GLS2 links glutamine metabolism and atherosclerosis by remodelling artery walls (MOVAS).
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE270056 | GEO | 2024/10/17
REPOSITORIES: GEO
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Project description:Metabolic dysregulation, including perturbed glutamine-glutamate homeostasis, is common in atherosclerotic cardiovascular disease. Here, we reveal that modulation of glutaminolysis or glutamate availability in culture media is critical for smooth muscle cell line (MOVAS) phenotypic switching. Cells were treated for 24 hours with glutaminase inhibitors (50mM DON, Sigma-SML0601) in presence or absence of 2mM glutamate suplementation (Gibco-35050061). High-throughput transcriptional profiling revealed that modulation of glutamine and glutamate homeostasis impacted genes involved in protein and extracellular matrix organization, cell motility and microtubule. Thus, we uncovered a novel role for glutamine metabolism in the phenotypic switch in SMCs, a hallmark of vascular remodelling.
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Project description:Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here, we reveal that glutaminase (GLS) 1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis in mice. In addition, impaired macrophage glutaminolysis exacerbates atherosclerosis, a condition during which efficient apoptotic cell debris clearance is critical to limit disease progression. Gls1 expression strongly correlates with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling revealed that macrophage efferocytic capacity relies on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase (GLUD1) to fuel ɑ-ketogulatrate-dependent immunometabolism. This pathway is necessary to meet the unique requirements of efferocytosis for cellular detoxification and high energy cytoskeletal rearrangements. Thus, we uncovered a novel role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease in mouse and humans
2021-12-31 | GSE183176 | GEO
Project description:Metabolic dysregulation, including perturbed glutamine-glutamate homeostasis, is a hallmark of atherosclerotic diseases. We used single nuclei RNA sequencing (snRNA-seq) to analyze the impact of defective hepatic glutaminolysis on cell diversity in atherosclerotic aorta.
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Project description:It is becoming clear that the acquisition of T cell functions is closely linked to the reprogramming of the metabolic pathway. However, the impact of metabolic changes on the differentiation of helper T cell subsets remains unclear. We herein demonstrate a critical role of glutamine metabolism in regulating type 2-immune response. Bach2, a transcriptional repressor, binds to an AP-1 motif, and suppresses Th2 cell differentiation and glutaminolysis. Glutaminase 2, which controls glutamine metabolism, was identified as a Bach2 target gene. The pharmacological inhibition of glutamine metabolism normalized allergic lung inflammation that developed spontaneously in T-cell specific Bach2-deficient mice. These findings reveal the importance of the Bach2-dependent modulation of glutamine metabolism in regulating Th2 cell differentiation and Th2 cell- mediated inflammation.
2016-11-14 | GSE65083 | GEO
Project description:It is becoming clear that the acquisition of T cell functions is closely linked to the reprogramming of the metabolic pathway. However, the impact of metabolic changes on the differentiation of helper T cell subsets remains unclear. We herein demonstrate a critical role of glutamine metabolism in regulating type 2-immune response. Bach2, a transcriptional repressor, binds to an AP-1 motif, and suppresses Th2 cell differentiation and glutaminolysis. Glutaminase 2, which controls glutamine metabolism, was identified as a Bach2 target gene. The pharmacological inhibition of glutamine metabolism normalized allergic lung inflammation that developed spontaneously in T-cell specific Bach2-deficient mice. These findings reveal the importance of the Bach2-dependent modulation of glutamine metabolism in regulating Th2 cell differentiation and Th2 cell- mediated inflammation.
2016-11-14 | GSE63380 | GEO
Project description:Cancer cells can metabolize glutamine to replenish TCA cycle intermediates, leading to a dependence on glutaminolysis for cell survival. However, a mechanistic understanding of the role that glutamine metabolism has on the survival of glioblastoma (GBM) brain tumor stem cells (BTSCs) has not yet been elucidated. Here we report that, across a panel of twenty glioblastoma BTSC lines, glutaminase (GLS) inhibition showed a variable response – from complete blockade of cell growth to absolute resistance. Surprisingly, BTSC sensitivity to GLS inhibition was a result of reduced intracellular glutamate triggering the amino acid deprivation response (AADR) and not due to the contribution of glutaminolysis to the TCA cycle. Moreover, BTSC sensitivity to GLS inhibition negatively correlated with the expression of the astrocytic glutamate transporters EAAT1 and EAAT2. Blocking glutamate transport in BTSCs with high EAAT1/EAAT2 expression rendered these cells susceptible to GLS inhibition, triggering the AADR, and limiting cell growth. These findings uncover a unique metabolic vulnerability in BTSCs, support the therapeutic targeting of the upstream activators and downstream effectors of the AADR pathway in GBM, and demonstrate that gene expression patterns reflecting the cellular hierarchy of the tissue of origin can alter the metabolic requirements of the cancer stem cell population.
2020-12-25 | GSE155300 | GEO
Project description:The decline in sperm function is a major cause of human male infertility. Glutaminase, a mitochondrial enzyme that catalyzes the hydrolysis of glutamine to generate glutamate, takes part in many diverse biological processes such as neurotransmission, metabolism, and cellular senescence. Here we report a role of glutaminase in regulating sperm function. By generating a triple mutant that harbors a loss-of-function allele for each of all three mammalian glutaminase orthologs, we found that glutaminase gene activity is required for optimal C. elegans sperm function. Tissue-specific gene manipulations showed that germline glutaminase activity plays an important role. Moreover, transcriptional profiling and antioxidant treatment suggested that glutaminase promotes sperm function by maintaining cellular redox homeostasis. As maintaining a low level of ROS is crucial to human sperm function, it is very likely that glutaminase plays a similar role in humans and therefore can be a potential target for treating human male infertility.
2023-02-15 | GSE224117 | GEO
Project description:Activated T cells undergo metabolic reprogramming to meet anabolic, differentiation, and functional demands. Glutamine supports many processes in activated T cells, and inhibition of glutamine metabolism alters T cell function in autoimmune disease and cancer. Multiple glutamine-targeting molecules are under investigation, yet the precise mechanisms of glutamine-dependent CD8 T cell differentiation remain unclear. We show that distinct strategies of glutamine inhibition by glutaminase-specific inhibition with small molecule CB-839, pan-glutamine inhibition with 6-diazo-5-oxo-L-norleucine (DON), or by glutamine deprivation (No Q) produce distinct metabolic differentiation trajectories in CD8 T cells. T cell activation with CB-839 treatment had a milder effect than DON or No Q treatment. A key difference was that CB-839-treated cells compensated with increased glycolytic metabolism, while DON and No Q-treated cells increased oxidative metabolism. However, all glutamine treatment strategies elevated CD8 T cell dependence on glucose metabolism, and No Q treatment caused adaptation toward reduced glutamine dependence. DON treatment reduced histone modifications and numbers of memory-like cells in adoptive transfer studies, but those T cells that persisted could expand normally upon secondary antigen encounter. In contrast, No Q-treated cells persisted well yet demonstrated decreased secondary expansion. Consistent with impaired function, CD8 T cells activated in the presence of DON had reduced ability to control tumor growth and reduced tumor infiltration in adoptive cell therapy. Overall, each approach to inhibit glutamine metabolism confers distinct effects on CD8 T cells and highlights that targeting the same pathway in different ways can elicit opposing metabolic and functional outcomes.
2023-05-12 | GSE232241 | GEO
Project description:The tumor microenvironment (TME) contains a rich source of nutrients that sustain cell growth and ultimately facilitate tumor progression. The availability of glucose and glutamine in the TME are essential for the development and activation of effector T cells that exert anti-tumor function. Recently, inhibition of glutaminase, the enzyme that hydrolyzes glutamine to glutamate, has garnered interest as an approach to both decrease tumor metabolism and growth, while increasing available glutamine in the TME for effector T cells. Checkpoint blockade immunotherapy unleashes anti-tumor effector capabilities of T cells, and although there are good responses in many solid tumors, a significant proportion of patients respond poorly. In lung adenocarcinoma, response to immunotherapy is reported to be impaired in KRAS-mutant patients harboring concurrent KEAP1 and STK11/Lkb1 mutations. To investigate the metabolism and immune microenvironment of KRAS-mutant lung adenocarcinoma, we generated a series of murine models that reflect the KEAP1 and STK11/Lkb1 mutational landscape seen in patients. Here we show increased glutamate abundance in the Lkb1-deficient TME associated with CD8 T cell activation in response to anti-PD1 checkpoint immunotherapy. Combination treatment with the glutaminase inhibitor CB-839 inhibited clonal expansion and cytotoxic activation of tumor-infiltrating CD8 T cells. Thus, CD8 T cells exposed to checkpoint immunotherapy have a dependence on glutamine and reliance on glutaminase activity and are negatively impacted by the glutaminase inhibitor in this highly activated state. Therefore, we discern that the combination of immunotherapy and glutaminase inhibition is not efficacious for CD8 T cell activation in the tumor microenvironment.
2022-05-02 | GSE193895 | GEO
Project description:Corynebacterium glutamicum, a gram-positive soil bacterium used for the industrial production of amino acids such as L-glutamate and L-lysine, is able to use a number of different nitrogen sources, such as ammonium, urea, or creatinine. In this communication, we show that L-glutamine serves as an excellent nitrogen source for C. glutamicum and allows similar growth rates in glucose minimal medium as ammonium. A transcriptome comparison revealed a strong induction of the nitrogen starvation response when glutamine was used as nitrogen source. Subsequent growth experiments with a variety of mutants defective in nitrogen metabolism showed that glutamate synthase is crucial for glutamine utilization, while a putative glutaminase is dispensable under the experimental conditions used. The fact that the glutamate synthase encoding gltBD operon is under strict nitrogen control explains the necessity for induction of the nitrogen starvation response. The paradox situation that the nitrogen starvation response is induced although intracellular L-glutamine levels are high has implications on nitrogen sensing. In contrast to other gram-positive and gram-negative bacteria such as Bacillus subtilis, Salmonella typhimurium, and Klebsiella pneumoniae, a drop in glutamine concentration obviously does not serve as a nitrogen starvation signal in C. glutamicum. Three biological replicates were performed. To analyse how L-glutamine influences global gene expression when used as sole nitrogen source instead of ammonium, DNA microarray analyses were performed. For this purpose RNA was isolated from exponentially growing cells cultivated in CgXII medium containing glucose as carbon source and either L-glutamine or ammonium sulphate as nitrogen source.
2010-10-05 | E-GEOD-19779 | biostudies-arrayexpress