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PubMed1982

Progression of carcinogen-induced foci of gamma-glutamyltranspeptidase-positive hepatocytes to hepatomas in rats fed a choline-deficient diet.

Following previous findings that feeding a choline-deficient (CD) diet to rat strongly promotes the evolution of liver cells, initiated by a chemical carcinogen, to foci of gamma-glutamyltranspeptidase (gamma GT)-positive hepatocytes, we investigated whether a CD diet could also promote the evolution of gamma GT-positive foci to hepatomas. gamma GT-positive foci were induced in male Sprague-Dawley rats by administration of a single dose of diethylnitrosamine followed by 2 weeks' feeding on a CD diet containing 0.02% acetylaminofluorene. Immediately thereafter, one group of rats was fed a plain CD diet and the other a choline-supplemented (CS) diet, and subgroups of animals were killed periodically for analysis of the number and size of gamma GT-positive foci and development of hepatomas. During the first 7 weeks after switching the diets, the number and size of the foci increased in both groups. At 12 and 16 weeks, the number and size of foci began to decline in rats fed the CS diet. However, in the CD group, there was a progressive increase in the size with coalescence of the foci, as well as development of neoplastic nodules. These lesions were followed at 20 and 28 weeks by development of hepatomas at a high incidence rate. In rats fed the CS diet, a few scattered gamma GT-positive foci, and small neoplastic nodules remained in the liver at 20 and 28 weeks, but no hepatomas developed. These results show that the CD diet is a potent promoter of the evolution of foci of altered hepatocytes to hepatomas, and that most of the gamma GT-positive foci are reversible lesions.

2-Acetylaminofluorene↗
PubMed1975

Reduced response to phenobarbital by the liver of rats fed a choline-deficient diet.

1. The response of the liver to phenobarbital administration was compared in rats fed either laboratory chow, a semipurified choline-supplemented diet or a semipurified choline-deficient diet. 2. The liver contents of proteins, lipids and cytochrome P-450, as well as the activity of aminopyrine and ethylmorphine demethylases, were measured after 5 days of feeding and five daily injections of phenobarbital. Liver sections were examined electron microscopically. 3. In rats fed the choline-supplemented diet, phenobarbital administration caused increases in cellular constituents, enzyme activities and smooth endoplasmic reticulum membranes as great as those seen in rats fed laboratory chow. However, in rats fed the choline-deficient diet, the response of the liver to phenobarbital administration was severely reduced in comparison to that in rats fed the other diets. 4. It is concluded that dietary choline and an adequate synthesis of lecithins are necessary for the induction of microsomal mixed-function oxidases and the concomitant accumulation of smooth endoplasmic reticulum in hepatocytes.

Animals↗
PubMed1983

The effect of choline deficiency on the outer membranes of rat liver mitochondria.

The outer membranes of mitochondria prepared from the liver of rats kept 12 days on a choline-deficient diet were analyzed for changes in phospholipid and protein content. The total amount of phospholipid in the outer membranes was not affected by the deficiency. There was, however, a significant decrease in the amount of phosphatidylcholine and an increase in phosphatidylethanolamine. The alterations in the membrane phospholipids were reflected in a reduction in the fluorescence of the membrane probe, 8-anilino-1-naphthalene sulfonate. Choline deficiency also affected the protein composition of the outer membranes as judged by electrophoretic analysis; however, the activity of several enzymes which serve as markers for the outer membrane was not affected by the deficiency.

Animals↗
PubMed1988

Sex- and substrate-dependent changes in hepatic cytosolic glutathione S-transferase enzymes produced by dietary choline-deficiency.

The effect of 30 week intake of a choline-deficient (CD) diet on cytosolic glutathione S-transferase (GST) activity was investigated in rats of both sexes. GST activities in choline-supplemented (CS) control male cytosol were higher than those in CS-female cytosol for five test substrates--1-chloro-2, 4-dinitrobenzene (CDNB), 1,2-epoxy-3-(p-nitrophenoxy)-propane, trans-4-phenyl-3-buten-2-one, p-nitrobenzyl chloride (PNBC) and 1,2-dichloro-4-nitrobenzene (DCNB). The CD dietary regimen produced a relatively uniform decrease in GST activities in male liver to 37-59% of CS-control. With the exception of CDNB conjugation, GST activities in CD-male and CS-female cytosols were not significantly different. On the other hand, in female rats, the CD diet increased GST activity with PNBC and DCNB as substrates to 153 and 204% of respective CS-control female activities; other GSTs were unchanged. Hepatic cytosols from female rats were subfractionated on Whatman CM-52 and subjected to electrophoresis on polyacrylamide gels. The principal finding was that the relative concentration of GST subunit 3 (mol. wt approximately 27 kd) was apparently increased in CD-female rat cytosol; a finding that is consistent with the observed increase in DCNB- and PNBC-conjugation. Thus it is apparent that intake of the tumorigenic CD diet by male rats results in the feminization of GST activity, whereas in females GST subunit 3 is upregulated. The impaired regulation of these enzymes in CD-rats is an early event in relation to the development of hepatocellular carcinoma.

Animals↗
PubMed2004

Lack of peroxisome proliferator-activated receptor alpha in mice enhances methionine and choline deficient diet-induced steatohepatitis.

Pathogenesis of steatohepatitis, a common liver disease, remains controversial. It is proposed that fatty liver with a second hit capable of inducing necroinflammation results in nonalcoholic steatohepatitis. Long chain and very long chain fatty acids are considered important in induction of steatohepatitis. Peroxisome proliferator-activated receptor alpha (PPARalpha) plays an important role in beta-oxidation of long chain and very long chain fatty acids and mitogenic effect caused by peroxisome proliferators in the liver. To determine the role of PPARalpha in the pathogenesis of steatohepatitis and compensatory liver cell hyperplasia, we have used PPARalpha null mice and methionine and choline deficient nutritional model. Male and female PPARalpha null mice and wild type mice were fed methionine and choline deficient diet (MCDD) or normal chow for 4 weeks. Livers were analyzed morphologically for steatosis, steatohepatitis and hepatocyte proliferation (PCNA labeling) and biochemically for triglyceride levels. In addition, serum alanine transaminase, aspartate transaminase and triglyceride levels were measured. In MCDD fed PPARalpha null mice there was severe steatohepatitis and very high liver triglyceride levels compared to wild type mice. Serum aspartate transaminase levels were also significantly higher in MCDD fed PPARalpha null mice compared to wild type mice. The severity of steatohepatitis in MCDD fed male and female PPARalpha null mice was greater compared to wild type mice fed the same diet. The PCNA labeling index was similar in PPARalpha null mice and wild type mice fed MCDD, and significantly higher in both the groups compared to the mice fed control diet. These findings indicate that defective fatty acid oxidation aggravates steatohepatitis caused by methionine and choline deficiency and further establishes the role of long chain and very long chain fatty acids in the pathogenesis of steatohepatitis. In addition, the results of this study also indicate that there is no difference between males and females in the severity of steatohepatitis induced by MCDD and lack of PPARalpha does not affect compensatory hyperplasia in the liver.

Journal Article↗
PubMed2003

Fhit gene alterations in hepatocarcinogenesis induced by a choline-deficient L-amino acid-defined diet in rats.

Alterations of the fragile histidine triad (Fhit) gene were investigated in rat hepatocarcinogenesis induced by a choline-deficient L-amino acid-defined (CDAA) diet. Males of the F344 strain, 6 wk of age, were fed a CDAA diet, and subgroups were killed at 2, 4, 12, 20, and 75 wk after the beginning of the experiment. Fifteen hepatocellular carcinomas (HCCs) were noted in rats by the last time point; they were dissected free from the surrounding tissue. Normal control liver specimens were obtained from 6-wk-old rats. Total RNAs were extracted from whole livers of animals fed the CDAA diet for 2, 4, 12, and 20 wk and from HCCs, for assessment of aberrant transcription of the Fhit gene by reverse transcription-polymerase chain reaction. Aberrant transcripts were detected in livers of rats fed the CDAA diet for 4, 12, and 20 wk, but not 2 wk, as well as in 11 of 15 HCCs (73.3%). Southern blot analysis showed a genomic DNA abnormality in one of seven informative HCCs (14.3%), while Western blot analysis showed reduction of Fhit protein expression in seven of nine HCCs (77.8%). No abnormal expression was evident in the livers after exposure to the CDAA diet for 2-20 wk. These results suggest that Fhit alterations may play important roles in hepatocarcinogenesis due to choline deficiency in rats.

Acid Anhydride Hydrolases↗
PubMed1972

Lysosomes in the pathogenesis of the renal necrosis of choline-deficient rats.

Previously published data from our laboratories led us to postulate that alterations in lysosomes may play a cardinal pathogenic role in the fatal renal necrosis of choline-deficient weanling rats. To explore this hypothesis further a series of five different experiments were carried out. In the first two experiments the effect of a "stabilizer" of the lysosomes, hydrocortisone, was studied; conversely, in the third and fourth experiments, the effect of a "labilizer," vitamin A, was studied. Finally, in the fifth experiment, the renal levels of a lysosomal enzyme, acid phosphatase, were evaluated biochemically. Results of the first two experiments revealed a protective effect of hydrocortisone while those of the third and fourth an aggravating effect of vitamin A. Results of the fifth experiment indicated lysosomal changes in the prenecrotic and early necrotic stages. These results along with those from our previous studies, support the concept that lysosomal alterations play an important pathogenic role in renal changes of choline-deficient weanling rats.

Acid Phosphatase↗
PubMed1986

Stimulation of the methylation pathway for phosphatidylcholine synthesis in rat lungs by choline deficiency.

The methylation of phosphatidylethanolamine (PE) to form phosphatidylcholine (PC) was investigated using the isolated rat lung perfused with radiolabeled ethanolamine. Lungs from choline-deficient rats showed increased incorporation of radiolabel into PC at 2 h of perfusion. Increased PC synthesis from PE was also observed with lungs from rats fed a lipotrophic (choline plus methionine deficient) diet when methionine was added to the lung perfusate. These results indicate increased activity of the methylation pathway for lung PC synthesis during choline deficiency.

Animals↗
PubMed1993

Early hepatic lesions with marked glandular structures induced in rats by 0.1% ethionine in a choline deficient diet.

Early hepatic lesions in rats fed ethionine plus a choline deficient (ECD) diet were examined histopathologically. The purpose of this experiment was to examine preventive and suppressive effects of drugs on fatty or cirrhotic liver induced by ECD, but contrary to our expectations, all groups except the normal diet group showed neoplastic lesions in the liver. Macroscopically, milky-white nodules were seen in most all the rats except for a few dead ones. Microscopically, the characteristic lesions consisted of neoplastic nodules, glandular structures and oval cell hyperplasia. The glandular structures were already present in a rat that died on day 34 of administration and showed neoplastic developmental structures morphologically similar to cholangiofibroma. The neoplastic nodules appeared later than the glandules and were observed in rats that died after day 42. To the best of our knowledge, this is the first report of hepatic lesions consisting of mainly glandular structures induced by an ECD diet.

Animals↗
PubMed1978

Choline deficiency and the reversibility of renal lesions in rats.

A transient choline deficiency was induced in young rats subsequently fed a nutritionally complete purified diet during recovery periods of 0 to 119 days. The purpose was to investigate the pathomorphology of the renal lesions and relate this to observed biochemical changes. Acute renal lesions consisting of tubular epithelial cell necrosis and tubulorrhexis were observed in rats immediately after the insult. Chronic renal lesions consisting of interstitial nephritis and scarring were observed 28 to 119 days after the insult; these lesions were qualitatively similar at all times but showed a healing trend as the recovery period lengthened. Kidney and liver weights, liver fat concentration, and serum urea nitrogen concentration were higher in treated rats than in control rats at 0 days (no recovery period allowed) but treatment effects at all other times were minor. Significant changes occurred in serum phenylalanine and tyrosine concentrations and in the phenylalanine to tyrosine ratios after recovery periods of 0, 42 and 84 days. It was concluded that the proximal convoluted tubule was most seriously affected and that the chronic lesions represent a potential threat to kidney function in a stress situation. Some implications for human nutrition are discussed.

Animals↗
PubMed1968

Choline-deficiency fatty liver: impaired release of hepatic triglycerides.

After intravenous injection of palmitate-1-(14)C to rats fed a choline-deficient (CD) or choline-supplemented (CS) diet for 15-18 hr, liver triglycerides became labeled very rapidly. In CS, but not in CD rats, there was a considerable loss, with time, of radioactivity from liver triglycerides. At the same time, significantly less radioactivity appeared in plasma triglycerides of CD rats than of CS animals. No difference was seen in the triglyceride content of microsomes isolated from the liver of rats fed the two diets. The lower radioactivity in plasma triglycerides of CD rats was essentially due to a lower level and specific activity of very low density lipoprotein triglycerides. After intravenous injection of Triton and labeled palmitate, considerably less radioactivity accumulated in plasma triglycerides and phospholipids of CD rats than of CS animals. Post-Triton hyperphospholipidemia was also less pronounced in CD rats. It was concluded that the fatty liver observed in CD rats results from an impaired release of hepatic triglycerides into plasma.

Animals↗
PubMed1994

Differentiation of oval cells into duct-like cells in preneoplastic liver of rats placed on a choline-deficient diet supplemented with ethionine.

Feeding male Wistar rats a choline-deficient diet containing 0.07% DL-ethionine (CDE diet) for up to 5 weeks results in the production of two distinct non-parenchymal cell populations, oval and duct-like cells. These cells can undergo replication and display different patterns of expression of glutathione S-transferases (GSTs) and pyruvate kinases (PKs). Oval cells were first detected around the periportal region after 1 week of CDE treatment and infiltrated the parenchyma after 2 weeks. Duct-like structures first appeared as isolated ducts in the parenchymal region at 2 weeks and were easily detected after 2.5 weeks. These duct-like structures differed from the bile ducts which reside in the portal region. Large concentrations of duct-like structures in cyst-like clusters were detected after 5 weeks. Enlargement of these structures from single ducts to clusters of up to 20 ducts was observed over 3-5 weeks of CDE treatment. The number of cells forming a duct increased from 5 to 30 cells. We established a double immunocytochemical staining technique to characterize the oval and duct-like cells for their expression of GSTs and PKs. pi GST and M2-PK, which are fetal hepatocytes isoenzymes, are present in virtually all the oval and duct-like cells. Most of the oval cells are devoid of the adult hepatocytes markers, alpha GST, mu GST and L-PK. There are two sub-populations of duct-like cells, one which expresses only fetal markers and the other which co-expresses the adult and fetal isoenzymes. Hence, oval cells display characteristics of fetal hepatocytes and some duct-like cells appear more mature than oval cells. Using a combination of double immunocytochemical and [3H]thymidine labelling techniques we have established that oval cells differentiate into duct-like cells.

Animals↗
PubMed1991

Enhancing effect of a choline-deficient diet on alterations of hepatic drug-metabolizing enzymes in hepatitis- and hepatoma-predisposed rats (LEC rats).

Marked alterations of hepatic drug-metabolizing enzymes were observed in hepatitis- and hepatoma-predisposed rats (LEC rats) fed a choline-deficient diet. The diet enhanced the development of hepatitis with severe jaundice. The levels of two major classes of cytochrome P-450, P-450PB and P-450MC, were markedly decreased. GST-Yp was dramatically increased, whereas GST-Ya, Yb1 and Yb2 were decreased. LEA rats (the control rats to LEC) fed a choline-deficient diet mimicked LEC rats fed a normal diet in terms of the above enzyme alterations, indicating that hypomethylation is involved in the pathogenesis of hepatitis and hepatoma in LEC rats. Such hypomethylation may initiate the hepatocytes that spontaneously develop hepatitis and hepatoma.

Animals↗
PubMed1999

Different frequencies and patterns of beta-catenin mutations in hepatocellular carcinomas induced by N-nitrosodiethylamine and a choline-deficient L-amino acid-defined diet in rats.

To allow a study of beta-catenin mutations in hepatocellular carcinomas (HCCs) induced by exogenous and endogenous carcinogens, we induced tumors in male Fischer 344 rats with N-nitrosodiethylamine and a choline-deficient L-amino acid-defined diet. Administration of the former was followed by partial hepatectomy with colchicine to induce cell cycle disturbance and a selection pressure regimen (K. Ohashi et al., Cancer Res., 56: 3474-3479, 1996; M. Tsutsumi et al., Jpn. J. Cancer Res., 87: 5-9, 1996). HCCs were obtained after 42 weeks. With continuous choline-deficient L-amino acid-defined feeding, tumors were sampled after 75 weeks. Total RNA was extracted from individual lesions and mutations in the glycogen synthase kinase-3beta phosphorylation consensus motif of beta-catenin were investigated by reverse transcriptase-PCR-single-strand conformation polymorphism analysis followed by nucleotide sequencing. Changes were detected in 5 of 11 HCCs induced by the exogenous carcinogen. The observed shifts of C:G-->G:C or C:G-->A:T at codon 33 and G:C-->T:A transversions at codon 34 were associated with beta-catenin protein accumulation and confirmed by Western blot analysis. Only 2 of 15 HCCs induced in the endogenous carcinogenesis regimen demonstrated mutations, those being transitions of C:G-->T:A at codon 41 without amino acid alteration. These results suggest that different genetic pathways underlie exogenous and endogenous liver carcinogenesis in rats.

Amino Acids↗
PubMedDate not supplied

[Xanthurenuria at different stages of liver lesion induced by protein and choline deficiency].

The parallelism between xanthurenuria and liver affections caused by protein and choline deficiency was studied. At the stages marking the development of lipohepatosis and fibrosis there occurred an intensive passage of xanthurenic acid. The intensity of xanthurenuria at the stage marking the appearance of hyperplastic nodes continued to gain strength. With progressive advance of pathological changes, which by the 9--12th months of the experiment reached the stage of a fully developed nodular cirrhosis xanthurenuria gradually stopped.

Amino Acids↗
PubMed1978

Factors influencing lipoprotein lipase activity in choline deficiency.

Subcutaneous injections of the lipotropic agent, ethyl trichloracetate, to rats with established choline deficiency raised their plasma triglycerides by 60% and completely removed the hyperglyceridaemic response of Triton WR 1339. The plasma triglyceride levels of choline-supplemented rats were depressed slightly by ethyl trichloracetate administration, which was effective in abolishing response to Triton WR 1339. Lipoprotein lipase activity of epididymal fat pad was stimulated 60% while plasma lipoprotein was not stimulated by ethyl trichloracetate. The increased peripheral removal of low-density lipoprotein-triglyceride complex, allowing greater use to be made of existing apo-proteins, may explain the lipotropic character of the ester.

Adipose Tissue↗
PubMed1994

Choline deficiency in cultured adrenal medullary cells: effect on phosphatidylcholine biosynthesis.

The effect of choline deficiency on the composition and biosynthesis of the major membrane phospholipids was examined in adrenal medullary cells maintained in suspension cultures. The amount and proportions of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) in these cells were not affected by the removal of choline from the culture media. However, the rate of biosynthesis of choline at the phosphatide level by the stepwise methylation of PE increased twofold within 24 h after choline was removed from the culture media, while ethanolamine incorporation into PE was increased by 50%. In contrast, the rate of incorporation of labeled choline into PC, presumably via CDP-choline, was virtually identical in cells that had been preincubated in the presence or absence of 1 mM choline. These results demonstrate that cultured cells of neural origin are capable of compensating for lack of exogenous choline by forming choline at the phosphatide level through the sequential methylation of PE. The hypolipidemic drug, DH-990, when added to the culture media, inhibited conversion of phosphatidylmonomethylethanolamine (PME) to PC, but had no effect on the N-methylation of PE. This differential effect indicates that the initial N-methylation of PE is catalyzed by an enzyme that is distinguishable from the enzyme(s) catalyzing the conversion of PME to PC.

Adrenal Medulla↗
PubMed1988

Effect of methotrexate on homocysteine and other sulfur compounds in tissues of rats fed a normal or a defined, choline-deficient diet.

Methotrexate (MTX) affects homocysteine (Hcy) metabolism in both cultured cells and patients, and this may be explained by a lack of the 5-methyltetrahydrofolate required for salvage of Hcy to methionine. We here report the effect of MTX on Hcy in serum and Hcy, S-adenosylhomocysteine (AdoHcy), S-adenosylmethionine (AdoMet) and reduced glutathione (GSH) in tissues of rats fed either a normal or a defined, choline-deficient (CD) diet. The CD diet alone did not affect the amounts of Hcy in serum and tissues, but decreased the amount of AdoMet in most tissues and increased the GSH content in the liver. MTX increased the amount of Hcy about 2-fold in serum, liver and kidney, and decreased the amount of AdoMet in liver and kidney, whereas the AdoHcy content in these tissues was essentially unaffected. Accordingly, both choline deficiency and MTX treatment reduced the AdoMet to AdoHcy ratio. The increased GSH in the liver induced by CD diet seemed to be abolished by MTX. In the spleen MTX had only a marginal effect on the Hcy and AdoMet content and decreased the GSH content. It is concluded that the increase in serum Hcy during MTX exposure probably reflects a disturbance of the Hcy metabolism in some tissues, and especially in the liver. Altered metabolism of other sulfur-containing metabolites may only partly be related to the inhibition of Hcy salvage, and some metabolic effects of MTX may be modulated by tissue-specific metabolic pathways as well as by the diet.

Analysis of Variance↗