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At least 217 records · Page 12Linked to original sources
PubMed1990

Effects of a choline-deficient diet and a hypolipidemic agent on single glutathione S-transferase placental form-positive hepatocytes in rat liver.

Using the placental form of glutathione S-transferase (GST-P) as a marker of carcinogen-initiated hepatocytes, we investigated how a choline-deficient (CD) diet and BR931, a carcinogenic hypolipidemic agent, modify populations of single GST-P-positive hepatocytes. The liver of male Fischer rats (6-7 weeks old) fed a CS or basal diet contained mostly single or double GST-P-positive hepatocytes. Feeding a CD diet for 2-4 weeks led to increases in the number of aggregates of two and three GST-P-positive hepatocytes. By 8-12 weeks, there was an emergence of discrete foci of GST-P-positive hepatocytes consisting of more than 20 hepatocytes. Feeding a BR931 diet for 4-8 weeks resulted in no significant change in the number of single GST-P-positive hepatocytes in the liver as compared to feeding a basal diet. It is suggested that single GST-P-positive hepatocytes in the liver of relatively young rats maintained on a commercial diet may represent endogenously initiated cells. A CD diet promotes endogenously initiated cells to form larger aggregates or foci of GST-P-positive cells.

Animals↗
PubMed2004

Alterations of the M6p/Igf2 receptor gene in hepatocellular carcinomas induced by N-nitrosodiethylamine and a choline-deficient L-amino acid-defined diet in rats.

To elucidate whether the M6p/Igf2 receptor (M6p/Igf2r) gene might be involved in exogenous and endogenous liver carcinogenesis, we investigated its alteration in hepatocellular carcinomas (HCCs) induced by N-nitrosodiethylamine (DEN) and by a choline-deficient L-amino acid-defined (CDAA) diet in rats. Male F344 rats, 6 wk old, received a single intraperitoneal (i.p.) injection of DEN at a dose of 10 mg/kg body weight, followed by combined treatment with partial hepatectomy and colchicine to induce cell cycle disturbance, and a selection procedure regimen, HCCs being obtained after 42 wk. With continuous CDAA diet feeding, tumors were sampled after 75 wk. Total RNA was extracted from individual HCCs for assessment of mutations within exons 27, 28, 31, 33, and 34, and aberrant transcript of the M6p/Igf2r gene by reverse transcription (RT)-polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and RT-PCR analyses, respectively. Mutations were detected in three of 15 HCCs (20%) induced by the CDAA diet, a TTT to TTG (Phe to Leu) transversion at codon 1516 and two AAG to AGG (Lys to Arg) transitions at codon 1620, but in none of those caused by DEN. Aberrant transcripts were found in seven of 15 HCCs after DEN treatment (46.7%) and in two of 15 HCCs induced by the CDAA diet (13.3%). These results suggest that alterations of the M6p/Igf2r gene may be involved in both exogenous and endogenous liver carcinogenesis with the different patterns and frequencies.

Alkylating Agents↗
PubMed2005

Herbal medicine Rhei rhizome prevents liver fibrosis in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet.

The aim of this study was to investigate whether herbal medicine Rhei rhizome, extract powder from herbs, has influences on the development of liver fibrosis. In in vivo studies the effects of Rhei rhizome were examined using the choline-deficient L-amino acid-defined (CDAA) diet-induced liver fibrosis model. In In vitro studies the effects of Rhei rhizome on type I procollagen mRNA expression, alpha-smooth muscle actin (alpha-SMA), metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) of isolated hepatic stellate cell were examined. In vivo Rhei rhizome prevented fibrosis in a dose-dependent manner up to 1.0% (w/w) with a reduced number of activated stellate cells. In vitro the Rhei rhizome prevented stellate cell activation resulting in reduced type I procollagen mRNA, alpha-SMA and TIMP-1, 2 expression. These results indicate that Rhei rhizome significantly reduces liver fibrosis by the direct inhibition of stellate cell activation without reducing hepatocyte cell death.

Actins↗
PubMed2005

Temporal correlation of pathology and DNA damage with gene expression in a choline-deficient model of rat liver injury.

Hepatocellular carcinoma (HCC) is the terminal event in chronic liver diseases with repeated cycles of cellular injury and regeneration. Although much is known about the cellular pathogenesis and etiological agents leading to HCC, the molecular events are not well understood. The choline-deficient (CD) model of rodent HCC involves the consecutive emergence of a fatty liver, apoptosis, compensatory proliferation, fibrosis, and cirrhosis that is markedly similar to the sequence of events typified by human HCC. Moreover, oxidative stress is thought to play a pivotal role in the progression of the disease. Here, we hypothesize that gene expression profiling can temporally mirror the histopathology and oxidative DNA damage observed with this model. We show that clusters of highly co-regulated genes representing distinct cellular pathways for lipid biosynthesis and metabolism, apoptosis, cell proliferation, and tissue remodeling temporally correlate with the well-defined sequential emergence of pathological alterations in the progression of liver disease. Additionally, an oxidative stress signature was observed that was corroborated in a time-dependent manner with increases in oxidized purines and abasic sites in DNA. Collectively, expression patterns were strongly driven by pathology, demonstrating that patterns of gene expression in advanced stages of liver disease are primarily driven by histopathological changes and to a much lesser degree by the original etiological agent. In conclusion, gene expression profiling coupled with the CD model of HCC provides a unique opportunity to unveil the molecular events associated with various stages of liver injury and carcinogenesis and to distinguish between causal and consecutive changes.

Animals↗
PubMed1997

Inhibition by green tea extract of diethylnitrosamine-initiated but not choline-deficient, L-amino acid-defined diet-associated development of putative preneoplastic, glutathione S-transferase placental form-positive lesions in rat liver.

The effects of green tea extract (GTE) on exogenous and endogenous models of rat liver carcinogenesis using diethylnitrosamine (DEN) and a choline-deficient, L-amino acid-defined (CDAA) diet were studied. For the exogenous carcinogenesis study, male Fischer 344 rats, 6 weeks old, were given a single intraperitoneal dose of 200 mg/kg body weight of DEN, partially hepatectomized at week 3, and administered GTE at doses of 0, 0.01 and 0.1% in the drinking water from week 2 for 10 weeks. For the endogenous carcinogenesis study, rats were fed the CDAA diet and simultaneously given GTE for 12 weeks. All rats were killed at the end of week 12. After DEN-initiation, the apparent numbers of glutathione S-transferase placental form-positive foci, assayed as putative preneoplastic lesions, were decreased by the administration of GTE, though their sizes were not altered. In contrast, GTE did not significantly reduce the numbers of the lesions induced by the CDAA diet or affect their sizes. While the levels of 8-hydroxyguanine, a parameter of oxidative DNA damage, were reduced by the GTE administration in both experimental models, GTE did not protect against the CDAA-diet-associated liver tissue damage in terms of either histology or plasma marker enzyme levels. We conclude that, while GTE may be a possible chemopreventive agent for nitrosamine-initiated hepatocarcinogenesis in the absence of chronic hepatocyte damage, it does not significantly inhibit lesion development in hepatocarcinogenesis associated with the CDAA diet, a cirrhosis-associated model.

Alanine Transaminase↗
PubMed1998

Prevention by inhibitors of arachidonic acid cascade of liver carcinogenesis, cirrhosis and oxidative DNA damage caused by a choline-deficient, L-amino acid-defined diet in rats.

Effects of inhibitors of arachidonic acid (AA) cascade on the development of fatty liver, cirrhosis, glutathione S-transferase placental form (GST-P)-positive preneoplastic nodules, neoplastic nodules and generation of 8-hydroxydeoxyguanosine (8-OHdG), caused by a choline-deficient, L-amino acid-defined (CDAA) diet, were examined in Fischer 344 male rats by feeding CDAA diet supplemented with the inhibitors for 12 and 30 weeks. None of the inhibitors affected fatty liver. Among cyclooxygenase (COX) inhibitors, an irreversibly acting acetylsalicylic acid and a long-acting piroxicam, and to a much lesser extent the short-acting ibuprofen but not indomethacin, inhibited the development of cirrhosis, GST-P-positive and neoplastic nodules and generation of 8-OHdG. A phospholipase A2 inhibitor p-bromophenacylbromide (BPB) also exerted similar but lesser extent of inhibitory effects. Lipoxygenase inhibitors quercetin and nordihydroguiaretic acid inhibited GST-P-positive nodules but not cirrhosis or 8-OHdG. Present results suggest that perturbed AA cascade, particularly augmented COX pathway, might play key roles in the causation of liver lesions in the CDAA diet model.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1996

The prolyl 4-hydroxylase inhibitor HOE 077 prevents activation of Ito cells, reducing procollagen gene expression in rat liver fibrosis induced by choline-deficient L-amino acid-defined diet.

No effective therapy has yet developed for liver fibrosis by directory inhibiting the accumulation of extracellular matrix. The effect of a newly synthesized prolyl4-hydroxylase (PH) inhibitor, HOE 077 (pyridine-2, 4-di-carboxylic-di(2-methoxyethyl)amide), was examined using the model of choline-deficient L-amino acid (CDAA) defined diet-induced liver fibrosis in 16-week-old male Wistar rats. HOE 077 at doses up to 200 ppm prevented fibrosis in a dose-dependent manner, as indicated by reduced hydroxyproline content in liver as well as inhibition of increased serum fibrotic markers (PIIIP, 7S, hyaluronic acid). HOE 077 at 200 ppm reduced expression of type III procollagen alpha 1, messenger RNA (mRNA) in the liver, with a good correlation with serum PIIIP and hydroxyproline content of the liver. Histologically, HOE 077 at 200 ppm also reduced proliferation of myofibroblastlike cells (activated Ito cells). These results indicate that a PH inhibitor can prevent fibrosis by inhibiting not only the hydroxylation of proline but also the activation of Ito cells, which are considered the main collagen-producing cells, resulting in reduced expression of procollagen mRNA.

Amino Acids↗
PubMed1996

Inhibition by acetylsalicylic acid, a cyclo-oxygenase inhibitor, and p-bromophenacylbromide, a phospholipase A2 inhibitor, of both cirrhosis and enzyme-altered nodules caused by a choline-deficient, L-amino acid-defined diet in rats.

Effects of inhibitors of arachidonic acid (AA) metabolism on the development of fatty liver, cirrhosis, glutathione-S-transferase placental form (GST-P)-positive nodules and the generation of 8-hydroxydeoxyguanosine (8-OHdG) and thiobarbituric acid-reactive substances (TBARS), caused by a choline-deficient, L-amino acid-defined (CDAA) diet, were examined in male Fischer 344 rats by feeding CDAA diets supplemented with the inhibitors for 12 and 30 weeks. Acetylsalicylic acid (ASA) (at doses of 0.1 and 0.2%) and p-bromophenacylbromide (BPB) (0.1 and 0.2%) were used as inhibitors of, respectively, cyclo-oxygenase and phospholipase A2, and quercetin (QU) (0.75 and 1.5%) and nordihydroguaiaretic acid (NDGA) (0.1 and 0.2%) as inhibitors of lipoxygenase. None of the inhibitors affected the development of fatty liver caused by the CDAA diet. ASA at a doe of 0.2% almost completely prevented the appearance of cirrhosis, GST-P-positive nodules, 8-OHdG and TBARS in seven out of 11 (63.7%) rats. BPB at a dose of 0.2% also exerted inhibitory effects on all of these lesions but to a lesser extent than ASA. QU and NDGA exerted inhibitory effects limited to the GST-P-positive nodule case. The results indicate that a perturbed AA metabolism, particularly of the cyclo-oxygenase pathway, derived secondarily from depletion of labile methyl groups or phosphatidylcholine, might play key roles in the cirrhosis, hepatocarcinogenesis and oxidative stress caused by a CDAA diet. The results also indicated a possible involvement of the lipoxygenase pathway in hepatocarcinogenic processes.

Acetophenones↗
PubMed1990

Prevention by free radical scavenger AD5 of prooxidant effects of choline deficiency.

This study was designed to explore the possible preventive effects of a novel radicophile, N-p-methoxyphenylacetyl-dehydroalanine (AD5) and three other antioxidants, N,N'-diphenyl-p-phenylenediamine (DPPD), butylated hydroxyanisole (BHA) and a water-soluble analogue of vitamin E, trolox C, on the acute effects of the liver of feeding a choline-deficient (CD) diet. It has been suggested that some of the acute effects of a CD diet are related to free radicals, the generation or metabolism of which is disturbed in this acute dietary model. AD5 was found to be very effective in preventing nuclear lipid peroxidation, DNA damage and cell death induced by a CD diet but to have little effect on triglyceride accumulation ("fatty liver"). DPPD, BHA, and trolox C were ineffective. These results add strength to the hypothesis that oxygen free radicals might be an important component in the early events during carcinogenesis induced by feeding a CD diet.

Alanine↗
PubMed1987

Altered regulation of cytochrome P-450 enzymes in choline-deficient cirrhotic male rat liver: impaired regulation and activity of the male-specific androst-4-ene-3,17-dione 16 alpha-hydroxylase, cytochrome P-450UT-A, in hepatic cirrhosis.

Total microsomal cytochrome P-450 levels were decreased, to about 50% of control, in liver of male rats made cirrhotic by the prolonged intake of a choline-deficient diet. We have suggested previously that this decrease in cytochrome P-450 levels is not a generalized one, but is selective for certain forms of the enzyme. In the present study, levels of six cytochrome P-450 forms including the sex-specific cytochrome P-450 forms, P-450UT-A, P-450PCN-E, and P-450UT-l, were quantitated immunochemically in hepatic microsomes prepared from control and cirrhotic male rats and were related to changes in the regioselectivity of cytochrome P-450-mediated androst-4-ene-3,17-dione hydroxylation in these fractions. The principal finding of this study was that the male-specific androst-4-ene-3,17-dione 16 alpha-hydroxylase was decreased in cirrhotic microsomes to about 20% of control. The content of P-450UT-A decreased concurrently from about 0.40 to less than 0.01 nmol/mg of microsomal protein. Other pathways of androst-4-ene-3,17-dione hydroxylation were also affected, but to different extents than the 16 alpha-hydroxylase. 6 beta-Hydroxylation decreased in cirrhotic microsomes to about 45% of control, despite a marked decrease in P-450PCN-E from 0.27 to less than 0.002 nmol/mg of microsomal protein. The rate of androst-4-ene-3,17-dione 7 alpha-hydroxylation underwent a less pronounced reduction in cirrhosis to about two-thirds of control microsomal activity, and levels of the cytochrome P-450 associated with this activity, P-450UT-F, were decreased in proportion with the decrease in total microsomal cytochrome P-450. 16 beta-Hydroxylase activity was unaffected by the cirrhotogenic process. From spectral binding studies it was apparent that androst-4-ene-3,17-dione elicited a high affinity type I interaction in control microsomal fractions (Ks = 4.5 microM), whereas no interaction was apparent in cirrhotic liver microsomes. Levels of three other forms of cytochrome P-450--P-450PB-C (a constitutive form inducible by phenobarbital), P-450ISF-G (a major isosafrole-inducible form), and P-450UT-I (the major female sexually-differentiated isozyme)--were apparently unaltered in cirrhosis. These findings are consistent with the assertion that specific forms of cytochrome P-450 are subject to altered regulation in hepatic cirrhosis.

Androstenedione↗
PubMed2003

Adaptation of subcellular glutathione detoxification system to stress conditions in choline-deficient diet induced rat fatty liver.

The response of fatty liver to stress conditions (t-butyl hydroperoxide [t-BH] or 36 h of fasting) was investigated by assessing intracellular glutathione (GSH) compartmentation and redox status, GSH peroxidase (GSH-Px) and reductase (GSSG-Rx) activities, lipid peroxidation (TBARs) and serum ALT levels in rats on a choline-deficient diet. Baseline cytosolic GSH was similar between fatty and normal livers, while the mitochondrial GSH content was significantly lower in fatty livers. With the except of cytosolic GSH-Px activity, steatosis was associated with significantly higher GSH-related enzymes activities. Liver TBARs and serum ALT levels were also higher. Administration of t-BH significantly decreased the concentration of cytosolic GSH, increased GSSG levels in all the compartments, and increased TBARs levels in cytosol and mitochondria and serum ALT; all these alterations were more marked in rats with fatty liver. Fasting decreased the concentration of GSH in all the compartments both in normal and fatty livers, increased GSSG, TBARs and ALT levels, and decreased by 50% the activities of GSH-related enzymes. Administration of diethylmaleimide (DEM) resulted in cytosolic and microsomal GSH pool depletion. Administration of t-BH to DEM-treated rats further affected cytosolic GSH and enhanced ALT levels, whereas the application of fasting to GSH depleted rats mainly altered the mitochondrial GSH system, especially in fatty livers. This study shows that fatty livers have a weak compensation of hepatic GSH regulation, which fails under stress conditions, thus increasing the fatty liver's susceptibility to oxidative damage. Differences emerge among subcellular compartments which point to differential adaptation of these organelles to fatty degeneration.

Alanine Transaminase↗
PubMed2005

Steatohepatitis develops rapidly in transgenic mice overexpressing Abcb11 and fed a methionine-choline-deficient diet.

Nonalcoholic fatty liver disease is the most common reason for abnormal liver chemistries in the United States. The factors that lead from benign steatosis to nonalcoholic steatohepatitis are poorly understood. Transthyretin-Abcb11 (TTR-Abcb11) transgenic mice overexpress the bile salt transporter Abcb11 and hypersecrete biliary lipids. Thus the aim of this study is to employ feeding of the methionine-choline-deficient (MCD) diet to TTR-Abcb11 transgenic mice to further determine the mechanisms responsible for the development of steatohepatitis. FVB/NJ and TTR-Abcb11 mice were fed control or MCD diets for up to 30 days. Serum aminotransferase levels, serum and hepatic triglyceride content, cytokines, markers of oxidative stress, and expression of selective genes were examined. MCD diet-fed TTR-Abcb11, but not wild-type, mice have elevated serum aminotransferase levels when compared after 7 days. They also have significantly lower hepatic triglyceride levels at all time points studied. After 14 days on the MCD diet, TTR-Abcb11 mice have 3-fold increases in TNF-alpha mRNA and 3.9-fold increases in IL-6 mRNA compared with FVB/NJ mice. TTR-Abcb11 mice also had a greater increase in cytochrome P-450 2E1 expression. A greater decrease in sterol regulatory element binding protein-1c and fatty acid synthase mRNA expression was also seen in TTR-Abcb11 compared with wild-type mice fed an MCD diet. They also have enhanced TNF-alpha, IL-6, and cytochrome P-450 2E1 expression. We conclude that TTR-Abcb11 mice develop a more rapid hepatitis with less steatosis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Natural disruption of group 2 phospholipase A2 gene protects against choline-deficient ethionine-supplemented diet-induced acute pancreatitis and lung injury.

OBJECTIVES: Group 2 phospholipase A2 (PLA2) plays an important role in the pathogenesis of multiple organ failure associated with acute pancreatitis. C57 BL/6J mice are natural group 2 PLA2 knockout mice lacking group 2 PLA2 mRNA. To clarify the role of group 2 PLA2 in the exacerbation of acute pancreatitis, we studied the biologic and histologic alterations in choline-deficient and ethionine-supplemented (CDE) diet-induced pancreatitis in group 2 PLA2-deficient C57 BL/6J mice and compared them with those in wild-type mice. METHODS: Female C57 BL/6J mice weighing 20 to 22 g were fed a CDE diet for 3 days to induce pancreatitis. Female C3H/HEJ mice were used as controls. Mice were killed on days 1, 2, and 3 after the onset of the CDE diet. The severity of pancreatitis was evaluated by survival rate, plasma PLA2 activity, serum amylase level, histologic changes in the pancreas and lung, and myeloperoxidase activity in the lung. RESULTS: The survival rate of C57 BL/6J mice was 100% up to day 3 after the onset of the CDE diet, whereas that of the control mice was 42% on day 3. Plasma PLA2 activity in control mice increased on day 3 but did not increase in C57 BL/6J mice. Serum amylase activity on day 3 in C57 BL/6J mice was 15,480 +/- 3036 SU/dL, which was significantly lower than that in the control mice (43,760 +/- 8657 SU/dL, P < 0.01). Histologic changes in the pancreas of C57 BL/6J mice were markedly milder than in control mice. The degree of alveolar membrane thickening and infiltration of inflammatory cells in the lung of C57 BL/6J mice were overtly less than those of the controls. Myeloperoxidase activity in the lung of C57 BL/6J mice was lower, albeit insignificant, than in C3H/HEJ mice. CONCLUSIONS: Natural disruption of the group 2 PLA2 gene protects against CDE diet-induced acute pancreatitis and associated lung injury. These findings support the view that group 2 PLA2 is one of the factors in the exacerbation of severe acute pancreatitis.

Acute Disease↗
PubMed2001

A modified choline-deficient, ethionine-supplemented diet protocol effectively induces oval cells in mouse liver.

Several reliable and reproducible methods are available to induce oval cells in rat liver. Effective methods often involve inhibiting proliferation in hepatocytes using an alkylating agent, then subjecting the rat to partial hepatectomy (PH). The surgery is difficult to perform reproducibly in mice. Approaches that do not include partial hepatectomy, such as administration of D-galactosamine, are ineffective in mice. We found that a choline-deficient, ethionine-supplemented (CDE) diet, which is very effective in rats, leads to high morbidity and mortality when administered to mice. This article outlines an alternative protocol by which a CDE diet can be administered to mice. This diet is shown to be highly effective for oval cell induction, without causing high mortality. It takes less time and is at least as effective as other commonly used protocols for inducing oval cells in mice.

Animals↗
PubMed2004

Sex differences in choline-deficient diet-induced steatohepatitis in mice.

Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are common liver diseases in the United States. ASH and NASH occur more frequently in women than in men, and liver injury is also more severe in women. The role of estrogens in ASH has been well established, but their role in NASH has received relatively little study. The purpose of this study was to evaluate the effect of estrogens in methionine-choline deficient diet (MCDD)-induced steatohepatitis in mice. The degree of steatohepatitis was evaluated in males and in intact and ovariectomized females that were fed MCDD for 4 weeks, and in females that were fed MCDD containing tamoxifen. Hematoxylin and eosin-stained sections of livers showed marked steatohepatitis in all experimental groups. Compared to the control group, markers of hepatocyte injury such as aspartate transaminase (AST), alanine transaminase (ALT), and liver triglyceride levels increased significantly in males and in intact and ovariectomized female mice that were fed MCDD. Also, it was interesting that levels of AST and ALT increased much more in the MCDD + tamoxifen group than in the MCDD group. In female mice fed MCDD, hepatocyte proliferative and apoptotic indices increased slightly compared to mice that were fed a normal diet. Based on these results, it can be concluded that MCDD-induced steatohepatitis is comparable in male and female mice, and that ovariectomy or antiestrogen treatment had no protective effect in MCDD-induced steatohepatitis.

Animal Feed↗