Induction of steatohepatitis and liver tumorigenesis by enforced Snail expression in hepatocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE141110 | GEO | 2020/02/21
REPOSITORIES: GEO
Similar Datasets
Project description:Induction of steatohepatitis and liver tumorigenesis by enforced Snail expression in hepatocytes
| PRJNA592136 | ENA
Project description:Acute toxic responses to a single 50 mg/kg oral dose of 1-napthylisothiocyanate (ANIT) were evaluated by microarray analysis of laser capture-microdissected rat biliary epithelium or hepatic parenchyma at 2 and 6 hours post-dose. Selective and dramatic differences between the biliary epithelium and the hepatic parenchyma were evident as soon as 2 hours at which time 375 genes were altered in biliary epithelium, but only a nominal 38 genes were altered in the hepatic parenchyma. Gene expression analysis revealed increased expression of genes involved in the unfolded protein response and ER stress in biliary epithelial cells, but no alteration of these genes in hepatocytes. By 6 hours post dose, 620 genes showed altered expression in biliary epithelium while there were only 32 genes altered in hepatic parenchyma. At this timepoint, analysis of the biliary epithelium revealed decreased expression of genes involved in the unfolded protein response compared to the 2 hour time point, and increased expression at 6 hours of genes involved in protein degradation such as proteasome-ubquination pathways, and genes associated with cell death. Our analysis revealed early loss of biliary epithelial integrity and attempts at repair of damage with subsequent activation of protein degradation and cell fate decisions leading to death pathways within a 6 hour time course. During this same time interval, hepatic parenchymal gene expression changed little and mainly reflected a decrease in enterohepatic circulation of bile acids and an increase in ribosomal proteins which may signal an adaptive change to reduced bile acid delivery to the liver and an increased demand for bile acids and glutathione-mediated transport of ANIT. This versatile approach provides a precise evaluation of distinct cell populations, biliary epithelium and hepatic parenchyma, in situ. (Cullen et.al., Toxicologic Pathology 2010) Rat were exposed to a single dose of 1-napthylisothiocyanate (ANIT) or vehicle. Laser capture-microdissection was used to isolate rat biliary epithelium or hepatic parenchyma at 2 and 6 hours post-dose. Affymetrix GeneChips and Rosetta Resolver were used to determine differential gene expression.
2010-03-09 | E-GEOD-20498 | biostudies-arrayexpress
Project description:Abstract: Interruption of bile acid recirculation through inhibition of the apical sodium-dependent bile acid transporter (ASBT) is a promising strategy to alleviate hepatic cholesterol accumulation in non-alcoholic steatohepatitis, and improve the metabolic aspects of the disease. Putative disease-attenuating effects of the ASBT inhibitor volixibat (5, 15, and 30 mg/kg) were investigated in high-fat diet (HFD)-fed Ldlr-/-.Leiden mice over 24 weeks. Plasma and fecal bile acid levels, plasma insulin, lipids, and liver enzymes were monitored. Final analyses included liver histology, intrahepatic lipids, mesenteric white adipose tissue mass, and liver gene profiling. Consistent with its mechanism of action, volixibat significantly increased total bile acid excretion. At the highest dose, volixibat significantly attenuated the HFD-induced increase in hepatocyte hypertrophy, hepatic triglyceride and cholesteryl ester levels, and mesenteric white adipose tissue deposition, while total plasma bile acid levels remained constant. Non-alcoholic fatty liver disease activity score was significantly lower in volixibat-treated mice than in the HFD controls. Gene profiling showed that volixibat reversed the inhibitory effect of the HFD on metabolic master regulators, including peroxisome proliferator-activated receptor-γ coactivator-1β, insulin receptor, and sterol regulatory element-binding transcription factor 2. Volixibat may have beneficial effects on physiological and metabolic aspects of non-alcoholic steatohepatitis pathophysiology.
2019-06-07 | GSE129306 | GEO
Project description:Acute toxic responses to a single 50 mg/kg oral dose of 1-napthylisothiocyanate (ANIT) were evaluated by microarray analysis of laser capture-microdissected rat biliary epithelium or hepatic parenchyma at 2 and 6 hours post-dose. Selective and dramatic differences between the biliary epithelium and the hepatic parenchyma were evident as soon as 2 hours at which time 375 genes were altered in biliary epithelium, but only a nominal 38 genes were altered in the hepatic parenchyma. Gene expression analysis revealed increased expression of genes involved in the unfolded protein response and ER stress in biliary epithelial cells, but no alteration of these genes in hepatocytes. By 6 hours post dose, 620 genes showed altered expression in biliary epithelium while there were only 32 genes altered in hepatic parenchyma. At this timepoint, analysis of the biliary epithelium revealed decreased expression of genes involved in the unfolded protein response compared to the 2 hour time point, and increased expression at 6 hours of genes involved in protein degradation such as proteasome-ubquination pathways, and genes associated with cell death. Our analysis revealed early loss of biliary epithelial integrity and attempts at repair of damage with subsequent activation of protein degradation and cell fate decisions leading to death pathways within a 6 hour time course. During this same time interval, hepatic parenchymal gene expression changed little and mainly reflected a decrease in enterohepatic circulation of bile acids and an increase in ribosomal proteins which may signal an adaptive change to reduced bile acid delivery to the liver and an increased demand for bile acids and glutathione-mediated transport of ANIT. This versatile approach provides a precise evaluation of distinct cell populations, biliary epithelium and hepatic parenchyma, in situ. (Cullen et.al., Toxicologic Pathology 2010)
2010-02-24 | GSE20498 | GEO
Project description:Pathogenesis and factors for determining progression of alcoholic and non-alcoholic steatosis to steatohepatitis with risk of further progression to liver cirrhosis and cancer are poorly understood. In the present study, we aimed to identify potential molecular signatures for discrimination of steatohepatitis from steatosis. Global gene expression analysis was applied to unravel differentially expressed genes between steatohepatitis compared to steatosis and control samples. For functional annotation as well as the identification of disease-relevant biological processes of the differentially expressed genes the gene ontology (GO) database was used. Genes down-regulated in steatohepatitis were mainly involved in metabolic processes. Genes up-regulated in steatohepatitis samples were associated with cancer progression and proliferation. Further statistical and pathway analysis lead to the selection of 46 candidate genes which were validated in two sample cohorts by quantitative real-time PCR. In surgical liver resection samples 39 genes and in percutaneous liver biopsies 30 genes were significantly up-regulated in steatohepatitis. Conclusion: The development of steatohepatitis is characterized by distinct molecular changes. 44 human liver tissue surgical samples (normal n=13; steatosis n=19; steatohepatitis n=12, 8/2 cirrhotic/non-cirrhotic) obtained from patients undergoing liver surgery for HCC, other malignancy/metastatic disease, benign tumors of the liver and organ dedicated to transplantation. Virtually normal control samples in this cohort were taken from patients undergoing surgical resection of liver metastasis, but the surrounding liver tissue used for the molecular analyses was normal, non-tumorous liver tissue without detectable pathological changes. The samples were provided by the Biobank at the Medical University of Graz. This dataset is part of the TransQST collection.
2012-12-10 | E-GEOD-33814 | biostudies-arrayexpress
Project description:Transcriptional profiling of mouse 4T1 breast cancer cells stably tranduced with pLEX-MCS based lentivirus. Three groups were compared, Vector cells, SNAIL expressing cells; and SNAIL+FBXO11 expressing cells. SNAIL expression induced strong EMT phenotype while SNAIL/FBXO11 reversed cells back to epithelial cells.
2014-12-01 | GSE50887 | GEO
Project description:Farnesoid X receptor (FXR) agonism is emerging as an important potential therapeutic mechanism of action for multiple chronic liver diseases. The bile acid–derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in a phase 2 study in patients with nonalcoholic steatohepatitis (NASH). Here, we report efficacy of a novel, non–bile acid FXR agonist tropifexor (LJN452) in two distinct preclinical models of NASH. The efficacy of tropifexor at <1 mg/kg doses was superior to that of OCA at 25 mg/kg in the liver in both NASH models. In a chemical and dietary model of NASH (STAM model), tropifexor reversed established fibrosis and reduced nonalcoholic fatty liver disease activity score and hepatic triglycerides. In an insulin-resistant, obese NASH model (AMLN), tropifexor markedly reduced steatohepatitis, fibrosis, and profibrogenic gene expression. Transcriptome analysis of livers from AMLN mice revealed 461 differentially expressed genes following tropifexor treatment, which included a combination of signatures associated with reduction of oxidative stress, fibrogenesis, and inflammation. Conclusion: Based on the preclinical validation in animal models, tropifexor is a promising investigational therapy that is currently under phase 2 development for NASH.
2019-08-20 | GSE129389 | GEO
Project description:Our study shows that TGF-β signaling promotes tumorigenesis in the liver through upregulation of its target gene, Snail. We explored gene expression changes in tumors following TGF-β inhibition, and tumors ectopically expressing Snail with the TGF-β inhibition. RNA samples were harvested from tumors expressing Smad7 (S7HP tumors), firefly luciferase (LHP tumors), and Smad7 plus Snail (S7HP+Snail), respectively. Differentially expressed genes were investigated in LHP and S7HP+Snail tumors, compared with S7HP tumors.
2017-07-24 | GSE90024 | GEO
Project description:Transcriptional profiling of mouse HMLEN breast cancer cells (HMLE cells transformed with -Neu oncogene) stably tranduced with pLEX-MCS based lentivirus. Three groups were compared, Vector cells, SNAIL expressing cells; and SNAIL+FBXO11 expressing cells. SNAIL expression induced strong EMT phenotype while SNAIL/FBXO11 reversed cells back to epithelial cells.
2014-12-01 | GSE50888 | GEO
Project description:Due to the global obesity epidemic the incidences of nonalcoholic steatohepatitis (NASH) and NASH-related hepatocellular carcinoma (HCC) are on the rise. Non-invasive treatment options for HCC are scarce and innovative therapy regimes are urgently needed. The mechanistic target of rapamycin (mTOR) is of fundamental importance for the regulation of cellular metabolism and mTOR pathway activation is frequently observed in HCCs. However, mTOR inhibition failed to benefit the clinical course of HCC patients, demonstrating the need for a better understanding of the molecular and functional consequences of blocking mTOR signaling in primary liver cancer. To address this, we established a tumor cell-specific inactivation of mTOR in a murine model of non-alcoholic steatohepatitis (NASH)-driven HCC. After 30 weeks of diet, tumor, and liver volumes as well as whole body fat percentage were evaluated by non-invasive in vivo micro-computed tomography (µCT), and livers were collected for subsequent analyses. Unexpectedly, the tumor load exploded in mTORLEC livers and knock-out mice showed improved glucose tolerance among other signs of major metabolic alterations. Detailed proteome analysis indicated extensive changes in arachidonic and bile acid metabolism in the liver. The simulation of metformin intervention via kinetic modeling predicted the existence of a therapeutic window, in which the drug selectively targets mTORLEC HCC tissue.
2023-11-15 | PXD039944 | Pride