Similar Datasets
Project description:Paracetamol (acetaminophen, APAP) overdose severely damages mitochondria and triggers several apoptotic processes in hepatocytes, but the final outcome is fulminant necrotic cell death, resulting in acute liver failure and mortality. Here, we studied this switch of cell death modes and demonstrate a non-canonical role of the apoptosis-regulating BCL-2 homolog BIM/Bcl2l11 in promoting necrosis by regulating cellular bioenergetics. BIM deficiency enhanced total ATP production and shifted the bioenergetic profile towards glycolysis, resulting in persistent protection from APAP-induced liver injury. Modulation of glucose levels and deletion of mitofusins confirmed that severe APAP toxicity occurs only in cells dependent on oxidative phosphorylation. Glycolytic hepatocytes maintained elevated ATP levels and reduced ROS, which enabled lysosomal recycling of damaged mitochondria by mitophagy. The present study highlights how metabolism and bioenergetics affect drug-induced liver toxicity, and identifies BIM as important regulator of glycolysis, mitochondrial respiration, and oxidative stress signaling.
2023-09-08 | GSE242368 | GEO
Project description:The effects of adiponectin on hepatic glucose and lipid metabolism at transcriptional level are largely unknown. We profiled hepatic gene expression in adiponectin knockout (KO) and wild-type (WT) mice by RNA-Seq. Comparing to WT mice, adiponectin KO mice exhibited decreased mRNA expression of rate-limiting enzymes in several important glucose and lipid metabolic pathways including glycolysis, TCA cycle, fatty-acid activation and synthesis, triglyceride synthesis and cholesterol synthesis. In addition, binding of the transcription factor Hnf4a to DNAs encoding several key metabolic enzymes was reduced in KO mice, suggesting that adiponectin might regulate hepatic gene expression via Hnf4a. Phenotypically, adiponectin KO mice possessed smaller epididymal fat pads and showed reduced body weights comparing to WT mice. When fed a high fat diet, adiponectin KO mice showed significantly reduced lipid accumulation in the livers. These lipogenic defects are consistent with the downregulation of lipogenic genes in the KO mice.
2012-09-04 | GSE38144 | GEO
Project description:The effects of adiponectin on hepatic glucose and lipid metabolism at transcriptional level are largely unknown. We profiled hepatic gene expression in adiponectin knockout (KO) and wild-type (WT) mice by RNA-Seq. Comparing to WT mice, adiponectin KO mice exhibited decreased mRNA expression of rate-limiting enzymes in several important glucose and lipid metabolic pathways including glycolysis, TCA cycle, fatty-acid activation and synthesis, triglyceride synthesis and cholesterol synthesis. In addition, binding of the transcription factor Hnf4a to DNAs encoding several key metabolic enzymes was reduced in KO mice, suggesting that adiponectin might regulate hepatic gene expression via Hnf4a. Phenotypically, adiponectin KO mice possessed smaller epididymal fat pads and showed reduced body weights comparing to WT mice. When fed a high fat diet, adiponectin KO mice showed significantly reduced lipid accumulation in the livers. These lipogenic defects are consistent with the downregulation of lipogenic genes in the KO mice. Mice were fasted overnight before euthanization. Liver tissues from WT or adiponectin KO male mice (n = 9-10) at 12 weeks of age were harvested and subjected to total RNA extraction using an RNeasy Plus Mini Kit (Qiagen, Valencia, CA). Total RNA from nine to ten mice of the same strain was pooled together as one biological sample. The mRNA sequencing samples were prepared using the Illumina sample preparation protocol (RS-930-1001, Illumina, Inc. San Diego, CA). The cDNA fragments of 200–250 bp were purified on an agarose gel and then enriched by PCR with Phusion polymerase. The cDNA libraries were sequenced by an Illumina Genome analyzer II at the Whitehead Genome Technology Core.
2012-09-04 | E-GEOD-38144 | biostudies-arrayexpress
Project description:Myostatin is a negative regulator of muscle growth and metabolism and its inhibition in mice improves insulin sensitivity, increases glucose uptake into skeletal muscle, and decreases total body fat. A recently described mammalian protein called Mss51 is significantly downregulated with myostatin inhibition. In vitro disruption of Mss51 results in increased levels of ATP, β-oxidation, glycolysis and oxidative phosphorylation. To determine the in vivo biological function of Mss51 in mice, we disrupted the Mss51 gene by CRISPR/Cas9 and found that Mss51 KO mice have normal muscle weights and fiber-type distribution but reduced fat pads. Myofibers isolated from Mss51 KO mice showed an increased oxygen consumption rate compared to WT controls, indicating an accelerated rate of skeletal muscle metabolism. The expression of genes related to oxidative phosphorylation and fatty acid β-oxidation were enhanced in skeletal muscle of Mss51 KO mice compared to that of WT mice. We found that mice lacking Mss51 and challenged with a high fat diet were resistant to diet-induced weight gain, had increased whole-body glucose turnover and glycolysis rate, and increased systemic insulin sensitivity and fatty acid β-oxidation. These findings demonstrate that Mss51 modulates skeletal muscle mitochondrial respiration and regulates whole-body glucose and fatty acid metabolism, making it a potential target for obesity and diabetes.
2019-12-31 | GSE134519 | GEO
Project description:Paracetamol (acetaminophen, APAP) overdose severely damages mitochondria and triggers several apoptotic processes in hepatocytes, but the final outcome is fulminant necrotic cell death, resulting in acute liver failure and mortality. Here, we studied this switch of cell death modes and demonstrate a non-canonical role of the apoptosis-regulating BCL-2 homolog BIM/Bcl2l11 in promoting necrosis by regulating cellular bioenergetics. BIM deficiency enhanced total ATP production and shifted the bioenergetic profile towards glycolysis, resulting in persistent protection from APAP-induced liver injury. Modulation of glucose levels and deletion of mitofusins confirmed that severe APAP toxicity occurs only in cells dependent on oxidative phosphorylation. Glycolytic hepatocytes maintained elevated ATP levels and reduced ROS, which enabled lysosomal recycling of damaged mitochondria by mitophagy. The present study highlights how metabolism and bioenergetics affect drug-induced liver toxicity, and identifies BIM as important regulator of glycolysis, mitochondrial respiration, and oxidative stress signaling.
2024-09-24 | PXD045034 | Pride
Project description:Fission yeast in high glucose media preferentially uses fermentation for energy production, even under aerobic conditions, an analogous metabolic programme, aerobic glycolysis, is a hallmark of cancer and enables the proliferation of tumor cells. Fission yeast, unlike budding yeast, requires mitochondrial genomes and oxidative phosphorylation for survival, mitochondrial inheritance, genome organisation and RNA processing are strikingly different between the two yeasts, and S. pombe mitochondria resemble more the human mitochondria. However, mitochondrial biology and respiratory control is poorly understood in fission yeast. In this study, we used microarrays to profile gene expression before and at six time points after the shift from fermentative to respiratory medium. Cells were grown in yeast extract based media with 3% glucose to early exponential phase (time point 0), then the carbon source was changed to 3% glycerol, 0.1% glucose. Transcript levels were monitored by microarrays at several time points after the switch (0.2, 0.5, 1, 2; 04 and 24 hours). Sample from each time point is hybrydized with sample of all pooled time points. Experiment was repeated twice with the dye swap.
2016-11-01 | E-MTAB-4518 | biostudies-arrayexpress
Project description:The number of circulating endothelial progenitor cells (EPCs) predicts future development of atherosclerotic cardiovascular disease (ASCVD) and is reduced in patients with type 2 diabetes (T2DM) or impaired glucose tolerance (IGT). Recent studies revealed the contribution of tight control of glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), as well as fatty acid oxidation in the regulation of stem cell behavior. In this study, we show that how dysregulated glucose and triglyceride metabolism in T2DM/IGT affects the homeostasis of EPCs, i.e. bone marrow stem/progenitor cells (BMSCs). In our clinical study, consistent with previous reports, the patients with IGT or T2DM showed reduced level of circulating EPCs, as compared normal glucose tolerance. On the other hand, fasting or postprandial hypertriglyceridemia (hTG) itself did not affect the level of circulating EPCs. However, further analysis using single and multiple regression analyses strongly suggested that, in the presence of postprandial hTG, postprandial hyperglycemia exerts devastating effect on EPC homeostasis. We therefore carried out the proof of concept study in mice. Our experimental study revealed that repetitive glucose+lipid (G+L) spikes, but not repetitive glucose (G) spikes or lipid (L) spikes, rapidly upregulated p53 in BMSCs and induced premature aging phenotype of bone marrow cells, i.e. the impairment of BMSC quiescence and function, and myeloid-biased differentiation. Subsequent analysis implicated that p53-mediated augmentation of mitochondrial OXPHOS plays pivotal role for the impairment of BMSC quiescence and function. On the other hand, it is still not clear how repetitive G+L injection induced myeloid-biased differentiation. Because cell-fate decisions are executed by transcription factors in response to extracellular signals, and the best-known function of p53 is as a transcription factor, we asked to what extent repetitive glucose spikes and repetitive glucose+TG spikes affect transcriptional regulation in LSK cells.
2021-09-20 | GSE125682 | GEO
Project description:We evaluated two matched human cell lines derived from primary melanocytes, termed pmel+BRAF(V600E) and pmel+BRAF(V600E)+MITF. These cells are therefore isogenic with the exception of the expression of MITF. Gene Set Enrichment Analysis of microarray data identified a highly significant induction of oxidative phosphorylation gene set in MITF expressing cells compared to control cells.
2013-03-07 | E-GEOD-38007 | biostudies-arrayexpress
Project description:Elevated plasma cholesterol and Type 2 Diabetes (T2D) are associated with Coronary Artery Disease (CAD). Individuals treated with cholesterol-lowering statins have increased T2D risk, while individuals with hypercholesterolemia have reduced T2D risk. We explored the relationship between lipid and glucose control by constructing network models from the STARNET study with sequencing data from seven cardiometabolic tissues obtained from CAD patients during coronary artery by-pass grafting surgery. By integrating gene expression, genotype, metabolomic and clinical data, we identified a Glucose and Lipid Determining (GLD) regulatory network showing inverse relationships with lipid and glucose traits. Master regulators of the GLD network also impacted lipid and glucose levels in inverse directions. Experimental knockdown of one of the GLD network master regulators, Lanosterol Synthase (LSS), in mouse confirmed the inverse relationships to glucose and lipid levels as predicted by our model and provided mechanistic insights.
2020-09-01 | GSE157223 | GEO
Project description:Global gene expression analysis reveals that PIMT regulates many genes involved in energy metabolism, calcium signaling, and oxidative phosphorylation in myocardium.
2019-01-01 | GSE111862 | GEO