E47 modulates hepatic glucocorticoid action.

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.

There goes the neighborhood: Assembly of transcriptional complexes during the regulation of metabolism and inflammation by the glucocorticoid receptor.

Glucocorticoids (GCs), as ligands for the glucocorticoid receptor (GR), represent one of the most effective and frequently used classes of drugs for anti-inflammatory and immunosuppressive therapy. In addition, its role in physiological and pathophysiological processes makes the GR an important research target. The past decades have yielded a wealth of insight into the physiological and pharmacological effects of GCs. Today's era of next generation sequencing techniques is now beginning to elucidate the molecular and genomic circuits underlying GR's cell type-specific actions. This review focuses on the concepts and insights gained from recent studies in two of the most important tissues for GC action: the liver (mediating GR's metabolic effects) and macrophages (as the main target of anti-inflammatory GC therapy). We summarize results obtained from transgenic mouse models, molecular and genome-wide studies to illustrate GR's complex interactions with DNA, chromatin, co-regulators and other transcription factors. Characterizing the cell type-specific transcriptional complexes assembled around GR will pave the road for the development of new anti-inflammatory and metabolic therapies in the future.