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Nat Commun. 2019 Jan 18;10(1):306. doi: 10.1038/s41467-018-08196-5.

E47 modulates hepatic glucocorticoid action.

Author information

1
Molecular Endocrinology, Helmholtz Diabetes Center (HMGU) and German Center for Diabetes Research (DZD), IDO, Ingolstädter Landstr. 1, 85764, Neuherberg, Munich, Germany.
2
Department of Proteomics and Signal Transduction, Max Planck Institute for Biochemistry, Am Klopferspitz 18, 82152, Martinsried, Germany.
3
Center for Chronic Immunodeficiency, University Medical Center and Faculty of Biology, University of Freiburg, 79106, Freiburg, Germany.
4
The Salk Institute for Biological Studies & HHMI, 10010 N Torrey Pines Rd, La Jolla, CA, 92037, USA.
5
Cardiovascular and Metabolic Sciences & DZHK (German Center for Cardiovascular Research), Charité-Universitätsmedizin & Berlin Institute of Health (BIH), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle Strasse 10, 13125, Berlin, Germany.
6
Molecular Endocrinology, Helmholtz Diabetes Center (HMGU) and German Center for Diabetes Research (DZD), IDO, Ingolstädter Landstr. 1, 85764, Neuherberg, Munich, Germany. henriette.uhlenhaut@helmholtz-muenchen.de.
7
The Salk Institute for Biological Studies & HHMI, 10010 N Torrey Pines Rd, La Jolla, CA, 92037, USA. henriette.uhlenhaut@helmholtz-muenchen.de.
8
Cardiovascular and Metabolic Sciences & DZHK (German Center for Cardiovascular Research), Charité-Universitätsmedizin & Berlin Institute of Health (BIH), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle Strasse 10, 13125, Berlin, Germany. henriette.uhlenhaut@helmholtz-muenchen.de.
9
Gene Center, Ludwig-Maximilians-Universität München (LMU), Feodor-Lynen-Straße 25, 81377, Munich, Germany. henriette.uhlenhaut@helmholtz-muenchen.de.

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.

PMID:
30659202
PMCID:
PMC6338785
DOI:
10.1038/s41467-018-08196-5
[Indexed for MEDLINE]
Free PMC Article

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