E47 modulates hepatic glucocorticoid action

M. Charlotte Hemmer, Michael Wierer, Kristina Schachtrup, Michael Downes, Norbert Hübner, Ronald M. Evans and N. Henriette Uhlenhaut ()
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M. Charlotte Hemmer: Helmholtz Diabetes Center (HMGU) and German Center for Diabetes Research (DZD), IDO
Michael Wierer: Max Planck Institute for Biochemistry
Kristina Schachtrup: University Medical Center and Faculty of Biology, University of Freiburg
Michael Downes: The Salk Institute for Biological Studies & HHMI
Norbert Hübner: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Ronald M. Evans: The Salk Institute for Biological Studies & HHMI
N. Henriette Uhlenhaut: Helmholtz Diabetes Center (HMGU) and German Center for Diabetes Research (DZD), IDO

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08196-5

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