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PubMed2004

TNF/LTalpha double knockout mice display abnormal inflammatory and regenerative responses to acute and chronic liver injury.

Following acute liver injury, hepatocytes divide to facilitate regeneration. However, during chronic injury, hepatocyte proliferation is typically blocked and repair is mediated through liver progenitor (oval) cells. Signalling of the p55 tumour necrosis factor (TNF) receptor is central to these processes. Two ligands for p55 are known: TNF and lymphotoxin-alpha (LTalpha). However, one study suggests that another exists that mediates liver injury following viral challenge. We have therefore investigated whether ligands other than TNF and LTalpha are required for liver regeneration following either acute or chronic injury. Wild-type and double TNF/LTalpha knockout (TNF-/-LTalpha-/-) mice were subjected to either partial hepatectomy (PHx) or a choline-deficient ethionine-supplemented (CDE) diet. Proliferating hepatocytes, oval cells and inflammatory cells were identified and quantified in liver sections by immunohistochemistry. Liver inflammatory cells were characterised by cell surface antigen expression. Liver damage and mortality were monitored. Both hepatocyte and oval cell proliferation was reduced in TNF-/-LTalpha-/- mice. Lymphocyte clusters were evident in all TNF-/-LTalpha-/- livers and were heterogeneous, comprising B and T lymphocytes. PHx evoked liver inflammation in TNF-/-LTalpha-/- but not wild-type mice, whereas no difference was apparent between genotypes in CDE experiments. Thus, TNF/LTalpha signalling mediates liver regeneration involving both hepatocytes and progenitor cells. The hyper-inflammatory response following PHx in TNF-/-LTalpha-/- animals, which is absent following CDE-induced injury, demonstrates that the two forms of liver injury evoke discrete inflammatory responses and provides a model in which such differences can be examined further.

Acute Disease↗
PubMed2002

Induction of heat shock proteins fails to produce protection against trypsin-induced acute pancreatitis in rats.

Heat shock proteins (HSPs) are necessary in the synthesis, degradation, folding, transport, and translocation of different proteins. It is well known that the increased expression of HSPs may have a protective effect against cerulein-induced pancreatitis in rats or against choline-deficient ethionine-supplemented diet model pancreatitis in mice. The aim of this study was to investigate the potential effects of HSP preinduction by cold or hot water immersion on trypsin-induced acute pancreatitis in rats. Trypsin was injected into the interlobular tissue of the duodenal part of the pancreas at the peak level of HSP synthesis, as determined by Western blot analysis. The rats were sacrificed by exsanguination through the abdominal aorta 6 h after the trypsin injection. The serum amylase activity, the tumor necrosis factor-alpha, interleukin-1, and interleukin-6 levels, the pancreatic weight/body weight ratio, and the pancreatic contents of DNA, protein, amylase, lipase, and trypsinogen were measured. A biopsy for histology was taken. Hot water immersion significantly elevated the HSP72 expression, while cold water immersion significantly increased the HSP60 expression. Cold water immersion pretreatment ameliorated the pancreatic edema in trypsin-induced pancreatitis, however this was not due to the HSP60. Hot water immersion pretreatment did not have any effect on the measured parameters in trypsin-induced pancreatitis. The findings suggest that the induction of HSP60 or HSP72 are not enough to protect rats against the early phase of this localized necrohemorrhagic pancreatitis model.

Amylases↗
PubMed1982

Alteration of phospholipid composition of mouse liver microsomes in vivo and the effect on membrane properties.

Administration of the methylation inhibitor periodate-oxidized adenosine to male Swiss-Webster mice on a choline-deficient diet produced a decrease (17%) in phosphatidylcholine to phosphatidylethanolamine ratios compared to saline-injected controls in liver, and also in kidney (11%), but not in muscle microsome preparations. Both intact liver microsomes and reconstituted membranes from lipid extracts showed a higher fluorescence anisotropy of the hydrophobic probe 1,6-diphenyl-1,3,5-hexatriene than control samples in the temperature range of 20-31 degrees C.

Adenosine↗
PubMed1990

Effects of the tumor promoter 12-O-tetradecanoylphorbol 13-acetate on peroxisomal activities and enzyme activities involved in lipid metabolism in rat liver.

The effects of 12-O-tetradecanoylphorbol 13-acetate (TPA) on hepatic lipids and key enzymes involved in esterification, hydrolysis and oxidation of long-chain fatty acids at increasing doses were investigated in rats. TPA administration tended to decrease the mitochondrial activities of palmitoyl-CoA synthetase and carnitine palmitoyltransferase. The microsomal palmitoyl-CoA synthetase activity was increased. TPA administration was also associated with a dose-dependent increase of glycerophosphate acyltransferase activity both in the mitochondrial and microsomal fractions in particular. The data are consistent with a decreased catabolism of long-chain fatty acids at the mitochondrial level, and an increased capacity for esterification of fatty acids in the microsomal fraction. Peroxisomal beta-oxidation was increased about 2-fold in the peroxisome-enriched fraction of TPA-treated rats while the catalase and urate oxidase activities were only marginally affected. TPA administration revealed elevated capacity for hydrolysis of palmitoyl-CoA and palmitoyl-L-carnitine in the microsomal fraction. Neither increased cytosolic palmitoyl-CoA hydrolase activity nor increased hydroxylation of lauric acid nor changes of the hepatic content of cytochrome P-450 isoenzymic forms were observed in the TPA-treated animals. There was no induction of the protein content of the bifunctional enoyl-CoA hydratase. Thus, TPA behaves more like choline-deficient diet and ethionine treatment than well-known peroxisome proliferators. It seems possible that TPA selectively stimulated the peroxisomal activities, i.e., peroxisomal beta-oxidation rather than evoking a peroxisome proliferation capacity.

Animals↗
PubMed1985

Monovalent cation dependency for the inhibition of outward transport of [3H]norepinephrine.

Rat hearts were labelled with [3H]norepinephrine in vivo. Slices of ventricles were prepared, preincubated in Krebs-HCO3 medium (KRB), and then incubated in a Na+-deficient, choline+-Krebs HCO3 (Ch+-Ca2+). The choline+-Krebs HCO3 medium induced a delayed neurosecretion which could be inhibited by either one of the blockers of the uptake of NE, cocaine or desipramine, when included in both the Krebs and the Ch+-Ca2+. When either desipramine or cocaine was present in the Na+-rich preincubation medium only, the duration of action of desipramine was more prolonged than that of cocaine. When desipramine was first added to the Ch+-Ca2+ medium at various times after incubation, the inhibitory response became smaller as the duration of preliminary Na+-deprivation was increased. After incubation for 80 min neither desipramine nor cocaine inhibited secretion. Sodium (added to Ch+-Ca2+ medium or in a Krebs replacement medium) then slowed the rate of release stimulated by Ch+-Ca2+ and facilitated an inhibitory action for both inhibitors. The inhibition did not require the continued presence of Na+. Depolarizing concentrations of K+ in the Ch+-Ca2+ medium with Na+ and either one of the inhibitors, prevented the inhibition of neurosecretion. However, K+ which was added to the preincubation medium with either inhibitor did not prevent the prolonged inhibition of neurosecretion. By contrast with the secretory response to Ch+-Ca2+, the secretory response to K+ in Na+-enriched Ch+-Ca2+ medium was weakly inhibited by the inhibitors of transport.

Animals↗
PubMedDate not supplied

Effects of somatostatin and a somatostatin agonist on diet-induced pancreatitis in mice.

We examined the effects of somatostatin-14 and the potent somatostatin agonist (N-acetyl-[Des(Ala1,Gly2),p-Cl-Phe6,D-Trp8]-somatostatin amide) on choline deficient, ethionine enriched diet (CDED)-induced acute pancreatitis in mice. Serum amylase determinations were performed, and specimens from the pancreas were examined by light and electron microscopy. No significant beneficial effects of somatostatin or its agonist were found in this model of acute pancreatitis.

Acute Disease↗
PubMed1983

Inhibition of development of preneoplastic lesions in the livers of rats fed a weakly carcinogenic environmental contaminant.

The effects of di(2-ethylhexyl)phthalate (DEHP), a widely used plasticizer and environmental contaminant, on the emergence of gamma-glutamyltrans-peptidase positive (GGT+) preneoplastic foci in the liver was investigated. Sprague--Dawley male rats initiated with diethylnitrosamine (DEN) following partial hepatectomy were placed on: (1) a choline supplemented diet (CS); (2) a CS diet containing 2% DEHP (CS + DEHP); (3) a choline deficient diet (CD); (4) a CD diet containing a 0.06% phenobarbital (CD + PHB); or (5) a CD diet containing 2% DEHP (CD + DEHP). Rats maintained on the CS + DEHP diet for 5 and 10 weeks showed no increase in GGT + foci. The plasticizer effectively inhibited the appearance of the preneoplastic foci when it was included with the CD diet.

Animals↗
PubMed1991

Aneuploidy and progression in promoted preneoplastic foci during chemical hepatocarcinogenesis in the rat.

Since a number of rat hepatocarcinomas are aneuploid, the model DNA content of enzyme-altered foci was determined cytospectrophotometrically, to assess if ploidy changes occur before cancer is established. Male F344 rats treated with diethylnitrosamine and promoted with a choline-deficient, phenobarbital supplemented diet showed in most enzyme-altered foci a multimodal ploidy distribution with diploid, tetraploid and octoploid peaks. A minority of foci, however, exhibited an aneuploid pattern. This change in ploidy reflects irreversible genomic alterations, indicative of tumor progression. Thus, promotion and progression may coexist simultaneously in this model of carcinogenesis, long before hepatomas can be diagnosed.

Aneuploidy↗
PubMed1989

Sudden infant death syndrome and lipoproteins.

Lipoprotein secretion and vitamin E transport depend on an adequate supply of inositol which functions synergistically with choline. Feeding rats a choline deficient diet was associated with decreased linoleic and arachidonic acids and increased docosapentenoic and docosahexenoic acids in liver phosphatidylethanolamine. Lipoprotein secretion by the liver is impaired by long chain omega 3 fatty acids and by the high carbohydrate diet of Kwashiorkor. Pulmonary surfactant is a lipoprotein which functions in preventing alveolar collapse in the lung. Inositol supplements to premature infants altered the composition of surfactant phospholipids and reduced the need for oxygen therapy. Oxygen free radicals, generated in oxygen therapy, convert low density lipoproteins (LDL) into potent toxins, without adequate antioxidants and free radical scavengers to block free radical generation. Vitamin E deficiency predisposes humans to increased susceptability to oxygen toxicity leading to Bronchopulmonary dysplasia (BPD), a form of chronic pulmonary insufficiency.

Animals↗
PubMed2003

Hepatocyte growth factor exerts a proliferative effect on oval cells through the PI3K/AKT signaling pathway.

Hepatocyte growth factor (HGF) is a potent mitogen for a variety of cells including hepatocytes. While rat oval cells are supposed to be one of hepatic stem cells, biological effects of HGF on oval cells and their relevant signal transduction pathways remain to be determined. We sought to investigate them on OC/CDE22 rat oval cells, which are established from the liver of rats fed a choline-deficient/DL-ethionine-supplemented diet. The oval cells were cultured on fibronectin-coated dishes and stimulated with recombinant HGF, transforming growth factor-alpha (TGF-alpha), and thrombopoietin (TPO) under the serum-free medium condition. HGF treatment enhanced [3H]thymidine incorporation into oval cells in a dose-dependent manner. On the contrary, treatment with TGF-alpha or TPO had no significant effects on [3H]thymidine incorporation into the oval cells. c-Met protein was phosphorylated at the tyrosine residues after the HGF treatment. AKT, extracellular signal-regulated kinase 1/2 (ERK1/2), and p70(s6k) were simultaneously activated after the HGF stimulation, peaking at 30min after the treatment. The activation of AKT, p70(s6k), and ERK1/2 induced by HGF was abolished by pre-treatment with LY294002, a phosphoinositide 3-OH kinase (PI3K) inhibitor, and U0126, a mitogen-activated protein kinase/ERK kinase (MEK) inhibitor, respectively. When the cells were pre-treated with LY294002 prior to the HGF stimulation, the proliferative action of HGF was completely abrogated, implying that the PI3K/AKT signaling pathway is responsible for the biological effect of HGF. These in vitro data indicate that HGF exerts a proliferative action on hepatic oval cells via activation of the PI3K/AKT signaling pathway.

Cell Division↗
PubMed2005

Reduced expression of the E-cadherin gene and its aberrant DNA methylation in hamster pancreatic tumors.

The expression of the E-cadherin gene and its DNA methylation status in the 5' upstream region were investigated in pancreatic duct adenocarcinomas (PDAs) induced by N-nitrosobis(2-oxopropyl)amine (BOP) in hamsters. Female Syrian golden hamsters received 70mg/kg BOP, followed by repeated exposure to an augmentation pressure regimen consisting of a choline-deficient diet combined with dl-ethionine then l-methionine and a further administration of 20mg/kg BOP. A total of 15 PDAs were obtained, along with total RNA for assessment of expression by real-time quantitative reverse transcription-polymerase chain reaction. The expression of the E-cadherin was significantly reduced in PDAs (p<0.05) compared with normal pancreatic tissue. For the analysis of methylation status, bisulfite sequencing was performed with two normal pancreatic tissues and six tumors. The normal pancreatic tissue was all demethylated in this region of E-cadherin. In contrast, six PDAs were highly methylated, correlating with reduced expression of the E-cadherin. These results suggest that aberrant DNA methylation of the E-cadherin gene may play a role in the development of PDAs induced by BOP in hamsters.

Adenocarcinoma↗
PubMed2006

Aberrant DNA methylation of the 5' upstream region of Tslc1 gene in hamster pancreatic tumors.

To determine if the Tslc1 gene is involved in pancreatic carcinogenesis, the expression level of Tslc1 and the DNA methylation status of its 5' upstream region were investigated in pancreatic duct adenocarcinomas (PDAs) induced in hamsters by N-nitrosobis(2-oxopropyl)amine (BOP). Female Syrian golden hamsters received 70 mg/kg of BOP followed by repeated exposure to an augmentation pressure regimen consisting of a choline-deficient diet combined with ethionine-methionione-BOP injection. Total RNA was extracted from 11 PDAs and the level of Tslc1 expression was measured in each by real-time quantitative reverse transcription (RT)-polymerase chain reaction (PCR). The expression level of Tslc1 was significantly reduced in PDAs (p < 0.05) compared with normal pancreatic tissues. In order to assess the DNA methylation status of the 5' upstream region of Tslc1, bisulfite sequencing was performed. Although this region was unmethylated in normal pancreatic tissue, it was highly methylated in four PDAs, correlating with reduced Tslc1 expression. These results suggest that a reduction in the expression of Tslc1 due to aberrant DNA methylation might be involved in the development of PDAs induced in hamsters by BOP.

5' Untranslated Regions↗
PubMed2004

Aberrant transcription of FHIT gene in intrahepatic cholangiocellular carcinomas induced by N-nitrosobis(2-oxopropyl)amine in hamsters.

Aberrant transcription of the fragile histidine triad (FHIT) gene was investigated in intrahepatic cholangiocellular carcinomas (ICCs) induced by N-nitrosobis(2-oxopropyl)amine (BOP) in female Syrian golden hamsters. The animals received 70 mg/kg of BOP followed by repeated exposure to an augmentation pressure regimen consisting of a choline-deficient diet combined with DL-ethionine and then L-methionine and administration of 20 mg/kg BOP. A total of 14 ICCs were obtained 10 weeks after the beginning of the experiment and total RNAs were extracted from each for assessment of aberrant transcription of the FHIT gene by reverse transcription-polymerase chain reaction analysis. Aberrant transcripts were detected in four out of 14 ICCs (28.6%), as absence in the regions of nucleotides (nt) -75 to 279, nt -75 to 348 and nt -75 to 447. These results suggest that alteration of the FHIT gene may play a role in a small fraction of ICCs induced by BOP in the hamster.

Acid Anhydride Hydrolases↗
PubMed2005

Fas/FasL play a central role in pancreatitis-induced hepatocyte apoptosis.

Liver injury is a clinical prognostic indicator in acute pancreatitis (AP). We have demonstrated that Kupffer cell-derived FasL mediates liver injury during AP and sought to determine its role in AP-induced hepatocyte apoptosis. AP was induced in National Institutes of Health (NIH) Swiss mice, C57/C57, and Fas-/-, FasL-/- mice by a choline-deficient ethionine-supplement diet. Liver Fas, FasL, p38-mitogen activated phosphokinase (p38-MAPK), poly-ADP ribose polymerase (PARP), and cytochrome C were measured by immunoblotting. Apoptosis was assessed by terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) and DNA fragmentation (ELISA). AP upregulated liver FasL (4280 +/- 580 vs. 733 +/- 336), Fas (2866 +/- 595 vs. 649 +/- 111), cytochrome C (6980 +/- 237 vs. 903 +/- 156), and PARP (6393 +/- 591 vs. 466 +/- 261) as well as increased TUNEL staining (40 +/- 2 vs. 14 +/- 1) and DNA fragmentation (all P < 0.03 vs. control). In FasL-/- and Fas-/- mice, AP-induced upregulation of p38-MAPK, PARP, and cytochrome C was significantly attenuated (all P < 0.01 compared to C57/C57 control). In addition, AP-induced DNA fragmentation was reduced 60% in Fas-/- and FasL-/- mice (P < 0.01 vs. C57/C57). AP induces apoptosis by transcriptional activation of Fas/FasL. AP-induced apoptosis was significantly reduced in Fas and FasL knockout mice along with downregulation of p38-MAPK, PARP, and cytochrome C, thereby suggesting a central role for Fas/FasL in hepatocyte apoptosis. The manipulation of interactions between Kupffer cell-derived FasL and hepatocytes may have important therapeutic implications.

Acute Disease↗
PubMed2006

The role of p65 NF-kappaB/RelA in pancreatitis-induced Kupffer cell apoptosis.

Acute pancreatitis induces liver injury by upregulating Kupffer cell-derived Fas/FasL; on the other hand, acute pancreatitis induces apoptosis of Kupffer cells via NF-kappaB-dependent pathways. The balance between upregulation of Fas/FasL and Fas/FasL-induced apoptosis of its originator cell may determine the severity of pancreatitis-related liver injury. The aim of our study was to determine the role of p65 NF-kappaB/RelA in pancreatitis-induced Kupffer cell apoptosis. Acute pancreatitis was induced in NIH Swiss mice by a choline-deficient ethionine-supplement (CDE) diet. In vitro mouse Kupffer cell line was transfected with p65 siRNA and treated with pancreatic elastase to mimic pancreatitis. CDE pancreatitis upregulated nuclear translocation of p65 NF-kappaB/RelA, Fas/FasL, caspase-3, and DNA fragmentation in mice livers (all P < 0.001). In vitro, pancreatic elastase mimicked CDE-pancreatitis by upregulating nuclear translocation of p65 NF-kappaB/RelA, Fas/FasL, caspase-3, DNA fragmentation, and apoptosis in Kupffer cells (all P < 0.001). Transfection with p65 siRNA attenuated the elastase-induced nuclear translocation of p65 NF-kappaB/RelA, upregulation of Fas/FasL, caspase-3, DNA fragmentation, and apoptosis in Kupffer cells (all P < 0.001). Acute pancreatitis activates p65 NF-kappaB/RelA and induces apoptosis of Kupffer cells. Inhibition of p65NF-kappaB/RelA attenuates elastase-induced upregulation of proapoptotic pathways and apoptosis in Kupffer cells. The ability of Kupffer cells to autoregulate their stress response by inducing self-apoptosis warrants further investigation.

Acute Disease↗
PubMed2004

Thioacetamide-induced hepatic damage in a rat nutritional model of steatohepatitis.

BACKGROUND:: Nonalcoholic steatohepatitis is most often attributed to the effects of obesity, hyperlipidemia, diabetes mellitus and drugs. It is still unknown whether livers with steatohepatitis are more vulnerable to toxic damage. AIM:: To determine the effect of the hepatotoxicant thioacetamide in a rat nutritional model of hepatic steatohepatitis. METHODS:: Steatohepatitis was induced in rats by placing them on a methionine-choline deficient diet for 1 month. Thioacetamide was administered by three consecutive intraperitoneal injections (300mg/kg) at 24h intervals. RESULTS:: Following treatment with thioacetamide, the elevated serum levels of liver enzymes and blood ammonia, liver necroinflammation and the survival rate after 48h were not different between rats with normal or fatty liver. However, those parameters were significantly worse when steatohepatitis regressed after return to normal diet for 1 month (P < 0.01). Western blot analysis of hepatic extracts revealed no difference in cytochrome P4502E1 levels between livers with steatohepatitis and steatohepatitis after regression, suggesting that the enhanced hepatotoxicity after regression of steatohepatitis could not be attributed to increased cytochrome P4502E1. CONCLUSIONS:: In a nutritional model of steatohepatitis, rats with fatty liver were not more vulnerable than normal rats to liver damage induced by thioacetamide. However, liver damage was significantly more severe in rats with steatohepatitis after 1 month regression.

Journal Article↗
PubMed2005

Diagnosis of NASH using delayed parenchymal imaging of contrast ultrasound.

BACKGROUND AND AIMS: Non alcoholic steatohepatitis (NASH) is one of the representative liver diseases in the developed countries. Diagnosis of NASH is dependent on histological findings from liver biopsy. Usefulness of contrast ultrasound with Levovist for diagnosis of NASH is described. METHODS AND MATERIALS: Clinical study: Ultrasound contrast agent, Levovist of 2.5g was injected intravenously. The liver was scanned at 5, 10, 15, 20, 30, 40, and 50min after Levovist injection in different planes using a contrast specific ultrasound mode. Changes in microbubble accumulation in the liver were evaluated. The signal intensity from regions of interest (ROI) on the contrast images was measured and accumulation and decrescence of microbubbles were estimated using the time intensity curves (TICs). The image data and TICs were evaluated by blind reviewers. Fifteen patients with NASH, 8 with alcoholic steatohepatitis (ASH), 45 with non alcoholic fatty liver (NAFL), 10 with chronic hepatitis C (CHC) and 10 healthy volunteers were studied. Animal study: Methionine-choline-deficient diet (MCDD) fed rats were used for NASH model. Correlation between microbubble accumulation and morphological and functional changes of sinusoidal endothelium and macrophage was evaluated. RESULTS: The maximum intensity of contrast ultrasound was decreased and time course decrescence was more rapid in NASH than the other groups. These changes were correlated to the degree of centrilobular and pericellular fibrosis but not to steatosis in histological study. Disturbance of microbubble accumulation was correlated with sinusoidal function rather than morphological changes such as fibrosis and parenchymatitis in the animal studies. CONCLUSIONS: The Levovist contrast study enables differential diagnosis between NASH and other diseases that provoke steatosis and fibrosis.

Journal Article↗
PubMed2005

The role of oxidative stress in NASH and fatty liver model.

The aim of this study was to investigate whether oxidative stress is related to the development of liver injury and an iron chelator, deferoxamine (DFO) can prevent lipid peroxidation resulting in reduced liver injury as well as reduce preneoplastic lesions induced by a choline-deficient l-amino acid-defined (CDAA) diet. CDAA diet administration resulted in an increased serum ALT level after one week. Hepatocytes in rat liver fed a CDAA diet showed malondialdehyde (MDA) accumulation. But simultaneous DFO treatment for one week reduced this elevation of ALT as well as MDA accumulation in the liver. Feeding rats a CDAA diet for 14 weeks led to the development of severe liver fibrosis and preneoplastic lesions detected as enzyme-altered lesions. DFO treatment also prevented the expression of activated stellate cells, resulting in the reduction of liver fibrosis as well as reducing the development of preneoplastic lesions. These results indicate that iron chelation can reduce the development of preneoplastic lesions in a CDAA diet model.

Journal Article↗