Background/aims: To learn more about tissue remodelling in fibrotic livers of tetracycline-controlled TGF-beta1 transgenic mice (TGF-beta1-on-mice) and during regeneration after removal of the fibrotic stimulus (off-mice), we investigated the expression of glutamine synthetase (GS), an exclusive pericentrally expressed enzyme.
Methods: GS was localised immunohistochemically and quantified by real-time RT-PCR and enzymatic activity measurement. Apoptosis in livers of TGF-beta1-on-mice was demonstrated by in situ apoptosis detection kit (TUNEL reaction).
Results: Livers of TGF-beta1-on-mice harbour a reduced number of GS-positive hepatocytes and expression of GS is downregulated, while multiple starved mice serving as controls for malnutrition during TGF-beta1 exposure surprisingly showed an impressive amplification of GS-positive hepatocytes. Apoptotic events were frequent around central veins in livers of TGF-beta1-on-mice, while in multiple induced mice apoptosis was dominant around all vessels and weak in midzonal areas. During regeneration from fibrosis, control levels were regained within 21 days. Beta-catenin was dislocated from plasma membrane to cytoplasm exclusively in pericentral hepatocytes during a short time slot after a unique expression of TGF-beta1.
Conclusions: Reduction of GS in TGF-beta1-on-mice results from apoptosis of GS-positive hepatocytes rather than downregulation of GS expression. Beta-catenin seems involved in the recovery of GS-positive hepatocytes.
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Background: Glutamine synthetase (GS) and arginase 1 (Arg1) are widely used pathological markers that discriminate hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma; however, their clinical significance in HCC remains unclear.
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Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations.
Cell Metab
May 2019
Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address:
Based on their lobule location, hepatocytes display differential gene expression, including pericentral hepatocytes that surround the central vein, which are marked by Wnt-β-catenin signaling. Activating β-catenin mutations occur in a variety of liver tumors, including hepatocellular carcinoma (HCC), but no specific therapies are available to treat these tumor subsets. Here, we identify a positive relationship between β-catenin activation, its transcriptional target glutamine synthetase (GS), and p-mTOR-S2448, an indicator of mTORC1 activation.
View Article and Find Full Text PDFGadoxetic acid-enhanced magnetic resonance imaging reflects co-activation of β-catenin and hepatocyte nuclear factor 4α in hepatocellular carcinoma.
Hepatol Res
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Department of Radiology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Aim: The aim of this study is to clarify the correlation of the co-activation of β-catenin and hepatocyte nuclear factor (HNF)4α with the findings of gadoxetic acid-enhanced magnetic resonance imaging (MRI), organic anion transporting polypeptide (OATP)1B3 expression, and histological findings in hepatocellular carcinoma (HCC).
Methods: One hundred and ninety-six HCCs surgically resected from 174 patients were enrolled in this study. The HCCs were classified into four groups by immunohistochemical expression of β-catenin, glutamine synthetase (GS), and HNF4α: (i) β-catenin/GS (positive [+]) HNF4α (+); (ii) β-catenin/GS (+) HNF4α (negative [-]); (iii) β-catenin/GS (-) HNF4α (+); and (iv) β-catenin/GS (-) HNF4α (-).
Expressional changes of carbamoyl phosphate synthetase and glutamine synthetase in the liver of rat with thioacetamide-induced cirrhosis.
J Med Assoc Thai
January 2013
Department of Science, Faculty of lnternational College, Mahidol University, Bangkok, Thailand.
Background: In order to detoxify ammonia, mammalian livers use carbamoyl phosphate synthetase (CPS) and glutamine synthetase (GS) for conversion into respective non-toxic urea and glutamine. CPS is expressed in the periportal hepatocytes whereas GS is contained in the pericentral hepatocytes.
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Cellular concentrations of glutamine synthetase in murine organs.
Biochem Cell Biol
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Department of Anatomy and Embryology, University of Maastricht, Netherlands.
Glutamine synthetase (GS) is the only enzyme that can synthesize glutamine, but it also functions to detoxify glutamate and ammonia. Organs with high cellular concentrations of GS appear to function primarily to remove glutamate or ammonia, whereas those with a low cellular concentration appear to primarily produce glutamine. To validate this apparent dichotomy and to clarify its regulation, we determined the GS concentrations in 18 organs of the mouse.
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