropic agent, facilitating the mobilization of fat from the liver. Du Vigneaud therefore tried supplementing homcys-... 

Vitamin Bjj (8.50, cobalamin) is an extremely complex molecule consisting of a corrin ring system similar to heme. The central metal atom is cobalt, coordinated with a ribofuranosyl-dimethylbenzimidazole. Vitamin Bjj occurs in liver, but is also produced by many bacteria and is therefore obtained commercially by fermentation. The vitamin is a catalyst for the rearrangement of methylmalonyl-CoA to the succinyl derivative in the degradation of some amino acids and the oxidation of fatty acids with an odd number of carbon atoms. It is also necessary for the methylation of homocysteine to methionine. 

The transsulfuration pathway involves conversion of homocysteine to cysteine by the sequential action of two pyridoxal phosphate (vitamin B6)-dependent enzymes, cystathionine- 5-synthase (CBS) and cystathionine y-lyase (Fig. 21-2). Transsulfuration of homocysteine occurs predominantly in the liver, kidney, and gastrointestinal tract. Deficiency of CBS, first described by Carson and Neill in 1962, is inherited in an autosomal recessive pattern. It causes homocystinuria accompanied by severe elevations in blood homocysteine (>100 (iM) and methionine (>60 (iM). Homocystinuria due to deficiency of CBS occurs at a frequency of about 1 in 300,000 worldwide but is more common in some populations such as Ireland, where the frequency is 1 in 65,000. Clinical features include blood clots, heart disease, skeletal deformities, mental retardation, abnormalities of the ocular lens, and fatty infiltration of the fiver. Several different genetic defects in the CBS gene have been found to account for loss of CBS activity. 

Animal experiments have shown that faulty nutrition, i.e. > 90% fat, < 10% protein and < 2 mg choline per day, leads to pronounced fatty fiver and even fatty cirrhosis within a few weeks. The same changes could be observed when the protein intake remained more or less normal, while extremely little methionine and choline was offered. With a partial surplus of certain foodstuffs, the special nature of the excessive nutritional components is also of considerable importance. The term partial malnutrition may, for example, be associated with a pronounced protein deficiency (and thus possibly inadequate production of lipoproteins) or a lack of lipotropic substances (such as methionine, choline, cystine, glycocoUbetaine, pyridoxine, casein and various N- or S-methylated substances). Protein deficiency has particularly severe consequences when toxic substances are absorbed at the same time or when the organism has to fight bacterial or parasitic infections. A diseased liver reacts to both a serious deficiency in and an excessive supply of different nutrients (e.g. proteins, certain kinds of amino acids, various lipids, trace elements) with unfavourable or even complicative developments during the course of disease. 

Ascorbic acid is involved in carnitine biosynthesis. Carnitine (y-amino-P-hydroxybutyric acid, trimethylbetaine) (30) is a component of heart muscle, skeletal tissue, liver and other tissues. It is involved in the transport of fatty acids into mitochondria, where they are oxidized to provide eneigy for the ceU and animal. It is synthesized in animals from lysine and methionine by two hydroxjiases, both containing ferrous iron and L-ascorbic acid. Ascorbic acid donates electrons to the enzymes involved in the metabolism of L-tyrosine, cholesterol, and histamine (128). 

Unlike the other B vitamins, choline is not a metabolic catalyst but forms an essential structural component of body tissues. It is a component of lecithins, which play a vital role in cellular structure and activity. It also plays an important part in hpid metabolism in the liver, where it converts excess fat into lecithin or increases the utilisation of fatty acids, thereby preventing the accumulation of fat in the hver. Choline is a component of acetylcholine, which is responsible for the transmission of nerve impulses. Finally, choline serves as a donor of methyl groups in transmethylation reactions that involve folic acid or vitamin B12- Although other compounds, such as methionine and betaine, can also act as methyl donors, they cannot replace choline in its other functions. 

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