Hepatic glucocorticoid receptor transcriptome profiling in normal and hypogonadal females
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE99309 | GEO | 2018/04/10
REPOSITORIES: GEO
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Project description:Glucocorticoids (GC) are potent anti-inflammatory agents that are frequently used to treat inflammatory diseases. Chronic glucocorticoid treatment, however, causes unwanted adverse effects such as hypertriglyceridemia and hepatic steatosis. Hepatic sphingosine-1-phosphate receptor 2 knockdown in mice reduced chronic GC treatment induced triglyceride accumulation in the liver and plasma. Chronic glucocorticoid treatment increased the recruitment of sterol regulatory element-binding protein 1c (Srebp1c) to the sterol regulatory element of mouse fatty acid synthase (Fasn) gene. This response was attenuated in hepatic S1PR2 knockdown mice. Chronic glucocorticoid treatment also increased the recruitment of carbohydrate response element binding protein (ChREBP) to the carbohydrate response elements (ChOREs) of lipogenic and glycolytic genes such as pyruvate kinase L/R (Pklr) and malic enzyme 1 (Me1) in mice liver. This response was also reduced in hepatic S1PR2 knockdown mice. Reducing hepatic ChREBP expression reduced the expression of Pklr, Me1 and Fasn. However, long-term glucocorticoid induced triglyceride accumulation in the liver and the plasma were not affected whereas the hepatic lactate levels were decreased. Thus, ChREBP plays a major role in chronic glucocorticoid induced glycolysis whereas its role in hypertriglyceridemia and hepatic steatosis was modest. Overall, this study demonstrated that hepatic S1PR2 signaling is involved in chronic glucocorticoid exposure activated Srebp1c and ChREBP, which promote lipogenesis and glycolysis, respectively.
2025-07-23 | GSE286363 | GEO
Project description:Glucocorticoids play a key role in metabolic adaptation during stress, such as fasting and starvation. Excess and/or chronic glucocorticoid exposure, however, cause metabolic disorders that include insulin resistance dyslipidemia and hepatic steatosis. We previously showed that chronic glucocorticoid treatment elevates hepatic production of ceramides and sphingosine-1-phosphate (S1P). Ceramides are converted to sphingosine that is further converted to S1P. We showed that ceramide-initiated signaling in turn inhibits insulin signaling and increases lipogenic program in hepatocytes. However, the role of S1P, a signaling molecule that modulates physiological responses through membrane S1P receptors (S1PRs), in glucocorticoid actions is unclear. Here we found that inhibiting S1PR2 activity, but not S1PR1 and S1PR3, resulted in improved glucocorticoid-induced insulin resistance. Similarly, reducing hepatic S1PR2 expression showed similar results. Interestingly, reducing S1PR2 expression did not affect the ability of glucocorticoids to modify insulin signaling. Instead, glucocorticoids enhanced gluconeogenesis was reduced. Moreover, glucocorticoid-induced dyslipidemia and fatty liver was also compromised in mice with reduced hepatic S1PR2 expression. Indeed, RNA sequencing analysis showed that lipogenic, gluconeogenic and glycolytic genes are significantly lower in glucocorticoid-treated hepatic S1PR2 knockdown mice than those of glucocorticoid-treated hepatic scramble small hairpin RNA (shRNA) expressing mice (Control). Overall, our studies highlight the importance role of S1PR2 signaling in the mediating glucocorticoid regulation on gluconeogenesis and hepatic lipid homeostasis.
2023-05-13 | GSE150626 | GEO
Project description:Glucocorticoid plays an essential role in various stress responses and metabolism, which is mediated by the glucocorticoid receptor (GR) in cells. This hormonal action is integrated to transcriptional control of the GR target genes in cell type-specific and condition-dependent manners. In this study, we report that GR regulates the angiopoietin-like 4 (ANGPTL4) gene in a CCCTC-binding factor (CTCF)-mediated chromatin context in human hepatic HepG2 cells. There were at least four CTCF-enriched sites and two GR-binding sites in the ANGPTL4 locus. Among them, major CTCF-enriched site was positioned nearly GR-bound enhancer of this gene. Using treatment with the synthetic glucocorticoid dexamethasone (Dex), our data showed that CTCF is required for proper induction and subsequent silencing of ANGPTL4 gene. Interestingly, this gene induction was diminished under the long-term Dex pretreatment. Although ANGPTL4 locus maintains stable higher-order chromatin conformation at the basal and the Dex-treated states, liganded GR activated the ANGPTL4 gene, but not the neighboring three genes, via the interactions between enhancer, promoter and CTCF sites. These results reveal that liganded GR spatiotemporally controls ANGPTL4 gene in the chromosomal context.
2017-01-10 | GSE85343 | GEO
Project description:Nuclear Receptor Corepressors Non-Canonically Drive Glucocorticoid Receptor-Dependent Activation of Hepatic Gluconeogenesis
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Project description:Aim: We investigated the effect of acute and chronic glucocorticoid exposure on the hepatic transcriptome and its dependency on active androgen signaling. Methods: Adult male mice were used in the experiments. For the chronic exposure, mice were implanted with CORT (20mg) or vehicle pellets and administered ENZA (40mg/kg/day) or solvent via oral gavage. For the acute exposure, mice were pre-treated with ENZA (40mg/kg/day) or solvent every 12 hours for 24 hours via oral gavage and subsequently subcutaneously injected with 3mg/kg CORT or vehicle. Livers of all animals were dissected after 3 hours and snap-frozen. Next, total RNA was isolated and send for 100bp paired-end sequencing by BGI.
2022-03-28 | GSE180445 | GEO
Project description:Muscle fibers have the capacity to modulate their size in response to hormones, including glucocorticoids. Their effects are mediated by the ubiquitously expressed glucocorticoid receptor (GR). However, GR-mediated transcriptional regulation in skeletal muscle at physiological glucocorticoid levels remains elusive. Our study reveals an increased expression of numerous anabolic factors in GR-deficient myofibers, and a reduced expression of antianabolic factors, leading to fiber hypertrophy. Genome-wide analyses demonstrate that myofiber GR controls broad gene networks by binding to glucocorticoid response elements (GREs) at enhancers. Moreover, we provide topological and molecular insights into the chromatin landscape of GR-controlled genes in myofibers. We demonstrate that cooperative binding of GR with the transcription factors Myod1 and Foxf2 in enhancer regions, in collaboration with Nrf1 at promoters, plays a key role in the negative regulation of muscle mass. Thus, these results open new perspectives to counteract muscle weakness in various diseases.
2021-04-10 | GSE144228 | GEO
Project description:Hepatic lipid metabolism is highly dynamic, and disruption of several circadian transcriptional regulators results in hepatic steatosis. This includes genetic disruption of the glucocorticoid receptor (GR) as the liver develops. To address the functional role of GR in the adult liver, we used an acute hepatocyte-specific GR knockout model (hepGRKO) to study temporal hepatic lipid metabolism governed by GR at several pre- and postprandial timepoints. Lipidomics analysis revealed significant temporal lipid metabolism, with GR disruption resulting in impaired regulation of specific triglycerides, non-esterified fatty acids, and sphingolipids. This correlated with increased number and size of lipid droplets and mildly reduced mitochondrial respiration, most noticeably in the postprandial phase. Proteomics and transcriptomics analyses suggest that dysregulated lipid metabolism originates from pronounced induced expression of enzymes involved in fatty acid synthesis, -oxidation, and sphingolipid metabolism. Integration of GR cistromic data suggests that induced genes are a result of regulatory actions secondary to direct GR effects on transcription.
2023-09-07 | PXD041168 | Pride
Project description:Hepatic transcriptome analysis after acute and chronic glucocorticoid exposure combined with androgen receptor antagonism.
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Project description:Glucocorticoids are primary stress hormones and their synthetic derivatives are widely used clinically. The therapeutic efficacy of these steroids is limited by severe side effects and glucocorticoid resistance. Multiple glucocorticoid receptor (GR) isoforms are produced by alternative translation initiation; however, the role individual isoforms play in controlling tissue-specific responses to glucocorticoids in vivo is unknown. We have generated knockin mice that exclusively express the most active receptor isoform, GR-C3. The GR-C3 knockin mice die at birth due to respiratory distress but can be completely rescued by antenatal glucocorticoid administration. To evaluate the GR-C3 transcriptome, we prepared mouse embryonic fibroblasts (MEFs) from E12.5 wild-type (WT) and GR-C3 knockin embryos and treated the cells with vehicle or the synthetic glucocorticoid Dexamethasone (Dex) for 6 hours. The GR-C3 isoform was found to have a markedly different gene-regulatory profile than GR in WT MEFs.
2018-04-23 | GSE103675 | GEO
Project description:Nuclear receptor corepressors (NCORs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3). In the liver, loss of HDAC3 causes a marked hepatosteatosis largely due to derepression of genes involved in lipid metabolism. Here we show that adult loss of both NCOR1 and 2 (dKO) in hepatocytes phenocopies the hepatomegalic fatty liver phenotype. In addition, dKO livers exhibited a dramatic reduction in glycogen storage and gluconeogenic gene expression that was not observed with hepatic KO of individual NCORs nor HDAC3, resulting in profound fasting hypoglycemia. This surprising HDAC3-independent activation function of NCOR1/2 was due to an unexpected loss of chromatin accessibility upon deletion of NCORs that prevented glucocorticoid receptor binding and stimulatory effect on gluconeogenic genes. These studies reveal an unanticipated, non-canonical activation function of NCORs that is required for metabolic health.
2024-02-22 | GSE234233 | GEO