Transcriptomic analysis of the peripheral nervous system of Schwann cell-conditional FASN knockout mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE71373 | GEO | 2018/02/02
REPOSITORIES: GEO
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Project description:The fatty acid synthase (FASN) is the major fat synthesizing enzyme. FASN is an indispensable enzyme because mice with genetic deletion of Fasn are not viable. Apart from its physiological function, previous studies indicated that FASN could also exert a pathophysiological role, in the heart, because patients with heart failure showed up-reguation of FASN. To investigate the in vivo function of FASN up-regulation in the heart, we generated mice with myocardium-specific expression of FASN under control of the alpha-MHC promoter. Two different founder lines were generated with high and low FASN over-expression. Microarray gene expression profiling of heart tissue was performed of heart tissue from transgenic mice with high and low FASN expression Microarray gene expression profiling was performed with heart tissue isolated from three study groups: (i) Transgenic mice with high cardiac FASN expression, (ii) transgenic mice with low cardiac FASN expression, and (iii) B6 control mice.
2013-07-31 | E-GEOD-49351 | biostudies-arrayexpress
Project description:Fatty acid synthase (FASN) inhibition effect with IPI-9119 compound in prostate cancer cells C4-2
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Project description:The fatty acid synthase (FASN) is the major fat synthesizing enzyme. FASN is an indispensable enzyme because mice with genetic deletion of Fasn are not viable. Apart from its physiological function, previous studies indicated that FASN could also exert a pathophysiological role, in the heart, because patients with heart failure showed up-reguation of FASN. To investigate the in vivo function of FASN up-regulation in the heart, we generated mice with myocardium-specific expression of FASN under control of the alpha-MHC promoter. Two different founder lines were generated with high and low FASN over-expression. Microarray gene expression profiling of heart tissue was performed of heart tissue from transgenic mice with high and low FASN expression
2013-07-31 | GSE49351 | GEO
Project description:Fatty acid synthase is a major enzyme involved in de novo lipogenesis, associated with energy homeostasis, lipid storage and signalling in normal liver cells. The effect of fatty acid synthase knockdown in normal liver cells (THLE 2) using siRNA mediated gene silencing were assesed for global gene deregulations. The deregulated metabolism, cell signalling and cell cycle pathway related gene expressions were analysed. Statistical significance values were also recorded. This expermental analysis clearly points to a important biochemical role for FASN in normal liver cell physiology. Total RNA was extracted from the THLE 2 cells transfected with FASN siRNA at 48h, along with its untransfected control cells. cDNA converted samples were run on microarray platform- Illumina HumanHT-12 V4.0 expression beadchip
2016-06-02 | E-GEOD-82096 | biostudies-arrayexpress
Project description:Fate and behaviour of neural progenitor cells is tightly regulated during mammalian brain development. Metabolic pathways, such as glycolysis and oxidative phosphorylation, that are required for supplying energy and providing molecular building blocks to generate cells, govern progenitor function. However, the role of de novo lipogenesis, which is the conversion of glucose into fatty acids through the multi-enzyme protein fatty acid synthase (FASN), for brain development remains unknown. Using Emx1Cre-mediated, tissue-specific deletion of Fasn in the mouse embryonic telencephalon, we show that loss of FASN causes severe microcephaly, largely due to altered polarity of apical, radial glia progenitors (APs) and reduced progenitor proliferation. Further, genetic deletion and pharmacological inhibition of FASN in human embryonic stem cell (ESC)-derived forebrain organoids identifies a conserved role of FASN-dependent lipogenesis for radial glia cell polarity and progenitor expansion in the developing human forebrain. Thus, our data establish a role of de novo lipogenesis for mouse and human brain development and identify a link between progenitor cell polarity and lipid metabolism.
2022-01-14 | PXD026110 | Pride
Project description:In the central nervous system, oligodendrocytes encase axons with myelin, a highly organized multilayered membrane structure. Myelin allows the rapid propagation of action potentials along the axons, while also supporting their mantainance metabolically. Fatty acids are basic building blocks for both glyco- and phospholipids, key constituents of cell membranes. Moreover, fatty acids can modify proteins via palmitoylation and activate transcriptional networks, e.g. through the PPARs transcription factors. Due to the high demand of membrane oligodendrocytes face to produce myelin, we hypothesized that they strongly rely upon fatty acid synthesis rather than mostly on their intake from the dietary pool. We tested this hypothesis by deleting the enzyme Fatty Acid Synthase specifically from neonatal oligodendrocyte progenitor cells, in vivo in C57Bl/6 olig2Cre FASN floxed mice. We addressed the consequences of this depletion on oligodendrocytes differentation and myelination potential in the central nervous system. In particular, we analyzed by RNA-seq how lack of FASN affected the transcriptome of optic nerves dissected from P14 mutant (olig2Cre FASN lox/lox) versus control (FASN lox/lox) mice.
2019-05-03 | GSE112725 | GEO
Project description:Mechanisms controlling the proliferative activity of neural stem/progenitor cells (NSPCs) play a pivotal role to ensure life-long neurogenesis in the mammalian brain. How metabolic programs are coupled with NSPC activity remains unknown. Here we show that fatty acid synthase (FASN), the key enzyme of de novo lipogenesis, is highly active in adult NSPCs and that conditional deletion of FASN in NSPCs impairs adult neurogenesis. The rate of de novo lipid synthesis and subsequent proliferation of NSPCs is regulated by Spot14, a gene we found to be selectively expressed in low proliferating adult NSPCs. Spot14 reduces the availability of malonyl-CoA, which is an essential substrate for FASN to fuel lipogenesis. Thus, we here identified a functional coupling between the regulation of lipid metabolism and adult NSPC proliferation. 6 samples were analyzed. Spot14+: Spot14 GFP positive mouse neural stem cell, 3 biological rep Spot14-: Spot14 GFP negative mouse neural stem cell, 3 biological rep
2012-11-02 | E-GEOD-27391 | biostudies-arrayexpress
Project description:Background & Aims: Aberrant activation of fatty acid synthase (FASN) is a major metabolic event during the development of HCC. We evaluated the therapeutic efficacy of TVB3664, a novel FASN inhibitor, either alone or in combination, for HCC treatment. Approach & Results: The therapeutic efficacy and the molecular pathways targeted by TVB3664, either alone or with tyrosine kinase inhibitors or the checkpoint inhibitor anti-PD-L1 antibody, were assessed in human HCC cell lines and multiple oncogene-driven HCC mouse models. RNAseq was performed to characterize the global gene expression and metabolic profiles. TVB3664 effectively ameliorated the fatty liver phenotype in the aged mice and AKT activation-induced hepatic steatosis. TVB3664 monotherapy showed moderate efficacy in NASH-related murine HCCs, induced by loss of PTEN and c-MET overexpression. TVB3664, in combination with cabozantinib, triggered tumor regression in this mouse HCC model but did not improve the responsiveness to immunotherapy. Global gene expression revealed that TVB3664 predominantly modulated metabolic processes, while TVB3664 synergized with cabozantinib to downregulate multiple cancer-related pathways, especially the AKT/mTOR pathway and cell proliferation genes. TVB3664 also improved the therapeutic efficacy of sorafenib and cabozantinib in the FASN-dependent c-MYC HCC model. However, TVB3664 had no efficacy nor synergistic effects in FASN-independent mouse HCC models. Conclusions: This preclinical study suggests the limited efficacy of targeting FASN as monotherapy for HCC treatment. However, FASN inhibitors could be combined with other drugs for improved effectiveness. These combination therapies could be developed based on the driver oncogenes, supporting precision medicine approaches for HCC treatment.
2022-01-28 | GSE189529 | GEO
Project description:Oligodendrocytes are the main myelinating and remyelinating cells of the central nervous system. We identified N-myc downstream regulated gene family member 1 (NDRG1) as a specific mature marker of the oligodendroglial lineage, regulated by mTORC2 kinase activity. By generating a transgenic reporter murine line, we managed to precisely characterize the effect of cuprizone-induced treatment on myelinating cells. We also created a new and adult-specific whole genome transcriptomic profile of the oligodendroglial lineage, from proliferative OPC (using P60 PDGFRa::GFP sorted cells), to pre-myelinating OL (using P60 PLP::GFP sorted cells) and then mature OL (using P60 NDRG1-eGFP sorted cells). This new reporter murine line and its associated RNA-Sequencing dataset could help us better understand the specific biology of adult myelinating oligodendrocytes, compared to previously published developmental tools and databases.
2021-12-01 | GSE113614 | GEO
Project description:Alveolar epithelial type II cells (AEC2) strictly regulate lipid metabolism to maintain surfactant synthesis. A loss in AEC2 cell function and surfactant production are implicated in the pathogenesis of the smoking related lung disease, chronic obstructive pulmonary disease (COPD). It is unclear if smoking alters lipid synthesis in AEC2 cells and if altering lipid metabolism in AEC2 cells contributes to COPD development. In this study, high throughput lipidomic analysis revealed increased lipid biosynthesis in AEC2 cells isolated from mice chronically exposed to cigarette smoke (CS). Mice with a targeted deletion of the de novo lipogenesis enzyme, fatty acid synthase (FASN) in AEC2 cells (FasniAEC2) exposed to CS exhibited higher bronchoalveolar lavage fluid (BALF) neutrophils, higher BALF protein, more severe air-space enlargement and were more susceptible to age-induced emphysema. FasniAEC2 mice exposed to CS had lower levels of key surfactant phospholipids but higher levels of BALF ether phospholipids, sphingomyelins and polyunsaturated fatty acid containing-phospholipids, as well as increased BALF surface tension. FasniAEC2 mice exposed to CS also had higher markers of ferroptosis in the lung. These data suggest that AEC2 cell FASN modulates the response of the lung to smoke by regulating the composition of the surfactant phospholipidome.
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