Liver precursor cells increase hepatic fibrosis induced by chronic carbon tetrachloride intoxication in rats.

Hepatic fibrosis, the major complication of virtually all types of chronic liver damage, usually begins in portal areas, and its severity has been correlated to liver progenitor cells (LPC) expansion from periportal areas, even if the primary targets of injury are intralobular hepatocytes. The aim of this study was to determine the potential fibrogenic role of LPC, using a new experimental model in which rat liver fibrosis was induced by chronic carbon tetrachloride (CCl(4)) administration for 6 weeks, in combination with chronic acetylaminofluorene treatment (AAF), which promotes activation of LPC compartment. Treatment with CCl(4) alone caused a significant increase in serum transaminase activity as well as liver fibrosis initiating around central veins and leading to formation of incomplete centro-central septa with sparse fibrogenic cells expressing α-smooth muscle actin (αSMA).

Gas6 deficiency prevents liver inflammation, steatohepatitis, and fibrosis in mice.

The Gas6/Axl pathway has been increasingly implicated in regeneration and tissue repair and, recently, in the control of innate immunity. In liver, we have demonstrated that Gas6 and its receptor Axl are expressed in macrophages, progenitor cells, and myofibroblasts and that Gas6 deficiency reduced inflammation and myofibroblast activation, causing delayed liver repair in response to acute injury. All these data suggest a role of Gas6/Axl signaling in pathogenesis of chronic liver diseases.

Growth arrest-specific protein 6 deficiency impairs liver tissue repair after acute toxic hepatitis in mice.

Background/aims: Resident macrophages and myofibroblasts derived from hepatic stellate cells play a key role in liver wound healing. We previously reported that these sinusoidal cells secrete the growth arrest-specific protein 6 (Gas6) and express Axl, one of its receptors. Here we address the role of Gas6 in the healing process during acute liver injury.

Expression of matrix metalloproteinase-2 and -9 and of tissue inhibitor of matrix metalloproteinase-1 in liver regeneration from oval cells in rat.

Oval cells participate in liver regeneration when hepatocyte replication is impaired. These precursor cells proliferate in periportal regions and organize in ductules. They are surrounded by a basement membrane, the degradation of which by matrix metalloproteinases (MMP) might trigger their terminal differentiation into hepatocytes.

Induction of Gas6 protein in CCl4-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells.

The protein product of the growth arrest-specific gene 6 (Gas6) is a secreted ligand for tyrosine kinase receptors, among which Axl is the most widely distributed and displays the highest affinity for Gas6. The Gas6/Axl signaling pathway has been increasingly implicated in growth and survival processes occurring during development and tissue repair. In liver, after an acute or chronic injury, repair involves macrophages and hepatic stellate cells (HSC) activated into myofibroblastic cells (HSC/MFB), which produce cytokines and matrix proteins.

gamma-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells.

gamma-Glutamyl transpeptidase (GGT) plays key roles in glutathione homeostasis and metabolism of glutathione S-conjugates. Rat GGT is transcribed via five tandemly arranged promoters into seven transcripts. The transcription of mRNA V is controlled by promoter 5.

Expression and role of Gas6 protein and of its receptor Axl in hepatic regeneration from oval cells in the rat.

Background & Aims: The growth arrest-specific gene 6 (Gas6) protein is a vitamin K-dependent protein that binds to the Axl subfamily of tyrosine kinase receptors and exerts antiapoptotic and proliferative effects. Because Gas6 plays a role in development and tissue remodelling, we studied its expression as well as that of its high-affinity receptor Axl in a well-characterized model of hepatic regeneration from precursor oval cells.

Methods: Hepatic regeneration was induced by treating rats with acetylaminofluorene followed by partial hepatectomy.

4-Hydroxynonenal induces rat gamma-glutamyl transpeptidase through mitogen-activated protein kinase-mediated electrophile response element/nuclear factor erythroid 2-related factor 2 signaling.

Gamma-glutamyl transpeptidase (GGT) plays critical roles in glutathione homeostasis and metabolism. Rat GGT is a single-copy gene from which seven types of GGT mRNA with a common protein encoding sequence, but different 5'-untranslated regions, may be transcribed. We previously showed that type V-2 was the predominant form of GGT mRNA in rat L2 epithelial cells, and that it could be induced by 4-hydroxynonenal (HNE) through the electrophile response element (EpRE) located in GGT promoter 5 (GP5).

Expression of stromal cell-derived factor-1 and of its receptor CXCR4 in liver regeneration from oval cells in rat.

Stromal cell-derived factor-1 is a chemokine that plays a major role during embryogenesis. Since stromal cell-derived factor-1 and its unique receptor CXCR4 are involved in the differentiation of progenitor cells, we studied the expression of this chemokine and of its receptor in hepatic regeneration from precursor oval cells. Hepatic regeneration was induced by treating rats with 2-acetylaminofluorene, and followed by partial hepatectomy.

Apoptosis of human hepatic myofibroblasts promotes activation of matrix metalloproteinase-2.

Liver fibrosis is potentially reversible after removal of the injurious agent. Fibrosis resolution is characterized by apoptosis of hepatic myofibroblasts and degradation of extracellular matrix components. Matrix metalloproteinase-2 (MMP-2) is involved in matrix remodeling.

The expression of gamma-glutamyltransferase in rat colon carcinoma cells is distinctly regulated during differentiation and oxidative stress.

Gamma glutamyltransferase (GGT) is a plasma membrane bound enzyme that initiates the degradation of glutathione. The presence of several promoters in the rat GGT gene indicates strict control and regulation of its expression. The aim of this study was to investigate whether the GGT gene was regulated differently after butyrate-induced differentiation and oxidative stress exposure of rat colon carcinoma cells and whether the regulation was related to the glutathione level.

In vitro differentiation of WB-F344 rat liver epithelial cells into the biliary lineage.

Differentiation of hepatic precursor cells in the biliary lineage has rarely been investigated, owing to the lack of convenient in vitro models. In this study, we used sodium butyrate and culture on Matrigel to promote differentiation of WB-F344 rat liver epithelial cells along the biliary phenotype. This differentiation was assessed by following the expression of phenotypic markers at the protein or mRNA level.

Differential expression of the rat gamma-glutamyl transpeptidase gene promoters along with differentiation of hepatoblasts into biliary or hepatocytic lineage.

gamma-Glutamyl transpeptidase (GGT), a major enzyme of glutathione (GSH) homeostasis, is often used as a biliary marker to follow the differentiation of hepatic precursor cells. The expression of the GGT gene is driven by different promoters and yields multiple mRNAs, depending on the cell type or the stage of differentiation. In the present study, we analyzed the GGT mRNA expression pattern by quantitative reverse transcriptase-polymerase chain reaction or by in situ hybridization i) in the liver, in vivo, at early stages of development; ii) in oval cells, which proliferate and differentiate into hepatocytes in response to galactosamine injury in vivo; and finally, iii) during hepatoblast differentiation, in vitro.

Gamma-glutamyl transpeptidase gene organization and expression: a comparative analysis in rat, mouse, pig and human species.

Gamma-glutamyl transpeptidase (GGT) is an enzyme located at the external surface of epithelial cells. It initiates extracellular glutathione (GSH) breakdown, provides cells with a local cysteine supply and contributes to maintain intracellular GSH level. GGT expression, highly sensitive to oxidative stress, is a part of the cell antioxidant defense mechanisms.

The gamma-glutamyl transpeptidase gene is transcribed from a different promoter in rat hepatocytes and biliary cells.

Gamma-glutamyl transpeptidase (GGT) activity is commonly used to follow the differentiation of liver precursor cells into the biliary lineage. However, the GGT expression in immature hepatocytes or its induction in adult hepatocytes following diverse carcinogenic or noncarcinogenic treatments has questioned the reliability of GGT expression as a biliary marker. In the present study, we investigated the GGT gene expression from its five different promoters in the late fetal, neonatal, and adult rat liver by Northern blot, reverse transcription-polymerase chain reaction, and in situ hybridization analysis.

A specific distal promoter controls gamma-glutamyl transpeptidase gene expression in undifferentiated rat transformed liver cells.

In rat undifferentiated hepatoma cells, the gamma-glutamyl transpeptidase (GGT) gene is transcribed into a 2.3 and a 2.6 kb mRNA which, in contrast with other rat GGT transcripts, are not detected in more differentiated liver cells or adult tissues.

Species differences in the localisation of gamma-glutamyl transpeptidase immunopositive cells at the blood-brain interface.

The expression of gamma-glutamyl transpeptidase (GGT) has been associated with the emergence of a functional blood-brain barrier. We have undertaken a precise localisation of this enzyme in the cerebral cortical vessels of different species, by immunocytochemistry using a polyclonal antibody and light and electron microscopy. GGT immunoreaction product was present on the luminal surface of endothelial cells in 1-day-old to 3-month-old rats, whereas in the mouse, monkey and human cortex, this protein was present in astrocytic endfeet around the vessels.

Control of gamma-glutamyl transpeptidase expression by glucocorticoids in the rat pancreas. Correlation with granule formation.

Glucocorticoids are known to promote the formation of zymogen granules in acinar cells of the exocrine pancreas in vivo as well as in vitro. To gain insight into the mechanism of this regulation, we studied the effects of glucocorticoids on the synthesis of two components of the secretory granule membrane, the glycoprotein 2 (GP-2) and the gamma-glutamyl transpeptidase (GGT). It was demonstrated that following adrenalectomy, degranulation of pancreatic acinar cells is accompanied by a sharp decrease in GGT and GP-2 synthesis as measured by mRNA and protein accumulation.

Three alternative promoters of the rat gamma-glutamyl transferase gene are active in developing lung and are differentially regulated by oxygen after birth.

The rat gamma-glutamyl transferase mRNA transcripts I, II, and III are derived from three alternative promoters, P(I), P(II), and P(III). In the adult only mRNA III is expressed in the lung. We show that mRNA III gene expression is developmentally regulated in the fetal lung; it is first expressed in gestation.

Expression of the rat gamma-glutamyl transpeptidase gene from a specific promoter in the small intestine and in hepatoma cells.

In the small intestine and in HTC hepatoma cells, the gamma-glutamyl transpeptidase (GGT) single-copy gene is transcribed into a 2.5 kb and a 2.2 kb mRNA.

Functional characterization of the rat gamma-glutamyl transpeptidase promoter that is expressed and regulated in the liver and hepatoma cells.

gamma-Glutamyl transpeptidase (GGT) is an enzyme encoded by multiple mRNAs (mRNAI to mRNAIV) that, in the rat, are transcribed from a single copy gene in a tissue-specific manner. In the liver, GGT expression is up-regulated in transformed cells, and this induction is the most widely used marker of liver cell transformation. We characterized the GGT mRNA species expressed in the liver (mRNAIII), and we report that this mRNA differs from the other GGT mRNA species by a 275-base alternate 5'-end sequence.

Multiple forms of gamma-glutamyl transpeptidase messenger ribonucleic acid are expressed in the adult rat testis and epididymis.

The expression of gamma-glutamyl transpeptidase (GGT) mRNA in tissues of the adult rat male reproductive tract was examined. Northern blot analysis of total RNA revealed that GGT mRNA expression occurs primarily in the initial segment and caput epididymidis. Multiple GGT mRNAs of varying sizes were detected in the testis and in different regions of the epididymis: testis, 2.

Immunocytochemical localization of gamma-glutamyltranspeptidase, GP-2 and amylase in the rat exocrine pancreas: the concept of zymogen granule membrane recycling after exocytosis.

We localized gamma-glutamyltranspeptidase (GGT) in the rat pancreas by immunocytochemistry using the protein A-gold technique. The enzyme was found in the apical and zymogen granule (ZG) membranes of the pancreatic acinar cell. With ZG at the onset of exocytosis, labeling was seen over membrane, whereas content was unreactive.