RNA Sequencing in LXR agonist fed Atp7b-/- mice (Wilson disease)
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE174015 | GEO | 2022/10/26
REPOSITORIES: GEO
Similar Datasets
Project description:RNA Sequencing in LXR agonist fed Atp7b-/- mice (Wilson disease)
| PRJNA728814 | ENA
Project description:Purpose：Wilson's disease (WD) is a rare hereditary disorder due to ATP7B gene mutation, causing pathologic copper storage mainly in the liver and neurological systems. Hepatocyte transplantation showed therapeutic potential, however, this strategy is often hindered by a shortage of quality donor cells and by allogeneic immune rejection. Here we evaluate the function and efficacy of autologous reprogrammed, ATP7B gene-restored hepatocytes using a murine model of WD Mathods and Results: By reprogramming hepatocytes from ATP7B-/- mice with small molecules, sufficient liver progenitor cells (LPCs) are harvested. After lentivirus-mediated miniATP7B gene transfection and re-differentiation, functional LPC-ATP7B-Heps are developed. RNA-seq data show that compared with LPC-GFP-Heps with enrichment of genes mainly in pathways of oxidative stress and cell apoptosis, in LPC-ATP7B-Heps under high copper stress pathways for copper ion binding and cell proliferation are enriched. LPC-ATP7B-Heps transplantation into ATP7B-/- mice alleviates deposition of excess liver copper with its associated inflammation and fibrosis, comparable to those observed using normal primary hepatocytes at four months after transplantation. Conclusion: We establish the autologous reprogrammed, ATP7B gene restored LPC-ATP7B-Heps and further transplantation demonstrate alleviated copper accumulation in WD mice.
2022-03-05 | GSE197948 | GEO
Project description:Wilson disease (WD) is a severe metabolic disorder caused by genetic inactivation of copper-transporting ATPase ATP7B. In WD, copper accumulates in several tissues, particularly in the liver, inducing marked time-dependent pathological changes. To identify initial events in the copper-dependent development of liver pathology we utilized the Atp7b-/- mice, an animal model for WD. Analysis of mRNA from livers of control and Atp7b-/- 6 weeks-old mice using oligonucleotide arrays revealed specific changes of the transcriptome at this stage of copper accumulation. Few messages (29 up-regulated and 46 down-regulated) change their abundance more than 2-fold pointing to the specific effect of copper on gene expression/mRNA stability. The gene ontology analysis revealed copper effects on distinct metabolic pathways. Experiment Overall Design: RNA isolation for microarrays: Immediately after removal, what size [mg] the liver pieces for RNA isolation were frozen in liquid nitrogen and stored till further use. The total RNA was isolated from frozen mouse livers using TRIZOL reagent (Invitrogen) according to manufacturerâs recommendations followed by a subsequent sample
2008-06-13 | E-GEOD-5348 | biostudies-arrayexpress
Project description:To understand whether hepatic cells use autophagy to defend against Cu toxicity in WD, we employed ATP7B knockout (ATP7B-KO) HepG2 cell line, by Quant-seq experiments. Transcriptome analysis of the of ATP7B KO cells and WT cells treated with Copper (Cu) compared with untreated cells.
2019-02-26 | GSE107323 | GEO
Project description:Wilson disease (WD) is a severe metabolic disorder caused by genetic inactivation of copper-transporting ATPase ATP7B. In WD, copper accumulates in several tissues, particularly in the liver, inducing marked time-dependent pathological changes. To identify initial events in the copper-dependent development of liver pathology we utilized the Atp7b-/- mice, an animal model for WD. Analysis of mRNA from livers of control and Atp7b-/- 6 weeks-old mice using oligonucleotide arrays revealed specific changes of the transcriptome at this stage of copper accumulation. Few messages (29 up-regulated and 46 down-regulated) change their abundance more than 2-fold pointing to the specific effect of copper on gene expression/mRNA stability. The gene ontology analysis revealed copper effects on distinct metabolic pathways. Keywords: comparative genomic hybridization
2006-12-19 | GSE5348 | GEO
Project description:Wilson disease (WD) is caused by mutations in the copper transporter ATP7B, leading to copper accumulation in the liver and brain. Excess copper inhibits S-adenosyl-L-homocysteine hydrolase, leading to variable WD phenotypes from widespread alterations in DNA methylation and gene expression. Previously, we demonstrated that maternal choline supplementation in the Jackson toxic milk (tx-j) mouse model of WD corrected higher thioredoxin 1 transcript levels in fetal liver. Here, we investigated the effect of maternal choline supplementation on genome-wide DNA methylation patterns in tx-j fetal liver by whole-genome bisulfite sequencing (WGBS). Tx-j Atp7b genotype-dependent differences in DNA methylation were corrected by choline for genes including, but not exclusive to, oxidative stress pathways. To examine phenotypic effects of postnatal choline supplementation, tx-j mice were randomized to one of six treatment groups: with or without maternal and/or continued choline supplementation, and with or without copper chelation with penicillamine (PCA) treatment. Hepatic transcript levels of thioredoxin 1 and peroxiredoxin 1 were significantly higher in mice receiving maternal and continued choline with or without PCA treatment compared to untreated mice. A comparison of WGBS of human WD liver compared to tx-j mouse liver demonstrated a significant overlap of differentially-methylated genes associated with ATP7B deficiency. Further, eight genes in the thioredoxin pathway were differentially methylated in human WD liver samples. In summary, Atp7b deficiency and choline supplementation have a genome-wide impact, including on thioredoxin system-related genes, in tx-j mice. These findings could explain the variability of WD phenotype and suggest new complementary treatment options for WD.
2018-07-25 | GSE117592 | GEO
Project description:Wilson’s disease (WD) is a rare genetic disease caused by mutations in the ATP7B gene. These mutations impact the expression and/or function of the copper-transporting ATP7B protein, leading to massive toxic accumulation of copper in the liver and brain. Due to its low incidence and highly variable clinical presentations, WD is challenging to diagnose. Here, we explored the plasma proteome of the Atp7b-/- mouse, a genetic and phenotypic model of WD, to provide new insights into the pathogenic mechanisms of WD and discover potential biomarkers for WD diagnosis. A mass spectrometry (MS)-based proteomics workflow combining unbiased discovery analysis followed by targeted quantification was developed. Analysis of two independent groups of samples (discovery and validation cohorts) highlighted seven plasma proteins for which abundance was significantly modified (more than 2-fold) between Atp7b-/- mice and wild-type littermates. To assess the clinical significance and specificity of these seven proteins as potential biomarkers for WD, we adapted our targeted proteomics assay to allow the quantification of human orthologues in plasma from WD patients (treated with copper chelators), non-alcoholic steatohepatitis patients (disease-control group), and healthy donors. The plasma proteome changes observed in the Atp7b-/- mouse were not confirmed in treated WD patients, with the exception of alpha-1 antichymotrypsin, levels of which were decreased in WD patients compared to healthy individuals. Plasma ceruloplasmin was investigated in both the Atp7b-/- mouse model and human patients, and was found to be significantly decreased in the human form of WD only.
2020-04-14 | PXD011007 | Pride
Project description:LXR is a transcription factor. Two isoforms exist in mice (alpha and beta). They are both expressed in the liver. We examined the role of LXR by obtaining gene expression profiles from the livers of wild-type and LXR-/- mice from the same genetic background. Liver gene expression was measured from male mice (5 mice/group) of genotypes wild-type and LXR-/- on a mixed Sv129/C57Bl6J background (Repa et al. , 2000, Science, 289(5484):1524-9; Cummins et al., 2006, J Clin Invest,116(7):1902-12) fed for 7 weeks a normal diet (ND) or a Western diet (WD).
2012-11-07 | E-GEOD-38083 | biostudies-arrayexpress
Project description:The liver X receptors (LXRs) are nuclear receptors that form permissive heterodimers with retinoid X receptor (RXR) and are important regulators of lipid metabolism in the liver. We have recently shown that RXR agonist-induced hypertriglyceridemia and hepatic steatosis in mice is dependent on LXR and correlates with an LXR-dependent hepatic induction of lipogenic genes. To further investigate the role of RXR and LXR in the regulation of hepatic gene expression, we have mapped the ligand-regulated genome-wide binding of these factors in mouse liver. We find that the RXR agonist bexarotene primarily increases the genomic binding of RXR, whereas the LXR agonist T0901317 greatly increases both LXR and RXR binding. Functional annotation of putative direct LXR target genes revealed a significant association with classical LXR-regulated pathways as well as PPAR signaling pathways, and subsequent ChIP-seq mapping of PPARM-NM-1 binding demonstrated binding of PPARM-NM-1 to 71-88% of the identified LXR:RXR binding sites. Sequence analysis of shared binding regions combined with sequential ChIP on selected sites indicate that LXR:RXR and PPARM-NM-1:RXR bind to degenerate response elements in a mutually exclusive manner. Together our findings suggest extensive and unexpected cross-talk between hepatic LXR and PPARM-NM-1 at the level of binding to shared genomic sites LXR, RXR, PPARalpha and RNA Polymerase II ChIP-seq on livers from female C57BL/6 wild-type and/or LXRM-NM-1/M-NM-2-deficient mice (13 weeks of age, n=1) treated by oral gavage once daily for 14 days with the RXR agonist bexarotene (100 mg/kg body weight [mpk], in 1% carboxymethylcellulose), the LXR agonist T0901317 (T09, 30 mpk) or vehicle alone.
2012-01-31 | E-GEOD-35262 | biostudies-arrayexpress
Project description:Inactivating mutations in the copper transporter Atp7b result in Wilson’s disease. The Atp7b-/- mouse develops hallmarks of Wilson’s disease. The activity of several nuclear receptors is decreased in Atp7b-/- mice, and nuclear receptors are critical for maintaining metabolic homeostasis. Therefore, we anticipated that Atp7b-/- mice would exhibit altered progression of diet-induced obesity, fatty liver, and insulin resistance. Following 10 weeks on a chow or Western-type diet (40% kcal fat), parameters of glucose and lipid homeostasis were measured. Hepatic metabolites were measured by LC-MS and correlated with transcriptomic data. Atp7b-/- mice fed a chow diet had lower fat mass and were more glucose tolerant than wild type (WT) littermate controls although body weights did not differ between genotypes. On Western diet, Atp7b-/- mice exhibited reduced adiposity and hepatic steatosis compared with WT controls. Atp7b-/- mice fed either diet were more insulin sensitive than WT controls; however, fasted Atp7b-/- mice exhibited hypoglycemia after administration of insulin, due to an impaired glucose counter-regulatory response, as evidenced by reduced hepatic glucose production. Coupling gene expression with metabolomic analyses, we observed striking changes in hepatic metabolic profiles in Atp7b-/- mice. In addition, the active phosphorylated form of AMP kinase was significantly increased in Atp7b-/- mice relative with WT controls. Alterations in hepatic metabolic profiles and nuclear receptor signaling were associated with improved glucose tolerance and insulin sensitivity, as well as impaired fasting glucose production in Atp7b-/- mice.
2020-04-14 | GSE125637 | GEO