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| Status |
Public on Aug 18, 2023 |
| Title |
Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Nonalcoholic steatohepatitis (NASH) is epidemiologically associated with obesity and diabetes and can lead to liver cirrhosis and hepatocellular carcinoma if left untreated. The intricate signaling pathways that orchestrate hepatocyte energy metabolism and cellular stress, intrahepatic cell crosstalk, as well as interplay between peripheral tissues remain elusive and are crucial for the development of anti-NASH therapies. Herein, we reveal E3 ligase FBXW7 as a key factor regulating hepatic catabolism, stress responses, systemic energy homeostasis, and NASH pathogenesis, with attenuated FBXW7 expression as a feature of advanced NASH. Multiomics analysis and pharmacological intervention showed that loss of FBXW7 function in hepatocytes disrupts a metabolic transcriptional axis conjointly controlled by the nutrient-sensing nuclear receptors ERRa and PPARa, resulting in suppression of fatty acid oxidation, elevated ER stress, apoptosis, immune infiltration, fibrogenesis, and ultimately NASH progression. These results provide the foundation for developing alternative strategies co-targeting ERRa and PPARa for the treatment of NASH.
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| Overall design |
ChIP-seq analysis of livers isolated from 24 h-fasted flox (control) and liver-specific Fbxw7 KO (Fbxw7 LKO) on a C57BL/6J genetic background.
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| Contributor(s) |
Scholtes C, Xia H, Dufour CR, Giguere V |
| Citation(s) |
37914694 |
| |
| Submission date |
Jun 10, 2022 |
| Last update date |
Nov 16, 2023 |
| Contact name |
Vincent Giguère |
| E-mail(s) |
vincent.giguere@mcgill.ca
|
| Phone |
514-398-5899
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| Organization name |
McGill University
|
| Department |
Goodman Cancer Centre
|
| Street address |
1160 Pine Ave West, McIntyre Bldg Room 710
|
| City |
Montréal |
| State/province |
QC |
| ZIP/Postal code |
H3A 1A3 |
| Country |
Canada |
| |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (4)
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| This SubSeries is part of SuperSeries: |
| GSE205847 |
Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression |
|
| Relations |
| BioProject |
PRJNA847943 |
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