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*

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Abstrakt

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.

OriginalsprogEngelsk
Artikelnummer109938
TidsskriftCell Reports
Vol/bind37
Udgave nummer5
ISSN2211-1247
DOI
StatusUdgivet - 2. nov. 2021

Bibliografisk note

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

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