Characterization of liver injury, oval cell proliferation and cholangiocarcinogenesis in glutathione S-transferase A3 knockout mice

Hepatic stem cells (oval cells) proliferate within the liver after exposure to a variety of hepatic carcinogens and can generate both hepatocytes and bile duct cells. Oval cell proliferation is commonly seen in the preneoplastic stages of liver carcinogenesis, often accompanied by an inflammatory response. Tumor necrosis factor (TNF), an inflammatory cytokine, is also important in liver regeneration and hepatocellular growth. The experiments reported here explore the relationship among the TNF inflammatory pathway, liver stem cell activation, and tumorigenesis. We demonstrate that TNF is upregulated during oval cell proliferation induced by a choline-deficient, ethionine-supplemented diet and that it is expressed by oval cells. In TNF receptor type 1 knockout mice, oval cell proliferation is substantially impaired and tumorigenesis is reduced. Oval cell proliferation is impaired to a lesser extent in interleukin 6 knockout mice and is unchanged in TNF receptor type 2 knockout mice. These findings demonstrate that TNF signaling participates in the proliferation of oval cells during the preneoplastic phase of liver carcinogenesis and that loss of signaling through the TNF receptor type 1 reduces the incidence of tumor formation. The TNF inflammatory pathway may be a target for therapeutic intervention during the early stages of liver carcinogenesis.

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SEQUENTIAL QUANTITATIVE ANALYSIS OF OVAL CELL PROLIFERATION IN THIOACETAMIDE TREATED RATS

Image Analysis & Stereology ◽

10.5566/ias.v20.p105-112 ◽

2011 ◽

Vol 20 (2) ◽

pp. 105

Author(s):

Abdul M Zaitoun ◽

Christopher O Record ◽

Hanan Al-Mardini

Keyword(s):

Cell Proliferation ◽

Bile Duct ◽

Liver Injury ◽

Oval Cells ◽

Image Analysis System ◽

Oval Cell ◽

Hepatocyte Regeneration ◽

Duct Cells ◽

Complete Restoration ◽

Analysis System

Oval cells are the progeny of facultative stem cells found in the periportal areas in response to liver injury in experimental animals and humans. The aims of this study were to describe the morphological, stereological and morphometric features of oval cells, and to compare them with those of bile duct cells and hepatocytes. It was also aimed to study the fate of oval cells by morphological and morphometric criteria. Rats were given thioacetamide to induce liver injury. The livers from experimental and control groups were processed routinely and stereological and morphometric analysis assessed using a computer image analysis system. Eight morphometric parameters were assessed in oval cells, bile duct cells and hepatocytes from control and experimental rats. Mitoses were observed in both oval cells and hepatocytes. Stereological area fraction analysis indicated that necrosis reached its maximum extent at 30 hours followed by regeneration and almost complete restoration of liver cell parenchyma at 132 hours. Oval cell proliferation reached a peak at 48-52 hours but was not apparent at 132 hours. Morphometric findings have shown increases in the nuclear diameter and nuclear area of oval cells with changes in the roundness and contours ratios of the nuclear membrane. It is concluded from this study that in thioacetamide treated rats, the liver responds to injury by bile ductal proliferation in the periportal areas which, accompanied by hepatocyte regeneration, leads to restoration of the hepatic parenchyma. At a subcellular morphological level the nuclei of oval cells showed a progressive change to a hepatocyte phenotype from that of a normal biliary cell, suggesting the differentiation of these cells into hepatocytes.

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P0930 : Lessons from hepatocyte-specific CYP51 knockout mice: Impaired cholesterol synthesis leads to NASH-like oval cell driven liver injury

Journal of Hepatology ◽

10.1016/s0168-8278(15)31131-4 ◽

2015 ◽

Vol 62 ◽

pp. S693-S694

Author(s):

G. Lorbek ◽

M. Perse ◽

J. Jeruc ◽

P. Juvan ◽

R. Gebhardt ◽

...

Keyword(s):

Liver Injury ◽

Knockout Mice ◽

Cholesterol Synthesis ◽

Oval Cell

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Accelerated Partial Hepatectomy–Induced Liver Cell Proliferation Is Associated with Liver Injury in Nur77 Knockout Mice

American Journal Of Pathology ◽

10.1016/j.ajpath.2014.08.002 ◽

2014 ◽

Vol 184 (12) ◽

pp. 3272-3283 ◽

Cited By ~ 9

Author(s):

Ying Hu ◽

Qi Zhan ◽

Hui-Xin Liu ◽

Thinh Chau ◽

Yuyuan Li ◽

...

Keyword(s):

Cell Proliferation ◽

Liver Injury ◽

Partial Hepatectomy ◽

Liver Cell ◽

Knockout Mice

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Characterization of Endothelial Dysfunction in Microrna-34A Knockout Mice with Alcoholic Liver Injury

Gastroenterology ◽

10.1016/s0016-5085(17)33741-1 ◽

2017 ◽

Vol 152 (5) ◽

pp. S1111

Author(s):

Ying Wan ◽

Kelly M. McDaniel ◽

Nan Wu ◽

Sugeily Ramos-Lorenzo ◽

Tianhao Zhou ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Liver Injury ◽

Knockout Mice ◽

Alcoholic Liver Injury

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Characterization of glutathione S-transferase enzymes in Dictyostelium discoideum suggests a functional role for the GSTA2 isozyme in cell proliferation and development

PLoS ONE ◽

10.1371/journal.pone.0250704 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0250704

Author(s):

Mamatha Garige ◽

Eric Walters

Keyword(s):

Cell Proliferation ◽

Dictyostelium Discoideum ◽

Functional Role ◽

Model Organism ◽

Fruiting Bodies ◽

Percent Reduction ◽

Glutathione S Transferase ◽

Gst Activity ◽

Starvation Conditions

In this report, we extend our previous characterization of Dictyostelium discoideum glutathione S-transferase (DdGST) enzymes that are expressed in the eukaryotic model organism. Transcript profiling of gstA1-gstA5 (alpha class) genes in vegetative, log phase cells identified gstA2 and gstA3 with highest expression (6–7.5-fold, respectively) when compared to other gstA transcripts. Marked reductions in all gstA transcripts occurred under starvation conditions, with gstA2 and gstA3 exhibiting the largest decreases (-96% and -86.6%, respectively). When compared to their pre-starvation levels, there was also a 60 percent reduction in total GST activity. Glutathione (GSH) pull-down assay and mass spectroscopy detected three isozymes (DdGSTA1, DdGSTA2 and DdGSTA3) that were predominantly expressed in vegetative cells. Biochemical and kinetic comparisons between rDdGSTA2 and rDdGSTA3 shows higher activity of rDdGSTA2 to the CDNB (1-chloro-2,4-dinitrobenzene) substrate. RNAi-mediated knockdown of endogenous DdGSTA2 caused a 60 percent reduction in proliferation, delayed development, and altered morphogenesis of fruiting bodies, whereas overexpression of rDdGSTA2 enzyme had no effect. These findings corroborate previous studies that implicate a role for phase II GST enzymes in cell proliferation, homeostasis, and development in eukaryotic cells.

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