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PubMedDate not supplied

Role of eicosapentaenoic acid in lipid metabolism in the liver, with special reference to experimental fatty liver.

Choline-deficient feed was given to three groups (n = 7 in each) of male Sprague-Dawley rats for 4 weeks to induce the development of fatty liver. In addition, two of the groups received eicosapentaenoic acid (EPA), 1000 mg/kg/d, administered orally either for all 4 weeks or for only the last 2 weeks of the study, respectively. The third group received the choline-deficient diet but no EPA. The untreated control group (n = 7) received only normal feed. The efficacy of EPA in preventing fatty liver was assessed based on the evaluation of pathologic and biochemical parameters and hepatic blood flow. EPA markedly improved fatty liver, probably due to both direct effects (inhibition of the synthesis of triglyceride in the liver) and indirect effects (increased hepatic blood flow). Decreased blood flow due to sinusoidal block is responsible for the progression of fatty liver. EPA has been shown to decrease thromboxane A2 production and blood viscosity and to enhance red cell deformability. These effects are thought to have contributed to the increases in hepatic blood flow.

Animals↗
PubMed1990

The effect of choline and methionine deficiencies on the number and volume percentage of altered hepatic foci in the presence or absence of diethylnitrosamine initiation in rat liver.

The ability of methyl-deficient, amino-acid-defined diets to produce enzyme-altered foci was quantitatively determined in the livers of rats treated both with and without an initiating dose of diethylnitrosamine (DEN). Male weanling F-344 rats were fed a complete, amino-acid-defined diet for 1 week. They were then injected i.p. with a single dose of DEN (20 mg/kg body weight) and fed the complete diet for an additional week. Forty animals in each dose group were then maintained for 5-38 weeks on the complete diet (diet 1) or one of the three methyl-deficient diets customarily used in this laboratory: diet 2, devoid of methionine and choline; diet 3, devoid of methionine only; and diet 4, devoid of choline only. In diets 2 and 3, methionine was replaced by equimolar amounts of its metabolic precursor, DL-homocystine. Ten animals per group were killed 8, 12, 17, 24 and 41 weeks after DEN initiation. For 2 weeks prior to being killed, each group was maintained on the complete diet to minimize the histological abnormalities due to acute toxicity of the diets. Serial sections of the livers were obtained, stained sequentially for gamma-glutamyltranspeptidase, ATPase and glucose-6-phosphatase, and the quantitation of the focal lesions scored by these markers was carried out by quantitative stereology. The results indicated that, regardless of the enzyme marker(s) examined, there was a general correspondence between the volume and number of altered hepatic foci (AHF) formed and the previously described tumor-promoting activities of each diet. Thus, while all DEN-treated groups contained significant numbers of AHF 24 weeks after initiation, only the diet-2-fed animals displayed such foci at 8 weeks. Similarly, among the uninitiated rats, only those fed diet 2 exhibited the presence of AHF throughout the experimental period. Interestingly, the livers of uninitiated, choline-deficient rats showed a small number of AHF at 24 and 42 weeks; these foci were not observed at all in the corresponding DEN-untreated animals fed diet 3, deficient in methionine only. The results provide evidence that the carcinogenic effects of the methionine- and choline-deficient diet result more from its strongly promoting effect than from any initiating activity by the diet.

Animals↗
PubMed1998

Choline availability modulates the expression of TGFbeta1 and cytoskeletal proteins in the hippocampus of developing rat brain.

Choline availability influences long-term memory in concert with changes in the spatial organization and morphology of septal neurons, however little is known concerning the effects of choline on the hippocampus, a region of the brain also important for memory performance. Pregnant rats on gestational day 12 were fed a choline control (CT), choline supplemented (CS), or choline deficient (CD) diet for 6 days and fetal brain slices were prepared on embryonic day 18 (E18). The hippocampus in these brain slices was studied for the immunohistochemical localization of the growth-related proteins transforming growth factor beta type 1 (TGFbeta1) and GAP43, the cytoskeletal proteins vimentin and microtubule associated protein type 1 (MAP1), and the neuronal cell marker neuron specific enolase (NSE). In control hippocampus, there was weak expression of TGFbeta1 and vimentin proteins, but moderately intense expression of MAP1 protein. These proteins were not homogeneously distributed, but were preferentially localized to cells with large cell bodies located in the central (approximately CA1-CA3) region of the hippocampus, and to the filamentous processes of small cells in the fimbria region. Feeding a choline-supplemented diet decreased, whereas a choline-deficient diet increased the intensity of immunohistochemical labeling for these proteins in E18 hippocampus. GAP43 and NSE were localized to peripheral nervous tissue but not hippocampus, indicating that the maturation of axons and neurite outgrowth in embryonic hippocampus were unaffected by the availability of choline in the diet. These data suggest that the availability of choline affects the differentiation of specific regions of developing hippocampus.

Aging↗
PubMed1981

Consumption coagulopathy in acute renal failure induced by hypolipotropic diets.

Weanling male rats fed on a hypolipotropic diet develop acute renal failure whose morphological features vary from focal tubular necrosis to cortical necrosis. We have sequentially studied the hemostatic mechanism in correlation with the morphology of various tissues, mainly renal and hepatic, in choline-deficient rats as well as in three control groups. No important changes were observed in the hemostatic mechanisms before the development of tubular necrosis. Along with tubular necrosis a consumption coagulopathy was found, evidenced mainly by a decrease in the activity of factors V and VIII as well as a prolongation in PTTK and Quick's time and a decrease in platelets. Fibrin degradation products were found in serum and urine and soluble fibrin monomer complexes in the former. Following tubular necrosis thrombi were found in the renal microvasculature. It is possible to speculate that the tubular necrosis induced by choline deficiency could produce an activation of the coagulation system which in turn would lead to thrombosis of the renal microcirculation and cortical necrosis.

Acute Kidney Injury↗
PubMed1984

Isolation and partial characterizations of oval and hyperplastic bile ductular cell-enriched populations from the livers of carcinogen and noncarcinogen-treated rats.

An oval cell-enriched population was isolated using two isopyknic centrifugation steps in Percoll gradients from the livers of young adult male rats maintained for 6 to 12 weeks on a choline-deficient diet containing 0.05% DL-ethionine. This cell population equilibrated sharply at densities ranging between 1.07 and 1.08 g/ml, possessed a mean cell diameter in fixed-cell smears of 13.6 micron, and showed viabilities of greater than 95% as judged by trypan blue dye exclusion. Contamination of this population by hepatocytes and Kupffer cells was determined to be less than 1% and between 4 and 14%, respectively. gamma-Glutamyl transpeptidase activity was demonstrated both biochemically and histochemically to be the most constant marker for evaluating the oval cell-enriched population isolated at various times over the 6 to 12 weeks of the choline-deficient/DL-ethionine dietary regimen. In contrast, the percentages of nonhepatocytic cells showing labeling for DNA synthesis and for alpha-fetoprotein were both found to be the highest in the oval cell-enriched population isolated at 6 weeks and lowest in that obtained at 12 weeks of dietary treatment. Furthermore, at 10 to 11 weeks, 19.2% of the nonhepatocytic cells in this population were positive for albumin, while 2.1% were positive for glucose-6-phosphatase activity, indicating some cells to be intermediate in function between the oval cell and the hepatocyte. In comparison, hyperplastic bile ductular epithelial cells in tissue preparations isolated from the livers of rats previously subjected to 13 weeks of chronic feeding of the noncarcinogenic cholestatic agent, 1-naphthyl isothiocyanate, or at 8 to 13 weeks following bile duct ligation were found to be strongly positive for gamma-glutamyl transpeptidase activity, as well as to be positive for alkaline phosphatase activity, but to be essentially negative for glucose-6-phosphatase activity, glycogen content, and albumin production. However, an occasional bile ductular cell in these preparations was found to exhibit a strong cytoplasmic binding of [6,7-3H]estradiol, an indirect measure of alpha-fetoprotein production. Also, a low, but demonstrable amount of DNA synthesis was noted in the bile ductular cells present in these preparations. Furthermore, a viable cell population highly enriched in bile ductular epithelial cells was isolated by isopyknic centrifugation in Percoll following enzymatic dissociation of the hyperplastic tissue preparation from bile duct ligated rats.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Naphthylisothiocyanate↗
PubMedDate not supplied

Release of latent glucuronosyltransferase activity contributes to the sparing of glucuronidation in experimental liver injuries.

In patients with parenchymal liver disease, glucuronidation of drugs is generally preserved but oxidation is impaired. This study explores the effects of liver injuries induced in rats by the administration of acute carbon tetrachloride, chronic bile duct ligation and chronic choline deficiency for 30 weeks on the glucuronidation of p-nitrophenol and 1-naphthol, both before and after solubilization of the microsomes and compares this to three measures of oxidation. Cytochrome P450 content was reduced to 17% of control values after acute carbon tetrachloride and to 35% of control values after bile duct ligation. Cytochrome C reductase fell to 58 and 32% of control and aniline hydroxylase to 46 and 13%, respectively, after acute carbon tetrachloride and bile duct ligation. P-nitrophenol glucuronidation by native microsomes was 206 and 73% of controls in the respective models, while 1-naphthol glucuronidation was 167 and 66% of control. Latent uridine diphosphate-glucuronosyltransferase (UDP-GT) activity, that is, differences between solubilized and native activity, was decreased by each liver injury. Chronic choline deficiency had little effect on the oxidation and native glucuronidation activity, although latent glucuronidation activity was lower. These studies suggest a preservation of glucuronidation compared to oxidation at the microsomal level in these experimental liver injuries. The data also support the hypothesis that a release of latent UDP-GT activity may contribute to this phenomenon.

Animals↗
PubMed1997

Possible involvement of 5-HT2 receptor activation in aggravation of diet-induced acute pancreatitis in mice.

Acute pancreatitis was induced in mice by feeding with a choline-deficient ethionine-supplemented diet. All the mice developed acute pancreatitis, and approximately 80% of them died within 4 days. Stereomicroscopic and light microscopic examinations revealed that pancreatic necrosis and circulatory disturbance that were not apparent on day 1 were increased markedly on days 2 and 3. Serum levels of pancreatic enzymes were normal or reduced on day 1 but then increased to peak on day 3. Plasma 5-hydroxyindoleacetic acid levels, which may indicate serotonin release, were significantly increased on days 1 through 3. Pretreatment with D, L-p-chlorophenylalanine methylester hydrochloride (200-400 mg/kg) significantly attenuated the mortality of the mice with pancreatitis. Dose-dependent attenuation was also obtained with ketaserin (0. 01-10 mg/kg), cyproheptadine (0.01-10 mg/kg), pindolol (0.1-100 mg/kg) and NAN-190 (0.1-100 mg/kg), but not with 0.01 to 10 mg/kg of ICS205-930 or M-840, and the activities were significantly correlated with the binding affinities for serotonin2 receptor on the rat cerebral cortex. In addition, ketanserin or cyproheptadine attenuated the morphologic changes in the choline-deficient ethionine-supplemented diet mice at a dose (3.2 mg/kg) that hardly affected the serum enzyme levels. We propose that serotonin2 receptor activation plays an important role in the aggravation of diet-induced acute pancreatitis.

Acute Disease↗
PubMed2006

Liver mitochondrial dysfunction and oxidative stress in the pathogenesis of experimental nonalcoholic fatty liver disease.

Oxidative stress and hepatic mitochondria play a role in the pathogenesis of nonalcoholic fatty liver disease. The aim of the present study was to evaluate the role of hepatic mitochondrial dysfunction and oxidative stress in the pathogenesis of the disease. Fatty liver was induced in Wistar rats with a choline-deficient diet (CD; N = 7) or a high-fat diet enriched with PUFAs-omega-3 (H; N = 7) for 4 weeks. The control group (N = 7) was fed a standard diet. Liver mitochondrial oxidation and phosphorylation were measured polarographically and oxidative stress was estimated on the basis of malondialdehyde and glutathione concentrations. Moderate macrovacuolar liver steatosis was observed in the CD group and mild liver steatosis was observed in the periportal area in the H group. There was an increase in the oxygen consumption rate by liver mitochondria in respiratory state 4 (S4) and a decrease in respiratory control rate (RCR) in the CD group (S4: 32.70 +/- 3.35; RCR: 2.55 +/- 0.15 ng atoms of O2 min-1 mg protein-1) when compared to the H and control groups (S4: 23.09 +/- 1.53, 17.04 +/- 2.03, RCR: 3.15 +/- 0.15, 3.68 +/- 0.15 ng atoms of O2 min-1 mg protein-1, respectively), P < 0.05. Hepatic lipoperoxide concentrations were significantly increased and the concentration of reduced glutathione was significantly reduced in the CD group. A choline-deficient diet causes moderate steatosis with disruption of liver mitochondrial function and increased oxidative stress. These data suggest that lipid peroxidation products can impair the flow of electrons along the respiratory chain, causing overreduction of respiratory chain components and enhanced mitochondrial reactive oxygen species. These findings are important in the pathogenesis of nonalcoholic fatty liver disease.

Animals↗
PubMed1993

Characterization of a mature bile duct antigen expressed on a subpopulation of biliary ductular cells but absent from oval cells.

Hybridomas were produced with immune spleen cells generated by immunization of Balb/c mice with oval cell antigen (OC.2)-positive 17-day fetal liver cells isolated on antibody-coated magnetic beads. A primary screen by indirect immunofluorescence on frozen sections of fetal and adult liver identified several hybridomas secreting antibodies reactive with bile ducts and oval cells. One of these recognized an epitope, designated BD1, which was expressed on intrahepatic bile ducts in 16-day fetal and adult rat liver and in liver from rats fed a choline-deficient diet containing ethionine and rats treated with 2-acetylaminofluorine, but was absent from morphologically defined oval cells induced by a choline-deficient diet containing ethionine or by 2-acetylaminofluorine. Double-labeling immunofluorescence analysis with monoclonal antibody BD1 and OV6, a monoclonal antibody that reacts uniformly with all bile ducts and oval cells, revealed that BD1 expression on the intrahepatic bile ductular cells of normal adult rat liver was heterogeneous with a major ductal cell population (60% to 70%) expressing high levels of BD1 and a minor ductal cell population (30% to 40%) displaying undetectable or low levels of BD1 expression. Analysis of fetal liver demonstrated the presence of BD1-positive cells at day 16 of gestation on duct-like structures in contact with portal mesenchyme, an observation suggesting that expression of BD1 was associated with commitment of hepatoblasts to a ductular lineage. Taken together, our findings suggest that oval cells may be derived from an antigenically distinct subpopulation of bile ductal cells.

2-Acetylaminofluorene↗
PubMed1997

[Blood rheological study in rats with fatty liver--with special reference to effects of ethyl icosapentate].

A blood rheological study was conducted using Kikuchi's micro-channel method in rats with fatty liver. Effects of eicosapentaenoic acid (EPA) on blood rheology were also evaluated. Male SD rats given normal feed served as the control. One group was given choline-deficient feed for 4 weeks (EPA (-) group), while another group was daily given EPA (1000 mg/kg) for 4 weeks together with choline-deficient feed (EPA (+) group). The micro-channel passage time was determined using 100 microliters of whole blood. The passage time significantly increased in the EPA (-) group compared to the control (p < 0.01). It significantly decreased in the EPA (+) group compared to the EPA (-) group (p < 0.01). Findings obtained in the present study suggested that blood rheological factors are related to the development of fatty liver and that EPA inhibits fatty changes of the liver by improving these rheological factors.

Animals↗
PubMed1978

[Clinical and experimental studies on changes in lysosomal enzyme activity in fatty livers (author's transl)].

In order to examine a role of lysosomes in the pathogenesis of fatty livers, analysis was made on possible etiologic factors, clinical signs and symptoms as well as laboratory data of routine liver function tests in 32 subjects with fatty livers. Of 18 cases, enzyme activities of serum acid phosphatase (Acp), beta-glucuronidase (betaG) and n-acetyl-beta-glucosaminidase (nbetaG) were measured and compared with those obtained in 20 normal subjects. Subjective symptoms were observed in 75% of the cases examined, liver swelling in 56%, positive GOT, GPT and BSP retention were in 59, 75 and 68%, respectively. The activity of serum lysosomal enzymes such as Acp, betaG and nbetaG were significantly increased and their incidence was 28, 89 and 78%, respectively. In animal experiments, activities of these enzymes in both serum and liver homogenate were examined in rats with choline-deficient, ethionine-treated, and alcoholic fatty livers. Results obtained were as follows: 1) Lysosomal enzyme activity in sera and livers of choline-deficient rats showed a significant decrease in lysosome-rich fraction and a significant increase in supernatant fraction and sera. 2) The enzyme activity in ethionine-treated rats decreased significantly in lysosome-rich fraction and tended to increase in supernatant fraction. The activity of betaG in sera increased markedly. 3) In rats given ethanol for 4 weeks, the enzyme activity of sera and liver homogenates significantly increased in lysosome-rich fraction. These results indicate that the analysis of serum lysosomal enzyme activity, in the light of clinical features and laboratory data of routine liver function tests, is useful for the diagnosis of the fatty liver. A discussion is given of a possible mode of variation of lysosomal enzymes in rats with fatty livers.

Acid Phosphatase↗
PubMed1995

Incorporation of a phosphonium analogue of choline into the rat brain as measured by magnetic resonance spectroscopy.

A clear understanding of choline metabolism is important in our goal to modify demyelination and remyelination in multiple sclerosis. To develop a technique capable of measuring metabolic changes in the brain, we have studied the incorporation of a phosphonium analogue of choline (P-choline) in tissue extracts of rats. After feeding adult rats a choline-deficient diet supplemented with P-choline, the analogue was not detectable by in vivo volume-localized 1H spectroscopy. However, in vitro 31P measurements of brain extracts revealed an 11% incorporation of P-choline into phosphatidylcholine. We report that P-choline incorporates preferentially into the lipid pool over the lipid precursor pool and we provide evidence that the choline peak resolved by in vivo 1H spectroscopy is only composed of small molecular weight choline-containing compounds.

Animals↗
PubMed1985

Acute hemorrhagic pancreatitis in mice: A study of glucoregulatory hormones and glucose metabolism.

In mice fed a choline-deficient diet containing 0.5% DL-ethionine (CDE) profound hypoglycemia develops, as do signs of shock, and the mice die of acute hemorrhagic pancreatitis (AHP). When fed a choline-supplemented diet containing 0.5% DL-ethionine (CSE), however, the mice have a chronic nonhemorrhagic pancreatitis with focal necrosis, do not show symptoms of shock, and survive. For investigation of the mechanism of hypoglycemia and the onset of shock in AHP, serum and pancreatic insulin and glucagon contents, serum glucose levels, and the morphologic characteristics of pancreatic islets were evaluated in mice fed laboratory Chow (LC); a choline-supplemented (CS) diet; a choline-deficient (CD) diet; or the CSE and CDE diets for 1, 2, or 3 days. The results indicate that onset of shock in animals with AHP may be due to hypoglycemia resulting from abnormal release of glucoregulatory hormones and their inability to maintain glucose output from liver and/or caused by active proteinases released from necrotic pancreas.

Acute Disease↗
PubMed1998

Esophageal varices in rat models of liver cirrhosis.

Animal models resembling the human situation are very useful to investigate human disease. However, there has been no evidence of esophageal varices in rats with liver cirrhosis. In the present study, to determine whether intrahepatic portal hypertension produced by liver cirrhosis induces esophageal varices in rats, the esophagus was examined endoscopically in rat models of liver cirrhosis. All rats given carbon tetrachloride or thioacetamide and six of seven rats given a choline-deficient diet had esophageal varices or venous dilatation after 16 weeks of treatment, although the varices in one rat given carbon tetrachloride and in two rats given a choline-deficient diet were reduced from weeks 16 to 18. These findings suggest that timing is important when studying esophageal varices in rat models of liver cirrhosis. It is concluded that certain models of liver cirrhosis in rats could be used as models of esophageal varices due to intrahepatic portal hypertension.

Animals↗
PubMed2001

Nutritional and metabolic considerations in the etiology of nonalcoholic steatohepatitis.

The aim of this study was to determine if a relationship exists between nonalcoholic steatohepatitis (NASH) and serum levels of free fatty acids, choline deficiency, or celiac disease. Forty-seven patients with liver biopsy proven NASH were enrolled. Total serum free fatty acids and anti-endomysial antibodies were determined in all patients, while plasma free and phospholipid-bound choline were determined in 29 patients. Total serum free fatty acid concentration correlated significantly with female gender and serum albumin concentration. Patients with severe fibrosis on liver biopsy had significantly greater serum concentration of free fatty acids than patients without severe fibrosis. Plasma free and phospholipid-bound choline levels were normal and no significant correlation was found between the concentration of plasma free or phospholipid bound choline, and the severity of liver damage. Only one of the 47 patients with NASH had a positive titer for the anti-endomysial antibody. In conclusion, increased serum concentrations of free fatty acids were found in NASH and were associated with development of more severe liver disease. Neither choline deficiency nor celiac sprue by anti-endomysial antibody testing was associated with NASH.

Celiac Disease↗
PubMed1983

Effects of prostaglandin and indomethacin on diet-induced acute pancreatitis in mice.

This study was performed to determine the effects of exogenous prostaglandin and a prostaglandin synthetase inhibitor on experimental pancreatitis in mice. An ethionine-supplemented choline-deficient diet was used to induce pancreatitis in 4-6-wk-old Swiss Webster mice. Mice were injected subcutaneously with 16,16-dimethyl prostaglandin E2 (0.1, 1.0, 10 micrograms X kg-1 X day-1), indomethacin (0.05, 0.5, 5 mg X kg-1 X day-1), or saline for 7 days. The ethionine-supplemented choline-deficient diet was introduced 24 h after the first injection, and animals ate the test diet for 48 h. A 55% mortality was observed in control animals (n = 100) treated with carrier alone. Treatment with 10 micrograms X kg-1 X day-1 of 16,16-dimethyl prostaglandin E2 significantly decreased (p less than 0.01) mortality to 12% (n = 100). Improved survival was accompanied by a significant (p less than 0.05) decrease in the pancreatic content of free chymotrypsin and a decrease in histologic damage. Treatment with 5 mg X kg-1 X day-1 of indomethacin (n = 30) significantly (p less than 0.01) increased mortality in diet-treated rats from a control rate of 55% to 100%. These studies demonstrate a protective effect of prostaglandin on the pancreas and suggest a role for endogenous prostaglandins in the pathophysiology of pancreatitis.

16,16-Dimethylprostaglandin E2↗
PubMed2002

Steatosis is not sufficient to cause an impaired regenerative response after partial hepatectomy in rats.

BACKGROUND/AIMS: Fatty liver is known to be associated with increased mortality and morbidity after liver resection. The ability of fatty liver to regenerate after two-thirds partial hepatectomy was studied in three different models of steatosis in rats: obese Zucker rats, orotic acid-fed Wistar rats and Wistar rats fed a methionine-low, choline-deficient diet. METHODS: Liver regeneration was assessed 24 h after partial hepatectomy by bromodeoxyuridine incorporation (immunohistochemistry), proliferating cell nuclear antigen, cyclin E and cyclin-dependent kinase 2 protein expression (Western blot analysis) and cyclin-dependent kinase 2 activity (kinase assays using histone H1 as a substrate). RESULTS: No significant difference of proliferative response was found between orotic acid or methionine-low, choline-deficient diet-fed and control Wistar rats 24 h after partial hepatectomy. In contrast, hepatocyte proliferation in obese Zucker rats after partial hepatectomy was significantly reduced when compared with their lean controls. CONCLUSIONS: Steatosis per se does not impair liver regeneration. The reduced liver regeneration observed in obese Zucker rats may not be due to fatty infiltration itself but to other factors such as leptin receptor dysfunction.

Animal Feed↗
PubMed1957

The role of intestinal bacteria in the development of dietary cirrhosis in rats.

Diffuse hepatic cirrhosis develops in rats on a choline-deficient diet within 300 days. Absorbable broad spectrum antibiotics added to the daily diet do not prevent the development of fatty infiltration, but they delay the development of cirrhosis for about 100 days more. Non-absorbable antibiotics added to the daily diet prevent the development of cirrhosis in most rats for as long as 750 days. The superiority of non-absorbable antibiotics to absorbable antibiotics excludes a systemic effect of the antibiotics and demonstrates that intestinal bacteria are largely, if not wholly, responsible for the cirrhosis in rats on a choline-deficient diet.

Animals↗