Browse
Submit Data
Databases
API
Help

Dataset Information

25 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

E47 modulates hepatic glucocorticoid action.

ABSTRACT: Glucocorticoids (GCs) are effective drugs, but their clinical use is compromised by severe side effects including hyperglycemia, hyperlipidemia and obesity. They bind to the Glucocorticoid Receptor (GR), which acts as a transcription factor. The activation of metabolic genes by GR is thought to underlie these adverse effects. We identify the bHLH factor E47 as a modulator of GR target genes. Using mouse genetics, we find that E47 is required for the regulation of hepatic glucose and lipid metabolism by GR, and that loss of E47 prevents the development of hyperglycemia and hepatic steatosis in response to GCs. Here we show that E47 and GR co-occupy metabolic promoters and enhancers. E47 is needed for the efficient recruitment of GR and coregulators such as Mediator to chromatin. Altogether, our results illustrate how GR and E47 regulate hepatic metabolism, and might provide an entry point for novel therapies with reduced side effects.

SUBMITTER: Hemmer MC

PROVIDER: S-EPMC6338785 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

E47 modulates hepatic glucocorticoid action.

Hemmer M Charlotte MC Wierer Michael M Schachtrup Kristina K Downes Michael M Hübner Norbert N Evans Ronald M RM Uhlenhaut N Henriette NH

Nature communications 20190118 1

Glucocorticoids (GCs) are effective drugs, but their clinical use is compromised by severe side effects including hyperglycemia, hyperlipidemia and obesity. They bind to the Glucocorticoid Receptor (GR), which acts as a transcription factor. The activation of metabolic genes by GR is thought to underlie these adverse effects. We identify the bHLH factor E47 as a modulator of GR target genes. Using mouse genetics, we find that E47 is required for the regulation of hepatic glucose and lipid metabo ...[more]

PMID: 30659202

Similar Datasets

The role of the bHLH factor E47 in modulating hepatic glucocorticoid receptor action (metabolism) [ChIP-seq]

Project description:We performed ChIP-Sequencing for E2A and GR in mouse livers and demonstrate that E47 co-occupies metabolic promoters and enhancers together with GR. Together with the corresponding RNA-Seq data, our results illustrate how GR and E47 synergize during the transcriptional activation of hepatic metabolism.

2018-11-30 | GSE111526 | GEO

The role of the bHLH factor E47 in modulating hepatic glucocorticoid receptor action (metabolism) [RNA-seq]

Project description:We performed RNA sequencing in different wildtype and E47ko tissues in response to treatment with glucocorticoids. We show a global deregulation of gene expression programs involved in lipid, triglyceride and cholesterol metabolism & transport for E47 mutant liver tissue.

2018-11-30 | GSE111877 | GEO

REVERBa couples the circadian clock to hepatic glucocorticoid action.

Project description:The glucocorticoid receptor (GR) is a major drug target in inflammatory disease. However, chronic glucocorticoid (GC) treatment leads to disordered energy metabolism, including increased weight gain, adiposity, and hepatosteatosis - all programs modulated by the circadian clock. We demonstrated that while antiinflammatory GC actions were maintained irrespective of dosing time, the liver was significantly more GC sensitive during the day. Temporal segregation of GC action was underpinned by a physical interaction of GR with the circadian transcription factor REVERBa and co-binding with liver-specific hepatocyte nuclear transcription factors (HNFs) on chromatin. REVERBa promoted efficient GR recruitment to chromatin during the day, acting in part by maintaining histone acetylation, with REVERBa-dependent GC responses providing segregation of carbohydrate and lipid metabolism. Importantly, deletion of Reverba inverted circadian liver GC sensitivity and protected mice from hepatosteatosis induced by chronic GC administration. Our results reveal a mechanism by which the circadian clock acts through REVERBa in liver on elements bound by HNF4A/HNF6 to direct GR action on energy metabolism.

| S-EPMC6160001 | biostudies-literature

Adipose glucocorticoid action influences whole-body metabolism <i>via</i> modulation of hepatic insulin action.

Project description:The connection between adipose glucocorticoid action and whole-body metabolism is incompletely understood. Thus, we generated adipose tissue-specific glucocorticoid receptor-knockout (Ad-GcR-/-) mice to explore potential mechanisms. Ad-GcR-/- mice had a lower concentration of fasting plasma nonesterified fatty acids and less hepatic steatosis. This was associated with increased protein kinase B phosphorylation and increased hepatic glycogen synthesis after an oral glucose challenge. High-fat diet (HFD)-fed Ad-GcR-/- mice were protected against the development of hepatic steatosis and diacylglycerol-PKCε-induced impairments in hepatic insulin signaling. Under hyperinsulinemic-euglycemic conditions, hepatic insulin response was ∼10-fold higher in HFD-fed Ad-GcR-/- mice. Insulin-mediated suppression of adipose lipolysis was improved by 40% in Ad-GcR-/- mice. Adipose triglyceride lipase expression was decreased and insulin-mediated perilipin dephosphorylation was increased in Ad-GcR-/- mice. In metabolic cages, food intake decreased by 3 kcal/kg per hour in Ad-GcR-/- mice. Therefore, physiologic adipose glucocorticoid action appears to drive hepatic lipid accumulation during stressors such as fasting. The resultant hepatic insulin resistance prevents hepatic glycogen synthesis, preserving glucose for glucose-dependent organs. Absence of adipose glucocorticoid action attenuates HFD-induced hepatic insulin resistance; potential explanations for reduction in hepatic steatosis include reductions in adipose lipolysis and food intake.-Abulizi, A., Camporez, J.-P., Jurczak, M. J., Høyer, K. F., Zhang, D., Cline, G. W., Samuel, V. T., Shulman, G. I., Vatner, D. F. Adipose glucocorticoid action influences whole-body metabolism via modulation of hepatic insulin action.

| S-EPMC6593882 | biostudies-literature

The role of the bHLH factor E47 in modulating hepatic glucocorticoid receptor action (metabolism) [ChIP-seq]

Project description:The role of the bHLH factor E47 in modulating hepatic glucocorticoid receptor action (metabolism) [ChIP-seq]

| PRJNA437299 | ENA

The role of the bHLH factor E47 in modulating hepatic glucocorticoid receptor action (metabolism) [RNA-seq]

Project description:The role of the bHLH factor E47 in modulating hepatic glucocorticoid receptor action (metabolism) [RNA-seq]

| PRJNA438469 | ENA

Investigations of Glucocorticoid Action in GN.

Project description:For several decades, glucocorticoids have been used empirically to treat rapid progressive GN. It is commonly assumed that glucocorticoids act primarily by dampening the immune response, but the mechanisms remain incompletely understood. In this study, we inactivated the glucocorticoid receptor (GR) specifically in kidney epithelial cells using Pax8-Cre/GRfl/fl mice. Pax8-Cre/GRfl/fl mice did not exhibit an overt spontaneous phenotype. In mice treated with nephrotoxic serum to induce crescentic nephritis (rapidly progressive GN), this genetic inactivation of the GR in kidney epithelial cells exerted renal benefits, including inhibition of albuminuria and cellular crescent formation, similar to the renal benefits observed with high-dose prednisolone in control mice. However, genetic inactivation of the GR in kidney epithelial cells did not induce the immunosuppressive effects observed with prednisolone. In vitro, prednisolone and the pharmacologic GR antagonist mifepristone each acted directly on primary cultures of parietal epithelial cells, inhibiting cellular outgrowth and proliferation. In wild-type mice, pharmacologic treatment with the GR antagonist mifepristone also attenuated disease as effectively as high-dose prednisolone without the systemic immunosuppressive effects. Collectively, these data show that glucocorticoids act directly on activated glomerular parietal epithelial cells in crescentic nephritis. Furthermore, we identified a novel therapeutic approach in crescentic nephritis, that of glucocorticoid antagonism, which was at least as effective as high-dose prednisolone with potentially fewer adverse effects.

| S-EPMC5407712 | biostudies-literature

Cocaine disrupts action flexibility via glucocorticoid receptors.

Project description:Many addictive drugs increase stress hormone levels. They also alter the propensity of organisms to prospectively select actions based on long-term consequences. We hypothesized that cocaine causes inflexible action by increasing circulating stress hormone levels, activating the glucocorticoid receptor (GR). We trained mice to generate two nose pokes for food and then required them to update action-consequence associations when one response was no longer reinforced. Cocaine delivered in adolescence or adulthood impaired the capacity of mice to update action strategies, and inhibiting CORT synthesis rescued action flexibility. Next, we reduced Nr3c1, encoding GR, in the orbitofrontal cortex (OFC), a region of the brain responsible for interlacing new information into established routines. Nr3c1 silencing preserved action flexibility and dendritic spine abundance on excitatory neurons, despite cocaine. Spines are often considered substrates for learning and memory, leading to the discovery that cocaine degrades the representation of new action memories, obstructing action flexibility.

| S-EPMC11233908 | biostudies-literature

Tissue-specific glucocorticoid action: a family affair.

Project description:Glucocorticoids exert a wide variety of physiological and pathological responses, most of which are mediated by the ubiquitously expressed glucocorticoid receptor (GR). The glucocorticoid response varies among individuals, as well as within tissues from the same individual, and this phenomenon can be partially explained through understanding the process of generating bioavailable ligand and the molecular heterogeneity of GR. This review focuses on the recent advances in our understanding of prereceptor ligand metabolism, GR subtypes and GR polymorphisms. Furthermore, we evaluate the impact of tissue- and individual-specific diversity in the glucocorticoid pathway on human health and disease.

| S-EPMC2720031 | biostudies-literature

Glucocorticoid Receptor Action in Breast Cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-10-02 | GSE222799 | GEO