Transcription profiling of liver from p38aDhep, IkkbDhep, and control mice 4h after injection of diethylnitrosamine
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Ivan Wick
PROVIDER: E-TABM-351 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Microarray expression profiling has become a valuable tool in the evaluation of the genetic consequences of metabolic disease. Although 3â??-biased gene expression microarray platforms were the first generation to have widespread availability, newer platforms are gradually emerging that have more up-to-date content and/or higher cost efficiency. Deciphering the relative strengths and weaknesses of these various platforms for metabolic pathway level analyses can be daunting. We sought to determine the practical strengths and weaknesses of four leading commercially-available expression array platforms relative to biologic investigations, as well as assess the feasibility of cross-platform data integration for purposes of biochemical pathway analyses. METHODS: Liver RNA from B6.Alb/cre,Pdss2loxP/loxP mice having primary Coenzyme Q deficiency was extracted either at baseline or following treatment with an antioxidant/antihyperlipidemic agent, probucol. Target RNA samples were prepared and hybridized to Affymetrix 430 2.0, Affymetrix Gene 1.0 ST, Affymetrix Exon 1.0 ST, and Illumina Mouse WG-6 expression arrays. Probes on all platforms were re-mapped to coding sequences in the current version of the mouse genome. Data processing and statistical analysis were performed by R/Bioconductor functions, and pathway analyses were carried out by KEGG Atlas and GSEA. RESULTS: Expression measurements were generally consistent across platforms. However, intensive probe-level comparison suggested that differences in probe locations were a major source of inter-platform variance. In addition, genes expressed at low or intermediate levels had lower inter-platform reproducibility than highly expressed genes. All platforms showed similar patterns of differential expression between sample groups, with â??steroid biosynthesisâ?? consistently identified as the most down-regulated metabolic pathway by probucol treatment. CONCLUSIONS: This work offers a timely guide for metabolic disease investigators to enable informed end-user decisions regarding choice of expression microarray platform best-suited to specific research project goals. Successful cross-platform integration of biochemical pathway expression data is also demonstrated, especially for well-annotated and highly-expressed genes. However, integration of gene-level expression data is limited by individual platform probe design and the expression level of target genes. Cross-platform analyses of biochemical pathway data will require additional data processing and novel computational bioinformatics tools to address unique statistical challenges. 4 samples are analyzed on each of 4 different Mouse Microarray Expression platforms (Affymetrix Mo430 2.0, Affymetrix Gene, Affymetrix Exon 1.0 ST, and Illumina Whole Genome 6).
2010-06-24 | E-GEOD-18677 | biostudies-arrayexpress
Project description:The liver plays a central role in whole-body lipid and glucose homeostasis. Increasing dietary fat intake results in increased hepatic fat deposition, which is associated with a risk for development of insulin resistance and type 2 diabetes. In this study, we demonstrate a role for the phosphate inorganic transporter 1 (PiT1/SLC20A1) in regulating metabolism. Specific knockout of Pit1 in hepatocytes significantly improved glucose tolerance and insulin sensitivity, enhanced insulin signalling, and decreased hepatic lipogenesis. We identified USP7 as a PiT1 binding partner and demonstrated that Pit1 deletion inhibited USP7/IRS1 dissociation upon insulin stimulation. This prevented IRS1 ubiquitination and its subsequent proteasomal degradation. As a consequence delayed insulin negative feedback loop and sustained insulin signalling were observed. Moreover, PiT1-deficient mice were protected against high fat diet-induced obesity and diabetes. Our findings indicate that PiT1 has potential as a therapeutic target in the context of metabolic syndrome, obesity, and diabetes.
2016-08-25 | E-MTAB-4989 | biostudies-arrayexpress
Project description:Suppressor of cytokine signaling 3 (SOCS3) down-regulates several signaling pathways in multiple cell types, and previous data suggest that SOCS3 may shut off cytokine activation at the early stages of liver regeneration. We developed hepatocyte-specific Socs3 knockout (Socs3 h-KO) mice to directly study the role of SOCS3 during liver regeneration after 2/3 partial hepatectomy (PH). Socs3 h-KO mice demonstrate marked enhancement of DNA replication and liver weight restoration after 2/3 PH in comparison with littermate controls. Without SOCS3, signal transducer and activator of transcription 3 (STAT3) phosphorylation is prolonged, and activation of the mitogenic kinases extracellular signal-regulated kinase 1/2 (ERK1/2) is enhanced after PH. In vitro, we show that SOCS3 deficiency enhances hepatocyte proliferation in association with enhanced STAT3 and ERK activation after epidermal growth factor (EGF) or interleukin 6 (IL-6) stimulation. Microarray analyses show that SOCS3 modulates a distinct set of genes after PH, which fall into diverse physiologic categories. Using a model of chemical-induced carcinogenesis, we found that Socs3 h-KO mice develop hepatocellular carcinoma (HCC) at an accelerated rate. By acting on cytokines and multiple proliferative pathways, SOCS3 modulates both physiologic and neoplastic proliferative processes in the liver, and may act as a tumor suppressor. Experiment Overall Design: Hepatocyte-specific excision of the Socs3 gene was achieved by breeding Socs3 fl/fl mice with mice expressing the Cre recombinase transgene under control of the albumin promoter (Alb-Cre+), yielding Socs3 h-KO mice. Socs3 fl/fl, Alb-Cre- littermates were used as controls for all experiments, and are henceforth referred to as littermates. All mice (C57BL/6) were free of Helicobacter species, housed in a specific pathogen free facility with 12-h light/dark cycles with free access to standard food and water. 2/3 PH and sham operations were performed as previously described (15, 50) (n=3-6 mice per genotype per time point). Liver remnants were weighed after removal of necrotic stumps and sutures, and compared to post-operative body weight. For HCC experiments, a single i.p. injection of DEN (5mg/kg, Sigma) was performed 12-14 d after birth. For short time points, a single injection of DEN (100mg/kg) (31) was given to 4 wk old mice. At indicated time points, mice were sacrificed by CO2 inhalation. All animal studies were carried out under approved IACUC protocols at the University of Washington.
2008-06-16 | E-GEOD-9549 | biostudies-arrayexpress
Project description:The HGF/c-Met system is an essential inducer of hepatocyte growth and proliferation. Although a fundamental role for the HGF receptor c-Met has been demonstrated in acute liver regeneration its cell specific role in hepatocytes during chronic liver injury and fibrosis progression has not been determined yet. In order to better characterize the role of c-Met in hepatocytes we generated a hepatocyte-specific c-Met knockout mouse (c-MetM-bM-^HM-^Fhepa) using the Cre-loxP system and studied its relevance after bile-duct ligation. Two strategies for c-Met deletion in hepatocytes were tested. Early deletion during embryonic development was lethal, while post-natal Cre-expression was successful leading to the generation of viable c-MetM-bM-^HM-^Fhepa mice. Bile-duct ligation in these mice resulted in extensive necrosis and lower proliferation rates of hepatocytes. Gene array analysis of c-MetM-bM-^HM-^Fhepa mice revealed a significant reduction of anti-apoptotic genes in c-Met deleted hepatocytes. These findings could be functionally tested as c-MetM-bM-^HM-^Fhepa mice showed a stronger apoptotic response after bile-duct ligation and Jo-2 stimulation. This phenotype was associated with increased expression of pro-inflammatory cytokines (TNF-a and IL-6) and an enhanced recruitment of neutrophils. Activation of these mechanisms triggered a stronger pro-fibrogenic response as evidenced by increased TGF-b1, a-SMA, collagen-1a mRNA expression and enhanced collagen-fiber staining in c-MetM-bM-^HM-^Fhepa mice. For gene array analysis c-MetDhepa and c-MetloxP/loxP controls were stimulated for 2 hours with 2M-BM-5g recombinant mouse HGF.Three animals per group were treated in parallel, before and after i.p. injection of recombinant HGF or NaCl.
2009-02-18 | E-GEOD-13992 | biostudies-arrayexpress
Project description:Transcription profiling of mouse livers in adult males and embryos with wild-type and TAF10 -/- hepatocytes.
2008-11-08 | E-MTAB-3 | biostudies-arrayexpress
Project description:A "Cartes d'Identite des Tumeurs" (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net). This work aims to demonstrate a key role for the Wnt/beta-catenin pathway in liver embryonic growth and in controlling the fate of hepatoblasts, preventing them to differentiate towards the hepatocyte lineage, and guiding them to a duct morphogenesis. Through the inactivation of Apc (adenomatous Polyposis Coli) tumor suppressor gene in hepatoblasts by a Cre-loxP strategy, the ectopic activation of beta-catenin targeted in hepatoblasts after liver bud formation leads to a lethal embryonic phenotype, characterized by liver hypoplasia, a blockade of hepatocyte differentiation and commitment to a biliary fate. (this work was supported by INSERM and the B^SLigue Nationale
2007-08-07 | E-TABM-295 | biostudies-arrayexpress
Project description:Quiescent hepatic stem cells (HSCs) can be activated when hepatocyte proliferation is compromised. Chemical injury rodent models have been widely used to study the locazation, biomarkers, and signaling pathways in HSCs, but these models usually exhibit severe promiscuous toxicity and fail to distinguish damaged and non-damaged cells. Our goal is to establish new animal models to overcome these limitations, thereby providing new insights into HSC biology and application. We generated mutant mice with constitutive or inducible deletion of Damaged DNA Binding protein 1 (DDB1), an E3 ubiquitin ligase, in hepatocytes. We show that deletion of DDB1 abolishes self-renewal capacity of mouse hepatocytes in vivo, leading to compensatory activation and proliferation of DDB1-expressing OCs. Importantly, the DDB1 mutant mice exhibit very minor liver damage, compared to a chemical injury model. Microarray analysis reveals several previously unrecognized markers, enriched in oval cells. This genetic model in which irreversible inhibition of hepatocyte duplication results in HSC-driven liver regeneration. The DDB1 mutant mice can be broadly applied to studies of HSC differentiation, HSC niche and HSCs as origin of liver cancer. Total RNA obtained from isolated EpCAM+ cells from DDB1 mutant mice compared to wild type hepatocytes
2012-01-01 | E-GEOD-31588 | biostudies-arrayexpress
Project description:Double transgenic mice with hepatocyte-specific expression of AEG-1 and c-Myc show aggressive HCC compared to single transgenics. Gene expression was analyzed to understand the molecular mechanism by which AEG-1 and c-Myc cooperate to promote hepatocarcinogenesis. Livers were collected from naïve adult mice (3 mice/group). Total RNA was extrancted and subjected to RNA-Seq.
2014-09-30 | E-GEOD-61875 | biostudies-arrayexpress
Project description:Short- and long-interval response of JY cells treated with Trichostatin A (TSA), used in gene pathway analysis. <br><br>Please note that the "Target IDs" used in the user submitted data files have been mapped to Illumina Probe_Ids (as recommended by Illumina) and this mapping is not 1 to 1. Original user submitted files have been included in the .mageml.tar.gz archive on the FTP site for this experiment.
2009-07-08 | E-TABM-356 | biostudies-arrayexpress
Project description:Chronic liver injury triggers complications such as liver fibrosis and hepatocellular carcinoma (HCC), which are associated with alterations in distinct signaling pathways. Of particular interest is the interaction between mechanisms controlled by IKKγ/NEMO, the regulatory IKK subunit, and Jnk activation for directing cell death and survival. In the present study, we aimed to define the relevance of Jnk in hepatocyte-specific NEMO knockout mice (NEMOΔhepa), a genetic model of chronic inflammatory liver injury. We generated global Jnk1-/-/NEMOΔhepa and Jnk2-/-/NEMOΔhepa mice by crossing NEMOΔhepa mice with Jnk1-/- and Jnk2-/- animals, respectively, and examined the progression of chronic liver disease. Moreover, we investigated the expression of Jnk during acute liver injury, evaluated the role of Jnk1 in bone marrow-derived cells, and analyzed the expression of NEMO and pJnk in human diseased-livers. Deletion of Jnk1 significantly aggravated the progression of liver disease, exacerbating apoptosis, compensatory proliferation and carcinogenesis in NEMOΔhepa mice. Jnk2-/-/NEMOΔhepa showed increased RIP-1 and RIP-3 expression and hepatic inflammation. Jnk1 in hematopoietic cells rather than hepatocytes had an impact on the progression of chronic liver disease in NEMOΔhepa livers. These findings are of clinical relevance since NEMO expression was down-regulated in hepatocytes of patients with HCC whereas NEMO and pJnk were expressed in a large amount of infiltrating cells. While Jnk1 is protective in NEMOΔhepa-depleted hepatocytes, Jnk1 in hematopoietic cells rather than hepatocytes is a crucial driver of hepatic injury. These results elucidate the complex function of Jnk in chronic inflammatory liver disease. Livers from global knockout mice for Jnk1 (Jnk1-/-) and Jnk2 (Jnk2-/- ), and double-knockout mice for Jnk1/NEMO (global Jnk1-/-/NEMOΔhepa) and Jnk2/NEMO (global Jnk2-/-/NEMOΔhepa), were subjected to gene expression profiling.
2015-06-22 | E-GEOD-59601 | biostudies-arrayexpress