Wildtype, Fah and Fah, p21 ON and OFF NTBC
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE11098 | GEO | 2008/04/09
SECONDARY ACCESSION(S): PRJNA106977
REPOSITORIES: GEO
Similar Datasets
Project description:Fumarylacetoacetate hydrolase (Fah), the last enzyme of the tyrosine degradation pathway, is specifically expressed in hepatocytes in the liver. Loss of Fah leads to liver failure in mice within 6-8 weeks. This can be prevented by blocking tyrosine degradation upstream of Fah with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). Here, we investigate the impact of p21 on global gene expression in Fah deficiency. Experiment Overall Design: Livers from adult wildtype, Fah or Fah, p21 knockout mice were analyzed either after continuous treatment (ON) with NTBC or after NTBC withdrawal for 14 days (OFF).
2008-06-11 | E-GEOD-11098 | biostudies-arrayexpress
Project description:Hereditary tyrosinemia type 1 (HT1) is a severe genetic disorder that affects the liver due to a defective fumarylacetoacetate hydrolase (Fah) enzyme in hepatocytes. The drug nitisinone (NTBC) has offered a life-saving treatment for HT1 patients by inhibiting the upstream enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD). We used microarray analyses to define the impact of short-term (ie. seven days) NTBC therapy discontinuation on the gene expression profile of liver tissue of Fah-deficient mice. Consequently, we investigated the modulation of canonical pathways related to oxidative stress, glutathione metabolism and liver regeneration.
2023-06-03 | GSE205434 | GEO
Project description:Hereditary tyrosinemia type 1 (HT1) is a severe genetic disorder that affects the liver due to a defective fumarylacetoacetate hydrolase (Fah) enzyme in hepatocytes. The drug nitisinone (NTBC) has offered a life-saving treatment for HT1 patients by inhibiting the upstream enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD). We used microarray analyses to define the impact of short-term (ie. seven days) NTBC therapy discontinuation on the gene expression profile of liver tissue of Fah-deficient mice. Consequently, we investigated the modulation of canonical pathways related to oxidative stress, glutathione metabolism and liver regeneration.
2020-12-23 | GSE161478 | GEO
Project description:Conventional therapy for hereditary tyrosinemia type-1 (HT1) with 2-(2-nitro-4- trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) delays and in some cases fails to prevent disease progression to liver fibrosis, liver failure, and activation of tumorigenic pathways. Here we demonstrate for the first time a cure of HT1 by direct, in vivo administration of a therapeutic lentiviral vector targeting the expression of a human fumarylacetoacetate hydrolase (FAH) transgene in the porcine model of HT1. This therapy was well tolerated and provided stable long-term expression of FAH in pigs with HT1. Genomic integration displayed a benign profile, with subsequent fibrosis and tumorigenicity gene expression patterns similar to wild-type animals as compared to NTBC-treated or diseased untreated animals. Indeed, the phenotypic and genomic data following in vivo lentiviral vector administration demonstrate comparative superiority over other therapies including ex vivo cell therapy and therefore support clinical application of this approach.
2021-11-20 | GSE189135 | GEO
Project description:Hereditary tyrosinemia type 1 (HT1) is a severe genetic disorder that affects the liver due to a defective fumarylacetoacetate hydrolase (Fah) enzyme in hepatocytes. The drug nitisinone (NTBC) has offered a life-saving treatment for HT1 patients by inhibiting the upstream enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD). We used microarray analyses to to identify changes in molecular pathways associated to the development and progression of the liver pathogenesis of HT1 that remain uncorrected under NTBC therapy by using gene expression profiling of Fah-deficient mouse livers subjected to continuous NTBC therapy and after seven days of NTBC therapy discontinuation. As a control of a TIMD without hepatic manifestation, we used the Hgd-deficient mouse model of AKU, also under continuous NTBC treatment and after seven days of NTBC therapy discontinuation. Consequently, we identified a set of 25 genes that discriminates HT1 livers from AKU livers, even under continuous NTBC therapy, as such representing remnants of an HT1-driven residual uncorrected liver disease phenotype.
2023-04-04 | GSE225001 | GEO
Project description:Reprogramming metabolism plays an important role in tumor cells for maintaining their abnormal biologic behaviors. Therefore, special factors could regulate metabolic processes and influence the overall status of tumor cells. This phenomenon was obviously found in melanoma. Fumarylacetoacetate hydrolase (fumarylacetoacetase, FAH) is an enzyme encoded by the FAH gene located on the chromosome 15q25.1 region and contains 14 exons. FAH enzyme catalyzes the hydrolysis of 4- fumarylacetoacetase into fumarate and acetoacetate. It is the last enzyme in the subpathway from L-phenylalanine and tyrosine degradation. Mutations in the FAH gene cause type I tyrosinemia, which is a hereditary error of metabolism that is characterized by increased tyrosine levels in the blood and urine of patients. In the present study, we will explore whether FAH is an essential enzyme to promote multiple metabolic processes and elucidate the functions of FAH in melanoma. Gene microarrays and bioinformatics analysis of the differentially expressed genes (DEGs) were performed using A375 cells, and we concentrated on the biologic functions of FAH. In general, our work revealed several functional mechanisms of FAH in melanoma, which indicated FAH might be a potentially therapeutic target and an independent prognostic indicator for this disease.
2018-02-14 | GSE86870 | GEO
Project description:Over half of the mature hepatocytes in mice and humans are aneuploid and yet retain full ability to undergo mitosis. This observation has raised the question whether this unusual somatic genetic variation evolved as an adaptive mechanism to hepatic injury. According to this model, hepatotoxic insults would select for hepatocytes with specific numerical chromosome abnormalities, rendering them differentially resistant to the injury. To test this hypothesis, we utilized a strain of mice heterozygous for a mutation in homogentisic acid dioxygenase (Hgd), located on chromosome 16. Loss of this allele can protect from fumarylacetoacetate hydrolase (Fah) deficiency. When adult Hgd+/- Fah-/- mice were exposed to chronic liver damage, injury-resistant nodules consisting of Hgd-null hepatocytes rapidly emerged. To determine whether aneuploidy played a role in this phenomenon, array comparative genomic hybridization (aCGH) and metaphase karyotyping were performed. Strikingly, loss of chromosome 16 was dramatically enriched in all mice that became completely resistant to tyrosinemia-induced hepatic injury. The frequency of chromosome 16-specific aneuploidy was ~50%. This result provides proof-of-principle that the selection of a specific aneuploid karyotype can result in the adaptation of hepatocytes to chronic liver injury. The extent to which aneuploidy promotes hepatic adaptation in humans is under investigation. 8 mouse hepatocyte samples were analyzed. Genomic DNA samples were derived from wild type mice (2), Hgd-/- Fah-/- mice off NTBC (2) and Hgd+/- Fah-/- off NTBC (4). Samples were compared to sex-mismatched reference genomic DNA isolated from wild type mouse splenocytes.
2012-07-16 | E-GEOD-38963 | biostudies-arrayexpress
Project description:Nitisinone (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, NTBC) is considered a potentially effective drug for the treatment of various metabolic diseases associated with disorders of L-tyrosine metabolism however, side-effects impede its widespread use. This work aimed to broaden the knowledge of the influence of NTBC and its metabolites 2-amino-4-(trifluoromethyl)benzoic acid (ATFA), 2-nitro-4-(trifluoromethyl)benzoic acid (NTFA), and cyclohexane-1,3-dione (CHD) on the catabolism of L-tyrosine and other endogenous compounds in Saccharomyces cerevisiae. Based on a targeted analysis performed by LC-ESI-MS/MS, based on multiple reaction monitoring, it was found that the dissipation kinetics of the parent compound and its metabolites are compatible with a first-order reaction mechanism. Moreover, it has been proven that formed NTBC metabolites, such as CHD, cause a decrease in L-tyrosine, L-tryptophan, and L-phenylalanine concentrations by about 34%, 59% and 51%, respectively, compared to the untreated model organism. The overall changes in the metabolism of yeast exposed to NTBC or its derivatives were evaluated by non-targeted analysis via LC-ESI-MS/MS in the ion trap scanning mode. Based on principal components analysis, a statistically significant similarity between metabolic responses of yeast treated with ATFA or NTFA was observed. These findings facilitate further studies investigating the influence of NTBC on the human body and the mechanism of its action.
2023-01-20 | MSV000091104 | MassIVE
Project description:The use of patient-derived induced pluripotent stem (iPS) cells as treatment for genetic diseases entails genetic repair or transfer of genetic information as a prerequisite. We have chosen the murine model of tyrosinemia type 1 (fumarylacetoacetate hydrolase deficiency; FAH(-/-) mice) as a paradigm for hereditary metabolic liver disorders and evaluated fibroblast-derived FAH(-/-)-iPS cell lines as targets for gene correction. By aggregating FAH(-/-)-iPS cells with tetraploid embryos, we obtained FAH-/--iPS cellâderived mice, which exhibited the phenotype of the founding FAH(-/-)-mice. We then rescued the diseased phenotype by lentiviral transduction of FAH-cDNA and performed embryo aggregation with these gene-corrected FAHgc-iPS cells to obtain viable healthy mice. Our results demonstrate that iPS cell technology is a valid approach to establish mouse disease models directly from somatic cells bearing genetic defects. Furthermore, established iPS cell lines can be genetically manipulated without loss of pluripotency for treatment of genetic diseases. 6 samples: 1 MEF, 1ESC, 4 iPSCs
2010-04-28 | E-GEOD-21343 | biostudies-arrayexpress
Project description:To gain a deeper understanding of the genetic basis of liver repopulation after injury, we utilize an innovative technique to profile the expression changes and chromatin landscape during the regenerative response. We utilize the Fah-/- mouse, a model for hereditary tyrosinemia deficient in fumarylacetoacetate hydrolase (FAH), that undergoes repopulation with FAH-expressing hepatocytes. We employ translating ribosome affinity purification followed by RNA-sequencing (TRAP-seq) and assay for transposase accessible chromatin using sequencing (ATAC-seq) to specifically isolate regenerating hepatocytes and performed high-throughput sequencing to identify the dynamic genomic and epigenomic changes during liver repopulation.
2018-01-24 | GSE109466 | GEO