Impaired glucocorticoid receptor expression in liver disrupts feeding-induced gene expression, glucose uptake, and glycogen storage

Stine M Præstholm, Catarina M Correia, Victor E Goitea, Majken S Siersbæk, Mathilde Jørgensen, Jesper F Havelund, Thomas Å Pedersen, Nils J Færgeman, Lars Grøntved*

*Corresponding author for this work

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Abstract

The transition from a fasted to a fed state is associated with extensive transcriptional remodeling in hepatocytes facilitated by hormonal- and nutritional-regulated transcription factors. Here, we use a liver-specific glucocorticoid receptor (GR) knockout (L-GRKO) model to investigate the temporal hepatic expression of GR target genes in response to feeding. Interestingly, in addition to the well-described fasting-regulated genes, we identify a subset of hepatic feeding-induced genes that requires GR for full expression. This includes Gck, which is important for hepatic glucose uptake, utilization, and storage. We show that insulin and glucocorticoids cooperatively regulate hepatic Gck expression in a direct GR-dependent manner by a 4.6 kb upstream GR binding site operating as a Gck enhancer. L-GRKO blunts preprandial and early postprandial Gck expression, which ultimately affects early postprandial hepatic glucose uptake, phosphorylation, and glycogen storage. Thus, GR is positively involved in feeding-induced gene expression and important for postprandial glucose metabolism in the liver.

Original languageEnglish
Article number109938
JournalCell Reports
Volume37
Issue number5
ISSN2211-1247
DOIs
Publication statusPublished - 2. Nov 2021

Keywords

  • feeding
  • Gck
  • gene expression
  • glucocorticoid receptor
  • glucose metabolism
  • liver
  • RNA-seq
  • temporal

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