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| Status |
Public on Sep 08, 2021 |
| Title |
Impaired GR expression in liver disrupts feeding induced gene expression, glucose uptake and glycogen storage |
| Organisms |
Mus musculus; Rattus norvegicus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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) knock-out (L-GRKO) model and primary hepatocytes to investigate the temporal 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, adding new insights to hepatic GR function. The GR-controlled feeding-induced genes include Gck encoding the glucokinase, which is important for hepatic glucose uptake, utilization and storage. We show that insulin and glucocorticoids cooperatively regulate Gck expression in primary hepatocytes in a GR-dependent manner. ChIP-seq experiments suggest direct GR regulation of Gck by GR occupancy of the promoter and two putative regulatory regions near the Gck gene (Gck -1kb and Gck -4.6kb). Enhancer-reporter assays and CRISPRi suggest that the 4.6kb upstream GR binding site is a functional Gck enhancer. L-GRKO blunts preprandial and early postprandial Gck expression and GR disruption ultimately affects early postprandial hepatic glucose uptake, phosphorylation and glycogen storage. Collectively, our study demonstrates how GR is positively involved in the hepatic feeding response exemplified in the direct regulation of the feeding-induced transcription of glucokinase, important for hepatic glucose metabolism.
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| Overall design |
Examination of feeding regulated gene expression in liver from C57BL/6 WT and liver specific GR KO mice. Analysis of dex and insulin mediated gene expression in primary hepatocytes
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| Contributor(s) |
Grøntved L, Præstholm S |
| Citation(s) |
34731602 |
| |
| Submission date |
May 03, 2021 |
| Last update date |
Nov 10, 2021 |
| Contact name |
Lars Grøntved |
| E-mail(s) |
larsgr@bmb.sdu.dk
|
| Phone |
+45 24 60 14 06
|
| Organization name |
University of Southern Denmark
|
| Department |
Biochemistry and Molecular Biology
|
| Street address |
Campusvej 55
|
| City |
Odense |
| ZIP/Postal code |
5230 |
| Country |
Denmark |
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| Platforms (3) |
| GPL18404 |
Illumina HiSeq 1500 (Rattus norvegicus) |
| GPL18480 |
Illumina HiSeq 1500 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (79)
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| Relations |
| BioProject |
PRJNA726880 |
| SRA |
SRP318197 |
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