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Gene expression profiling of hepatitis development and hepatocarcinogenesis initiation in LEC rats.

ABSTRACT: LEC rats are considered as interesting model for studying hepatitis and development of hepatocarcinogenesis related to copper accumulation and oxidative stress. LEC rats have a mutation in a gene related to liver copper excretion, the Atp7b gene. As a consequence, this rat strain shows an abnormal copper accumulation in the liver. This is believed to be the origin of the acute hepatitis and the subsequent hepatocellular carcinoma that spontaneously develop in these rats. Here, we present the gene expression profiles of LEC rats at different disease stages. LEC rats were classified as normal 6 weeks old (6w), normal 9 weeks old (9w), slight jaundice and jaundice according to age and disease state. D-penicillamine, a copper chelator agent, blocks both hepatitis and tumor development. D-penicillamine-trated LEC rats were used as control rats for gene expression comparison as they showed neither hepatitis development nor tumor marker expression. Gene expression differences in protein metabolism and tumor marker proteins add to the known oxidative stress and inflammation characterization of the hepatitis process, leading to new insights concerning hepatitis and hepatocarcinogenesis development. Keywords: disease state analysis

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE7654 | GEO | 2008/04/25

SECONDARY ACCESSION(S): PRJNA99747

REPOSITORIES: GEO

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Gene expression profiling of hepatitis development and hepatocarcinogenesis initiation in LEC rats.

Project description:LEC rats are considered as interesting model for studying hepatitis and development of hepatocarcinogenesis related to copper accumulation and oxidative stress. LEC rats have a mutation in a gene related to liver copper excretion, the Atp7b gene. As a consequence, this rat strain shows an abnormal copper accumulation in the liver. This is believed to be the origin of the acute hepatitis and the subsequent hepatocellular carcinoma that spontaneously develop in these rats. Here, we present the gene expression profiles of LEC rats at different disease stages. LEC rats were classified as normal 6 weeks old (6w), normal 9 weeks old (9w), slight jaundice and jaundice according to age and disease state. D-penicillamine, a copper chelator agent, blocks both hepatitis and tumor development. D-penicillamine-trated LEC rats were used as control rats for gene expression comparison as they showed neither hepatitis development nor tumor marker expression. Gene expression differences in protein metabolism and tumor marker proteins add to the known oxidative stress and inflammation characterization of the hepatitis process, leading to new insights concerning hepatitis and hepatocarcinogenesis development. Keywords: disease state analysis 6 weeks old LEC rats, 6 rats per group, were sacrified at different hepatitis stages. Biochemical and histological analyses were performed in order to classify the rats into normal, slight jaundice or jaundice groups. D-penicillamine-treated LEC rats (100 mg/kg/day p.o.) were used as control rats since they behave as normal rats. Microarray analysis was performed on liver samples, one replicate per rat, using dyes swap.

2008-04-24 | E-GEOD-7654 | biostudies-arrayexpress

Rattus norvegicus

Project description:Gene expression profiling of hepatitis development and hepatocarcinogenesis initiation in LEC rats.

| PRJNA99747 | ENA

Expression data from HepG2 and LX2 cells treated with a dual epigenetic inhibitor of G9A and DNMT1.

Project description:Hepatocarcinogenesis involves epigenetic abnormalities of great relevance. Both the histone methyltransferase G9A and the DNA methyltransferase DNMT1 are overexpressed in fibrosis and liver tumor development. We used microarrays to evaluate the global programme of gene expression in the human HCC cell line HepG2 and in the human Hepatic Stellate Cell LX2, trated with CM272. This molecule is an epigenetic inhibitor that simultaneously targets the methyltransferase activities of G9a and DNMT1.

2021-02-09 | GSE110418 | GEO

HF001-A: Gene expression patterns in the progression towards canine copper-associated chronic hepatitis

Project description:Copper is an essential trace element, but can become toxic when present in abundance. The severe effects of copper-metabolism imbalance are illustrated by the inherited disorders Wilson disease and Menkes disease. The Labrador retriever dog breed is a novel non-rodent model for copper-storage defects displaying identical phenotypic alterations and carrying mutations in genes known to be involved in copper transport. Besides disease initiation and progression of copper accumulation, the molecular mechanisms and pathways involved in copper accumulation and eventually progression towards copper associated chronic hepatitis still remains unclear. Using liver tissue of Labrador retrievers in different stages of copper-associated hepatitis, expression levels targeted at candidate genes as well as transcriptome microarrays, have shed light on involved molecular pathways. At the initial phase, viz. increased hepatic copper levels, transcriptomic alterations in livers revealed enrichment for cell adhesion, developmental, inflammatory, and cytoskeleton pathways. Upregulation of targeted MT1A and COMMD1 mRNA shows the livers first response to rising intrahepatic copper concentrations. In livers with copper-associated hepatitis mainly an activation of inflammatory pathways is detected. Once the hepatitis is in the chronic stage, transcriptional differences are found in cell adhesion adaptations and cytoskeleton remodelling. In view of the high similarities in hepatopathies between men and dog extrapolation of these dog data into human biomedicine seems feasible.

2017-05-02 | GSE86932 | GEO

Transcription profiling of rat liver samples from animals treated with D-penicillamine and controls

Project description:Idiosyncratic drug reactions (IDRs) cause significant morbidity and mortality. In an animal model of IDRs, 50-80% of Brown Norway rats exposed to D-penicillamine develop an autoimmune syndrome after several weeks of treatment. The symptoms of the IDR are similar to that observed in humans who take D-penicillamine. The mechanism of this reaction is unknown, and no effective biomarkers have been identified to predict susceptibility. We postulate that cell stress caused by drugs is required to initiate the response. We used a highthroughput approach to identify factors that might represent danger signals by profiling hepatic gene expression 6 h after dosing with D-penicillamine (150 mg/kg). Our results show that the drug-treated animals cluster into two distinct groups. One group exhibits substantial expression changes relative to control animals. The most significantly altered transcripts have a role in stress, energy metabolism, acute phase response, and inflammation. We used quantitative reverse transcriptase polymerase chain reaction to measure transcript levels in liver biopsies of 33 rats and found that resistant animals cluster together. This 'resistant' cluster of animals contains 87.5% (7/8) resistant animals but only 48% (12/25) 'sensitive' animals. This separation is statistically significant at the p 0.01 level. Experiment Overall Design: Single-channel Affy arrays used to profile 4 control Brown Norway rats and 8 D-Penicillamine treated Brown Norway rats.

2007-10-10 | E-GEOD-2825 | biostudies-arrayexpress

Wilson disease: intersecting DNA methylation and histone acetylation mechanisms affect gene expression regulation in a mouse model of hepatic copper accumulation [ChIP-Seq]

Project description:Prior investigations of DNA methylation differences in WD liver and blood and in a WD mouse model revealed an epigenetic signature of WD that included the histone deacetylase, HDAC5. To test the hypothesis that histone deacetylation and acetylation might be altered with respect to copper overload and aberrant DNA methylation in WD, we used the Jackson Laboratory toxic milk model (tx-j) of WD to study the involvement of Class IIa histone deacetylases (HDAC4 and HDAC5) and histone acetylation (H3K9ac and H3K27ac), and the effects of copper chelator D-penicillamine (PCA) and/or methyl group donor choline on histone modification. Next, we related acetylation profiles of H3K27ac to gene expression changes in wilson disease by ChIP and RNA-seq.

2021-07-09 | GSE168971 | GEO

Wilson disease: intersecting DNA methylation and histone acetylation mechanisms affect gene expression regulation in a mouse model of hepatic copper accumulation [RNA-Seq]

2021-07-09 | GSE168833 | GEO

Gene expression data from the LEC rat model with naturally occuring and oxidative stress induced liver tumorigenesis

Project description:To elucidate the fundamental molecular mechanisms responsible for multistep hepatotumorigenesis, this study investigated genes that were upregulated in a stepwise manner from the naïve liver condition through to chronic oxidative stress-induced hepatitis and liver tumor by time-series microarray analysis. The time-dependent gene expression profile should reflect the multistep process of hepatotumorigenesis, and might identify genes that function specifically in hepatotumorigenesis. We reduced several clinicopathological variables by using the Long-Evans Cinnamon rat, a model with naturally occurring and oxidative stress-induced hepatotumorigenesis. Gene expression patterns were analyzed serially by profiling liver tissue from naïve status (4 weeks old) rats through to those with chronic hepatitis (26 and 39 weeks old) to tumor development (67 weeks old). This study represents a normal versus diseased comparison with different time points of spontaneously developed liver tumor and normal liver tissue. In the first series of experiments, equivalent amounts of RNA from 2 pairs randomly selected from 8 paired liver tumor and adjacent nontumor tissue specimens were mixed and analyzed in order to normalize variations among mice. Average gene expression levels for tumor and non-tumor tissue samples were calculated using the 4 Affymetrix microarray datasets, respectively. In the following experiments, a mixture of equivalent amounts of RNA isolated from LEC rats at 4, 26, and 39 weeks of age and controls, respectively, was exploited as an RNA pool for Affymetrix microarray analyses. A total of 12 samples (4 sets of tumor-non-tumor pairs and a normal control, and 3 serial samples) were hybridized to Affymetrix Rat Expression 230 2.0 Arrays.

2009-07-30 | E-GEOD-17384 | biostudies-arrayexpress

Profiling of D-PA Induced Idiosyncratic Drug Reactions

2005-06-21 | GSE2825 | GEO

In the livers of rats treated with thioacetamide for 28 days

Project description:To clarify the regulatory molecular mechanisms behind cell cycle aberrations related to the early stages of hepatocarcinogenesis. We investigated the early stage of hepatocarcinogenesis using global expression analyses. Livers from rats treated with thioacetamide were subjected to microarray analysis. Results were compared with livers from rats untreated controls (n = 4 animals/group).

2012-12-21 | E-GEOD-43066 | biostudies-arrayexpress

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