Similar Datasets
Project description:Histone deacetylases (HDACs) have a wide range of targets and can rewire both the chromatin and lipidome of cancer cells. In this study, we show that valproic acid (VPA), a brain penetrant anti-epilepticseizure medication and histone deacetylase inhibitor, inhibits the growth of IDH1 mutant tumors in vivo and in vitro, with at least some selectivity over IDH1 wild-type tumors. Surprisingly, genes upregulated by VPA showed no change inenhanced chromatin accessibility at the promoter, but there was a correlation between VPA-downregulated genes and diminished promoter chromatin accessibility. VPA inhibited the transcription of lipogenic genes and these lipogenic genes showed significant decreases in promoter chromatin accessibility only in the IDH1 MT glioma cell lines tested. VPA inhibited the mTOR pathway and a key lipogenic gene, fatty acid synthase (FASN). Both VPA and a selective FASN inhibitor TVB-2640 rewired the lipidome and promoted apoptosis in an IDH1 MT but not in an IDH1 WT glioma cell line. We further find that HDACs are involved in the regulation of lipogenic genes and HDAC6 is particularly important for the regulation of FASN in IDH1 MT glioma. Finally, we show that FASN knockdown alone and VPA in combination with FASN knockdown significantly improved the survival of mice in an IDH1 MT primary orthotopic xenograft model in vivo. We conclude that targeting fatty acid metabolism through HDAC inhibition and/or FASN inhibition may be a novel therapeutic opportunity in IDH1 mutant gliomas.
2024-08-21 | GSE273404 | GEO
Project description:Histone deacetylases (HDACs) have a wide range of targets and can rewire both the chromatin and lipidome of cancer cells. In this study, we show that valproic acid (VPA), a brain penetrant anti-epilepticseizure medication and histone deacetylase inhibitor, inhibits the growth of IDH1 mutant tumors in vivo and in vitro, with at least some selectivity over IDH1 wild-type tumors. Surprisingly, genes upregulated by VPA showed no change inenhanced chromatin accessibility at the promoter, but there was a correlation between VPA-downregulated genes and diminished promoter chromatin accessibility. VPA inhibited the transcription of lipogenic genes and these lipogenic genes showed significant decreases in promoter chromatin accessibility only in the IDH1 MT glioma cell lines tested. VPA inhibited the mTOR pathway and a key lipogenic gene, fatty acid synthase (FASN). Both VPA and a selective FASN inhibitor TVB-2640 rewired the lipidome and promoted apoptosis in an IDH1 MT but not in an IDH1 WT glioma cell line. We further find that HDACs are involved in the regulation of lipogenic genes and HDAC6 is particularly important for the regulation of FASN in IDH1 MT glioma. Finally, we show that FASN knockdown alone and VPA in combination with FASN knockdown significantly improved the survival of mice in an IDH1 MT primary orthotopic xenograft model in vivo. We conclude that targeting fatty acid metabolism through HDAC inhibition and/or FASN inhibition may be a novel therapeutic opportunity in IDH1 mutant gliomas.
2024-08-21 | GSE273401 | GEO
Project description:Valproic acid targets IDH1 mutants through alteration of lipid metabolism
| PRJNA1141557 | ENA
Project description:Valproic acid targets IDH1 mutants through alteration of lipid metabolism [2022]
| PRJNA1141558 | ENA
Project description:Valproic acid targets IDH1 mutants through alteration of lipid metabolism [2020]
| PRJNA1141553 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-12-23 | E-GEOD-51545 | biostudies-arrayexpress
Project description:Valproic acid (VPA) is one of the most widely prescribed antiepileptic drugs, as VPA-induced hepatotoxicity is one of the most severe adverse reaction that can lead to death. The objective of this study was to gain an understanding of dysregulated lipid metabolism in mechanism of hepatotoxicity. Nontargeted lipidomics analysis with liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-Q-TOF/MS) was performed to explore differential lipids from the patient serum and L02 cells. Lipidomics data interpretation was augmented by gene expression analyses for the key enzymes in lipid metabolism pathways. From patient serum lipidomics, pronouncedly changed lipid species between abnormal liver function (ALF) patients and normal liver function (NLF) patients were identified. Among these lipid species, LPCs, Cers, and SMs were markedly reduced in the ALF group and showed negative relationships with liver injury severity [alanine aminotransferase (ALT) levels], while significantly increased triacylglycerols (TAG) with higher summed carbon numbers demonstrated a positive relationship with ALT levels. Regarding lipidomics in hepatic L02 cells, TAG was markedly elevated after VPA exposure, especially in TAGs with more than 53 summed carbons. Besides, gene expression analysis revealed dysregulated lipid metabolism in VPA-treated L02 cells. Peroxime proliferators-activated receptor (PPARγ) pathway played an important role in VPA-induced lipid disruption through inducing long-chain fatty acid uptake and TAG synthesis, which was also regulated by Akt pathway. Our findings present that VPA-induced lipid metabolism disruption might lead to lipotoxicity in the liver. This approach is expected to be applicable for other drug-induced toxicity assessments.
| S-EPMC6659130 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2013-12-23 | GSE51545 | GEO
Project description:Lipid metabolism is important for cellular energy homeostasis. Excessive cellular lipid accumulation is associated with various human diseases such as obesity, cardiovascular disease or even cancer. It has been recognized that miR-181a is an important modulator in regulating T lymphocyte differentiation, vascular development and cerebellar neurodegeneration. Here we reports a novel function of miR-181a in the regulation of lipid metabolism. MiR-181a is able to target isocitrate dehydrogenase 1 (IDH1), a metabolic enzyme in TCA cycle. Via targeting IDH1, miR-181a decreases expression of genes involved in lipid synthesis and increases expression of genes involved in β-oxidation, thereafter inhibiting lipid accumulation. MiR-181a transgenic mice show a lower body weight as compared with their wild-type littermates, and moreover, miR-181a transgenic mice exhibit less lipid accumulation. Collectively, these findings uncover a novel miR-181a-IDH1 axis that has an important role in regulating lipid metabolism, and implicate miR-181a as a potential therapeutic target for lipid metabolism disorders.
| S-EPMC4350072 | biostudies-literature
Project description:Although drug induced steatosis represents a mild type of hepatotoxicity it can progress into more severe non-alcoholic steatohepatitis. Current models used for safety assessment in drug development and chemical risk assessment do not accurately predict steatosis in humans. Therefore, new models need to be developed to screen compounds for steatogenic properties. We have studied the usefulness of mouse precision-cut liver slices (PCLS) as an alternative to animal testing to gain more insight into the mechanisms involved in the steatogenesis. To this end, PCLS were incubated 24 h with the model steatogenic compounds: amiodarone (AMI), valproic acid (VA), and tetracycline (TET). Transcriptome analysis using DNA microarrays was used to identify genes and processes affected by these compounds. AMI and VA upregulated lipid metabolism, whereas processes associated with extracellular matrix remodelling and inflammation were downregulated. TET downregulated mitochondrial functions, lipid metabolism, and fibrosis. Furthermore, on the basis of the transcriptomics data it was hypothesized that all three compounds affect peroxisome proliferator activated-receptor (PPAR) signaling. Application of PPAR reporter assays classified AMI and VA as PPARγ and triple PPARα/(β/δ)/γ agonist, respectively, whereas TET had no effect on any of the PPARs. Some of the differentially expressed genes were considered as potential candidate biomarkers to identify PPAR agonists (i.e. AMI and VA) or compounds impairing mitochondrial functions (i.e. TET). Finally, comparison of our findings with publicly available transcriptomics data showed that a number of processes altered in the mouse PCLS was also affected in mouse livers and human primary hepatocytes exposed to known PPAR agonists. Thus mouse PCLS are a valuable model to identify early mechanisms of action of compounds altering lipid metabolism.
| S-EPMC3906077 | biostudies-literature