Impaired GR expression in liver disrupts feeding induced gene expression, glucose uptake and glycogen storage
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ABSTRACT:
PROVIDER: PRJNA726880 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14402300.fastq.gz | Fastqsanger.gz | |||
| SRR14402301.fastq.gz | Fastqsanger.gz | |||
| SRR14402302.fastq.gz | Fastqsanger.gz | |||
| SRR14402303.fastq.gz | Fastqsanger.gz | |||
| SRR14402225_1.fastq.gz | Fastqsanger.gz |
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Project description:The transition from a fasted to a fed state is associated with extensive transcriptional remodeling in hepatocytes facilitated by hormonal- and nutritional-regulated transcription factors. Here, we use a liver-specific glucocorticoid receptor (GR) knock-out (L-GRKO) model and primary hepatocytes to investigate the temporal expression of GR target genes in response to feeding. Interestingly, in addition to the well described fasting-regulated genes, we identify a subset of hepatic feeding-induced genes that requires GR for full expression, adding new insights to hepatic GR function. The GR-controlled feeding-induced genes include Gck encoding the glucokinase, which is important for hepatic glucose uptake, utilization and storage. We show that insulin and glucocorticoids cooperatively regulate Gck expression in primary hepatocytes in a GR-dependent manner. ChIP-seq experiments suggest direct GR regulation of Gck by GR occupancy of the promoter and two putative regulatory regions near the Gck gene (Gck -1kb and Gck -4.6kb). Enhancer-reporter assays and CRISPRi suggest that the 4.6kb upstream GR binding site is a functional Gck enhancer. L-GRKO blunts preprandial and early postprandial Gck expression and GR disruption ultimately affects early postprandial hepatic glucose uptake, phosphorylation and glycogen storage. Collectively, our study demonstrates how GR is positively involved in the hepatic feeding response exemplified in the direct regulation of the feeding-induced transcription of glucokinase, important for hepatic glucose metabolism.
2021-09-08 | GSE173723 | GEO
Project description:Glycogen and lipid are major storage forms of energy that are tightly regulated by hormones and metabolic signals. Here, we evaluate the role of the glycogenic scaffolding protein PTG/R5 in energy homeostasis. We demonstrate that feeding mice a high-fat diet (HFD) increases hepatic glycogen, corresponding to increased PTG levels, increased activity of the mechanistic target of rapamycin complex 1 (mTORC1) and induced expression of sterol regulatory element binding protein 1c (SREBP1c). PTG promoter activity was increased by activation of mTORC1 and SREBP1, and PTG and glycogen levels were augmented in mice and cells in which mTORC1 is constitutively active. HFD-dependent increases in hepatic glycogen were prevented by deletion of the PTG gene in mice. Interestingly, PTG knockout mice fed HFD exhibited improved liver steatosis and decreased lipid levels in muscle, in coordination with decreased glycogen, suggesting possible crosstalk between glycogen and lipid stores in the overall control of energy metabolism. Together, these data suggest that transcriptional regulation of PTG by dietary and nutritional cues has profound effects on energy storage and metabolism.fi RNA-Seq analysis was used to characterize hepatic diet-associated gene expression changes between wild-type and PTG KO mice. Mice were maintained on a normal chow diet or a high-fat diet as indicated. 2-3 biological replicates per genotype/diet.
2014-06-13 | E-GEOD-45319 | biostudies-arrayexpress
Project description:Glycogen and lipid are major storage forms of energy that are tightly regulated by hormones and metabolic signals. Here, we evaluate the role of the glycogenic scaffolding protein PTG/R5 in energy homeostasis. We demonstrate that feeding mice a high-fat diet (HFD) increases hepatic glycogen, corresponding to increased PTG levels, increased activity of the mechanistic target of rapamycin complex 1 (mTORC1) and induced expression of sterol regulatory element binding protein 1c (SREBP1c). PTG promoter activity was increased by activation of mTORC1 and SREBP1, and PTG and glycogen levels were augmented in mice and cells in which mTORC1 is constitutively active. HFD-dependent increases in hepatic glycogen were prevented by deletion of the PTG gene in mice. Interestingly, PTG knockout mice fed HFD exhibited improved liver steatosis and decreased lipid levels in muscle, in coordination with decreased glycogen, suggesting possible crosstalk between glycogen and lipid stores in the overall control of energy metabolism. Together, these data suggest that transcriptional regulation of PTG by dietary and nutritional cues has profound effects on energy storage and metabolism.fi
2014-06-13 | GSE45319 | GEO
Project description:A single bout of exercise followed by intake of carbohydrates leads to glycogen supercompensation in the prior exercised muscle. The molecular mechanisms underlying this well-known phenomenon remain elusive. Here we report that a single bout of exercise induces marked activation of glycogen synthase (GS) and AMP-activated protein kinase (AMPK) for several days beyond normalized muscle glycogen content in man. Acute muscle specific deletion of AMPK activity in mouse muscle abrogated the ability for glycogen supercompensation, providing genetic evidence that AMPK serves as essential driver for glycogen supercompensation. Muscle proteomic analyses revealed elevated glucose uptake capacity in the prior exercised muscle while key proteins in fat oxidation and glycolysis largely remained unchanged. The temporal order of these sustained cellular alterations induced by a single bout of exercise provide a mechanism to offset the otherwise tight feedback inhibition of glycogen synthesis and glucose uptake by glycogen, ultimately leading to muscle glycogen supercompensation.
2018-08-30 | PXD009196 | Pride
Project description:Glucocorticoids (GCs) bind to the glucocorticoid receptor (GR) to regulate diverse biological functions from cell growth to apoptosis. Drugs that mimic their action are the most commonly prescribed therapeutic agents in the world and are currently used for the treatment of many diseases including asthma, autoimmune disorders, and some cancers. However, the mechanisms by which one hormone, via one receptor, modulates such diverse biological functions remain unclear. We hypothesized that epigenetic alteration to the GR may contribute to its signaling diversity, and here we demonstrate that Glycogen Synthase Kinase-3-beta phosphorylates GR on Serine 404 in a glucocorticoid-dependent manner. U-2 OS cells expressing a mutant GR that is incapable of Ser404 phosphorylation have enhanced global transcriptional responses, stronger NF-kappaB transrepression, and enhanced cell death in response to dexamethasone. Conversely, presence of Ser404 phosphorylation on the GR inhibits glucocorticoid-dependent NF-kappaB transrepression and cell death of these osteoblasts. Collectively, our results describe a novel convergence point of the GSK-3-beta pathway with the GR resulting in altered glucocorticoid regulated signaling. Our results also provide a mechanism by which the phosphorylation status of Ser404 in GR can dictate how cells will ultimately respond to GCs. Keywords: Glucocorticoid Receptor; GSK-3-beta; NF-kappaB Transrepression; Phosphorylation
2008-11-24 | GSE11205 | GEO
Project description:Background: Heart failure involves metabolic alterations including increased glycolysis despite unchanged or decreased glucose oxidation. The mitochondrial pyruvate carrier (MPC) regulates pyruvate entry into the mitochondrial matrix, and cardiac deletion of the MPC in mice causes heart failure. How MPC deletion results in heart failure is unknown. Methods: We performed targeted metabolomics and isotope tracing in wildtype (fl/fl) and cardiac-specific Mpc2-/- (CS-Mpc2-/-) hearts after in vivo injection of 13C-glucose. Cardiac glycogen was measured biochemically and by transmission electron microscopy. Cardiac glucose uptake of 2-deoxyglucose was measured and western blotting performed to analyze insulin signaling and enzymatic regulators of glycogen synthesis and degradation. Isotope tracing and glycogen analysis was also performed in hearts from mice fed either low-fat diet or a ketogenic diet previously shown to reverse the heart failure in CS-Mpc2-/- mice. Cardiac glycogen was also assessed in mice infused with angiotensin-II that were fed either low-fat or ketogenic diet. Results: Failing CS-Mpc2-/- hearts contained normal levels of ATP and phosphocreatine, suggesting their heart failure is not caused by energetic stress. These hearts displayed increased enrichment from 13C-glucose and increased glycolytic metabolite pool sizes. 13C enrichment and pool size was also increased for the glycogen intermediate UDP-glucose, as well as increased enrichment of the glycogen pool. Glycogen levels were increased ~6-fold in the failing CS-Mpc2-/- hearts, and glycogen granules were easily detected by electron microscopy. This increased glycogen synthesis occurred despite enhanced inhibitory phosphorylation of glycogen synthase and reduced expression of the priming enzyme glycogenin-1. In young, non-failing CS-Mpc2-/- hearts, increased glycolytic 13C enrichment occurred, but glycogen levels remained low and unchanged compared to fl/fl hearts. Feeding a ketogenic diet to CS-Mpc2-/- mice reversed the heart failure and normalized the cardiac glycogen and glycolytic metabolite accumulation. Cardiac glycogen levels were also elevated in mice infused with angiotensin II, and both the cardiac hypertrophy and glycogen levels were improved by ketogenic diet. Conclusions: Our results indicate that loss of MPC in the heart increases glycolytic metabolism and ultimately glycogen accumulation and heart failure, while a ketogenic diet can reverse both the glycogen accumulation and heart failure. We conclude that maintaining mitochondrial pyruvate import and metabolism is critical for the heart, unless cardiac pyruvate metabolism is dramatically reduced by consumption of a ketogenic diet.
2024-06-03 | GSE268694 | GEO
Project description:The Glucocorticoid Receptor (GR) is both one of the most widely used clinical drug targets and a very potent metabolic regulator. GR belongs to the nuclear hormone receptor family of ligand-gated transcription factors that govern mammalian physiology. Upon ligand binding, GR enters the nucleus to regulate gene expression both positively and negatively. It is known to bind to consensus DNA sequences termed glucocorticoid response elements (GREs), but the mechanisms determining transcriptional activation versus repression remain an unresolved molecular paradox. Prevailing models suggest that tethering of GR to AP-1 or NF-κB via protein-protein interactions, rather than direct DNA binding, specifies negative regulation. However, here we show that the repression of inflammatory genes as well as all other glucocorticoid responses, require direct DNA binding of GR. Generating GR point mutant mice that retain the ability to tether via protein-protein interactions while unable to recognize DNA sequences, we demonstrate that response element recognition via the Zinc finger is absolutely required for both transcriptional activation and repression. We have used ChIP-Seq and RNA-Seq in inflammatory and metabolic cells and tissues together with proteomics to reveal that DNA binding of GR is necessary for the assembly of a functional SWI/SNF coregulator complex. Generally, the desired anti-inflammatory actions of GR are attributed to the silencing of inflammatory genes, while its adverse effects are believed to result from the transcriptional upregulation of metabolic targets. Our findings not only challenge classical models and dogmas of GR mediated gene regulation, but will provide an important basis for the development of novel immunosuppressants with reduced side effect profiles.
2020-07-07 | PXD013772 | Pride
Project description:Glycogen is the largest soluble cytosolic macromolecule and considered as the principal storage form of glucose. Cancer cells generally increase their glucose consumption and rewire their metabolism towards aerobic glycolysis to promote growth. Here we report that glycogen accumulation is a key initiating oncogenic event and essential for malignant transformation. RNA-sequencing analysis reveals that G6PC, an enzyme catalyzing the last step of glycogenolysis, is frequently downregulated to augment glucose storage in pro-tumor cells. Accumulated glycogen undergoes liquid-liquid phase separation undergoes liquid-liquid phase separation, which results in the assembly of the laforin-Mst1/2 complex and consequently traps Hippo kinases Mst1/2 in glycogen liquid droplets to relieve their inhibition on Yap. Moreover, G6PC or another glycogenolysis enzyme PYGL deficiency in both human and mice result in glycogen storage disease with enlarged liver size and cancer development, phenocopying Hippo deficiency. Consistently, elimination of glycogen accumulation abrogates liver enlargement and cancer incidence, whereas increasing glycogen storage accelerates tumorigenesis. Thus, we concluded that glycogen not only provides nutrition and energy to the cells but also functions as a key initiating oncogenic metabolite, which physically blocks Hippo signaling through glycogen phase separation to augment pro-tumor cell initiation and progression.
2021-10-06 | GSE148933 | GEO
Project description:Anterior tibialis removed from 3-month old muscle glycogen synthase WT or knockout mouse. RNA was extracted using GibcoBRL TRIzol Reagent and a Quiagen RNeasy kit. Targets were produced using standard Affymetrix procedures from about 5ug of total RNA. GSM40057-GSM40063 AND GSM40956. Liver removed from 3-month old muscle glycogen synthase WT or knockout mouse. RNA was extracted using GibcoBRL TRIzol Reagent and a Quiagen RNeasy kit. Targets were produced using standard Affymetrix procedures from about 10ug of total RNA. GSM40064-GSM40071. Medial gastrocnemius removed from 3-month old muscle glycogen synthase WT or knockout mouse. RNA was extracted using GibcoBRL TRIzol Reagent and a Quiagen RNeasy kit. Targets were produced using standard Affymetrix procedures from about 5ug of total RNA. GSM40072-GSM40079. Medial gastrocnemius removed from 8-month old muscle glycogen synthase WT or overexpressing mouse. RNA was extracted using GibcoBRL TRIzol Reagent and a Quiagen RNeasy kit. Targets were produced using standard Affymetrix procedures from about 5ug of total RNA. GSM40080-GSM40089
2007-09-25 | E-GEOD-2198 | biostudies-arrayexpress