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PROVIDER: PRJNA997121 | ENA |
REPOSITORIES: ENA
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Project description:Objective: Insulin regulates amino acid metabolism. We investigated whether glycemia and 43 genetic risk variants for hyperglycemia/type 2 diabetes affect amino acid levels in a large population-based cohort. Subjects and Methods: A total of 9,371 non-diabetic or newly-diagnosed type 2 diabetic Finnish men from the population-based METSIM Study were studied. Proton NMR spectroscopy was used to measure plasma levels of 8 amino acids. Genotyping of 42 SNPs and mRNA microarray analysis from 200 subcutaneous adipose tissue samples were performed. Results: Increasing fasting and/or 2-hour plasma glucose levels were associated with increasing levels of alanine, valine, leucine, isoleucine, phenylalanine and tyrosine, and decreasing levels of histidine and glutamine. We also found significant correlations between insulin sensitivity (Matsuda ISI) and expression of genes regulating amino acid metabolism. Only one SNP (rs780094 in GCKR) of the 42 risk SNPs for type 2 diabetes or hyperglycemia was significantly associated with the levels of alanine, isoleucine, and glutamine. Conclusions : We observed that the levels of branched-chain, aromatic amino acids and alanine increased and the levels of glutamine and histidine decreased with increasing glycemia. These associations seemed to be mediated by insulin resistance, at least in part. GCKR rs780094 was significantly associated with several amino acids.
2012-04-02 | GSE32512 | GEO
Project description:Objective: Insulin regulates amino acid metabolism. We investigated whether glycemia and 43 genetic risk variants for hyperglycemia/type 2 diabetes affect amino acid levels in a large population-based cohort. Subjects and Methods: A total of 9,371 non-diabetic or newly-diagnosed type 2 diabetic Finnish men from the population-based METSIM Study were studied. Proton NMR spectroscopy was used to measure plasma levels of 8 amino acids. Genotyping of 42 SNPs and mRNA microarray analysis from 200 subcutaneous adipose tissue samples were performed. Results: Increasing fasting and/or 2-hour plasma glucose levels were associated with increasing levels of alanine, valine, leucine, isoleucine, phenylalanine and tyrosine, and decreasing levels of histidine and glutamine. We also found significant correlations between insulin sensitivity (Matsuda ISI) and expression of genes regulating amino acid metabolism. Only one SNP (rs780094 in GCKR) of the 42 risk SNPs for type 2 diabetes or hyperglycemia was significantly associated with the levels of alanine, isoleucine, and glutamine. Conclusions : We observed that the levels of branched-chain, aromatic amino acids and alanine increased and the levels of glutamine and histidine decreased with increasing glycemia. These associations seemed to be mediated by insulin resistance, at least in part. GCKR rs780094 was significantly associated with several amino acids. Total RNA was obtained from subcutaneous fat biopsies from 200 people participating in the METSIM study (4 samples were replicated for a total of 204 arrays).
2012-04-01 | E-GEOD-32512 | biostudies-arrayexpress
Project description:Transcriptional regulation of branched-chain amino acid metabolism in Saccharomyces cerevisiae involves two key regulator proteins, Leu3p and Gcn4p. Leu3p is a pathway-specific regulator, known to regulate six genes involved in branched-chain amino acid metabolism and one gene in nitrogen assimilation. Gcn4p is a global regulator, involved in the general response to amino acid and purine starvation. To investigate the contribution of Leu3p in regulation of gene expression, a leu3D strain was compared to an isogenic reference strain using DNA-microarray analysis. This comparison was performed for both glucose-grown, ammonium-limited and ethanol-limited, ammonium-excess chemostat cultures. In ethanol-limited cultures, absence of Leu3p led to reduced transcript levels of six of the seven established Leu3p target genes, but did not affect key physiological parameters. In ammonium-limited cultures, absence of Leu3p caused a drastic decrease in storage carbohydrate content. mRNA levels of genes involved in storage carbohydrate metabolism were also found reduced. Under N-limited conditions, the leu3D genotype elicited an amino-acid starvation response, leading to increased transcript levels of many amino acid biosynthesis genes. By combining the transcriptome data with data from earlier studies that measured DNA binding of Leu3p both in vitro and in vivo, BAT1, GAT1 and OAC1 were identified as additional Leu3p-regulated genes. This study demonstrates that unravelling of transcriptional regulation networks should preferably include several cultivation conditions and requires a combination of experimental approaches.
2007-07-07 | E-GEOD-2076 | biostudies-arrayexpress
Project description:Glucagon is a key regulator of glucose homeostasis, amino acid catabolism, and lipid metabolism. Glucagon receptor knock-out (GcgrKO) mice have slightly reduced blood glucose levels whereas plasma levels of amino acids are vastly increased reflecting disruption of hepatic amino acid catabolism. To dissect the molecular mechanisms underlying this effect, RNA sequencing of livers from male GcgrKO mice and wild-type littermates were performed. The mice were 10 weeks of age and were subjected to a short-term fast of 4 h before anesthesia with 2.5% isoflurane.
2022-10-11 | E-MTAB-12060 | biostudies-arrayexpress
Project description:Severe acute respiratory syndrome coronavirus (SARS-CoV) causes a respiratory disease leading to death in 10% of the infected people. A mouse adapted SARS-CoV lacking the envelope (E) protein (rSARS-CoV-MA15-?E) is attenuated in vivo. To identify E protein domains and host responses that contribute to rSARS-CoV-MA15-?E attenuation, several mutants (rSARS-CoV-MA15-E*) containing point mutations or deletions in the amino-terminal or the carboxy-terminal regions of E protein, respectively, were generated. Amino acid substitutions in the amino terminus, or deletion of domains in the internal carboxy terminal region of E protein led to viral attenuation. Attenuated viruses induced minimal lung injury and limited neutrophil influx to the lungs but, interestingly, increased CD4+ and CD8+ T cell counts in BALB/c mice. To analyze the host responses leading to rSARS-CoV-MA15-E* attenuation, the differential gene expression elicited by the native virus and the mutant ones in infected cells was analyzed. The expression levels of a large number of proinflammatory cytokines inducing lung injury was reduced in the lungs of rSARS-CoV-MA15-E* infected mice, whereas the levels of anti-inflammatory cytokines were increased, both at the mRNA and protein levels. These results suggested that the reduction in lung inflammation together with a specific antiviral T cell response, contributed to rSARS-CoV-MA15-E* attenuation. Interestingly, the attenuated viruses completely protected mice against the challenge with the lethal parental virus, being promising vaccine candidates. Three biological replicates were independently hybridized (one channel per slide) for each sample type (rSARS-CoV-MA15-wt, rSARS-CoV-MA15-?E, rSARS-CoV-MA15-?3, rSARS-CoV-MA15-?5, Mock). Slides were Sure Print G3 Agilent 8x60K Mouse (G4852A-028005)
2015-05-19 | E-GEOD-59185 | biostudies-arrayexpress
Project description:Development, growth and adult survival are coordinated with available metabolic resources. The insulin/IGF and TOR signaling pathways relay nutritional status, thereby ascertaining that the organism responds appropriately to environmental conditions. MicroRNAs are short (21-23 nt) regulatory RNAs that confer specificity on the RNA-induced silencing complex (RISC) to inhibit a given set of mRNA targets. We profiled changes in miRNA expression during adult life in Drosophila melanogaster and determined that miR-277 is down-regulated with age. This miRNA controls branched-chain amino acid (BCAA) catabolism and the activity of the TOR kinase, a central growth regulator. Metabolite analysis suggests that the mechanistic basis may be an accumulation of BCKAs, rather than BCAAs, thus avoiding potentially detrimental consequences of increased branched chain amino acid levels on e.g. translational fidelity. Constitutive miR-277 expression as well as transgenic inhibition with a miRNA sponge construct shortens lifespan. Furthermore, constitutive miR-277 expression is synthetically lethal with reduced insulin signaling. Thus, optimal metabolic adaptation requires tuning of cellular BCAA catabolism by miR-277 to be concordant with systemic growth signaling.
2015-01-19 | GSE42442 | GEO
Project description:A subset of triple negative breast cancers (TNBC) are characterized by genetic alterations in fibroblast growth factor receptors (FGFR) including amplifications, activating mutations or gene fusions. However, despite this genetic evidence of FGFR-dependency, FGFR inhibitors have shown only limited clinical efficacy in TNBC, suggesting the presence of intrinsic or adaptive resistance mechanisms. Using genome-wide CRISPR screens, we found that resistance to FGFR inhibition is mediated by activation of the mTORC1 and YAP pathways. Prolonged FGFR inhibition increased expression of several amino acid transporters resulting in increased cellular level of certain amino acids and activation of the mTORC1 amino acid sensing pathway. Epigenomic analyses revealed that FGFR inhibition reorganized YAP/TEAD associated enhancers leading to the upregulation of YAP target genes including the amino acid transporters upstream of mTORC1. Remarkably, mTORC1 and FGFR inhibitors synergistically blocked the growth of TNBC cells in vitro and in patient-derived xenografts. These findings define a novel epigenetic feedback mechanism involving intracellular amino acid levels leading to targeted therapy resistance in TNBC, and offers a combinatorial drug treatment strategy to improve clinical outcomes for this aggressive breast cancer subtype.
2021-09-09 | GSE168026 | GEO
Project description:A subset of triple negative breast cancers (TNBC) are characterized by genetic alterations in fibroblast growth factor receptors (FGFR) including amplifications, activating mutations or gene fusions. However, despite this genetic evidence of FGFR-dependency, FGFR inhibitors have shown only limited clinical efficacy in TNBC, suggesting the presence of intrinsic or adaptive resistance mechanisms. Using genome-wide CRISPR screens, we found that resistance to FGFR inhibition is mediated by activation of the mTORC1 and YAP pathways. Prolonged FGFR inhibition increased expression of several amino acid transporters resulting in increased cellular level of certain amino acids and activation of the mTORC1 amino acid sensing pathway. Epigenomic analyses revealed that FGFR inhibition reorganized YAP/TEAD associated enhancers leading to the upregulation of YAP target genes including the amino acid transporters upstream of mTORC1. Remarkably, mTORC1 and FGFR inhibitors synergistically blocked the growth of TNBC cells in vitro and in patient-derived xenografts. These findings define a novel epigenetic feedback mechanism involving intracellular amino acid levels leading to targeted therapy resistance in TNBC, and offers a combinatorial drug treatment strategy to improve clinical outcomes for this aggressive breast cancer subtype.
2021-09-09 | GSE168024 | GEO
Project description:Transcriptional regulation of branched-chain amino acid metabolism in Saccharomyces cerevisiae involves two key regulator proteins, Leu3p and Gcn4p. Leu3p is a pathway-specific regulator, known to regulate six genes involved in branched-chain amino acid metabolism and one gene in nitrogen assimilation. Gcn4p is a global regulator, involved in the general response to amino acid and purine starvation. To investigate the contribution of Leu3p in regulation of gene expression, a leu3D strain was compared to an isogenic reference strain using DNA-microarray analysis. This comparison was performed for both glucose-grown, ammonium-limited and ethanol-limited, ammonium-excess chemostat cultures. In ethanol-limited cultures, absence of Leu3p led to reduced transcript levels of six of the seven established Leu3p target genes, but did not affect key physiological parameters. In ammonium-limited cultures, absence of Leu3p caused a drastic decrease in storage carbohydrate content. mRNA levels of genes involved in storage carbohydrate metabolism were also found reduced. Under N-limited conditions, the leu3D genotype elicited an amino-acid starvation response, leading to increased transcript levels of many amino acid biosynthesis genes. By combining the transcriptome data with data from earlier studies that measured DNA binding of Leu3p both in vitro and in vivo, BAT1, GAT1 and OAC1 were identified as additional Leu3p-regulated genes. This study demonstrates that unravelling of transcriptional regulation networks should preferably include several cultivation conditions and requires a combination of experimental approaches. Keywords: ordered
2004-12-17 | GSE2076 | GEO
Project description:In this study, we used GC-MS analysis in combination with flux analysis and the Affymetrix ATH1 GeneChip to survey the metabolome and transcriptome of Arabidopsis leaves in response to manipulation of the thiol-disulfide status. Feeding low concentrations of the sulfhydryl reagent dithiothreitol (DTT) for one hour at the end of the dark period led to post-translational redox-activation of ADP-glucose pyrophosphorylase and major alterations in leaf carbon partitioning, including an increased flux into major respiratory pathways, starch- cell-wall-, and amino-acid synthesis and a reduced flux to sucrose. This was accompanied by a decrease in the levels of hexose-phosphates, while metabolites in the second half of the TCA cycle and various amino acids increased, indicating a stimulation of anaplerotic fluxes reliant on α-ketoglutarate. There was also an increase in shikimate as a precursor of secondary plant products and marked changes in the levels of the minor sugars involved in ascorbate synthesis and cell wall metabolism. Transcript profiling revealed a relatively small number of changes in the levels of transcripts coding for components of redox-regulation, transport processes and cell wall, protein and amino acid metabolism, while there were no major alterations in transcript levels coding for enzymes involved in central metabolic pathways. These results provide a global picture of the effect of redox and reveal the utility of transcript and metabolite profiling as systemic strategies to uncover the occurrence of redox-modulation in vivo. Experiment Overall Design: Leaf discs were incubated with or without 5mM DTT for one hour to affect the redox status of the cells. The effect of this treatment on global gene expression was analysed using affymetrix ATH1 microarrays. The experiments contains one control (-DTT) and one treatment (+DTT) and is performed with 2 biological replicas.
2008-06-12 | E-GEOD-4021 | biostudies-arrayexpress