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A hepatocyte-specific transcriptional program driven by Rela and Stat3 exacerbates experimental colitis in mice by modulating bile synthesis.
- Source :
-
ELife [Elife] 2024 Aug 13; Vol. 12. Date of Electronic Publication: 2024 Aug 13. - Publication Year :
- 2024
-
Abstract
- Hepatic factors secreted by the liver promote homeostasis and are pivotal for maintaining the liver-gut axis. Bile acid metabolism is one such example wherein, bile acid synthesis occurs in the liver and its biotransformation happens in the intestine. Dysfunctional interactions between the liver and the intestine stimulate varied pathological outcomes through its bidirectional portal communication. Indeed, aberrant bile acid metabolism has been reported in inflammatory bowel disease (IBD). However, the molecular mechanisms underlying these crosstalks that perpetuate intestinal permeability and inflammation remain obscure. Here, we identify a novel hepatic gene program regulated by Rela and Stat3 that accentuates the inflammation in an acute experimental colitis model. Hepatocyte-specific ablation of Rela and Stat3 reduces the levels of primary bile acids in both the liver and the gut and shows a restricted colitogenic phenotype. On supplementation of chenodeoxycholic acid (CDCA), knock-out mice exhibit enhanced colitis-induced alterations. This study provides persuasive evidence for the development of multi-organ strategies for treating IBD and identifies a hepatocyte-specific Rela-Stat3 network as a promising therapeutic target.<br />Competing Interests: J, BS, MY, AD, MM, PS, PN, NG, VA, DM, RG No competing interests declared, SB Reviewing editor, eLife<br /> (© 2023, Jyotsna et al.)
- Subjects :
- Animals
Mice
Gene Expression Regulation
Liver metabolism
Liver pathology
Mice, Inbred C57BL
STAT3 Transcription Factor metabolism
STAT3 Transcription Factor genetics
Colitis chemically induced
Colitis metabolism
Colitis genetics
Colitis pathology
Hepatocytes metabolism
Transcription Factor RelA metabolism
Transcription Factor RelA genetics
Bile Acids and Salts metabolism
Mice, Knockout
Disease Models, Animal
Subjects
Details
- Language :
- English
- ISSN :
- 2050-084X
- Volume :
- 12
- Database :
- MEDLINE
- Journal :
- ELife
- Publication Type :
- Academic Journal
- Accession number :
- 39137024
- Full Text :
- https://doi.org/10.7554/eLife.93273