Continuous activation of C/EBPβ transcription factor prevents fibrosis resolution after alcohol cessation.
Study Goal
The researchers aimed to investigate the role of C/EBPβ activation in fibrosis resolution after alcohol cessation in alcohol-associated liver disease (ALD) and identify potential therapeutic targets for patients who fail to recover post-abstinence.
Results Summary
The study found that alcohol-induced C/EBPβ activation impedes fibrosis resolution in ALD, and hepatocyte-specific Cebpb knockout promoted fibrosis resolution by altering hepatocyte-macrophage crosstalk. Restoring endothelial function with angiopoietin-1 supplementation reduced C/EBPβ and improved fibrosis resolution, suggesting a promising therapeutic target.
Population
Mice with alcohol-associated liver disease (ALD) induced by high-fat diet and 20% alcohol in drinking water.
Effective Dosage
20% alcohol in drinking water for 20 weeks (ALD induction), followed by 4 weeks of plain water (resolution phase).
Duration
20 weeks of alcohol exposure, followed by 4 weeks of cessation.
Interactions
None mentioned.
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
hepatocyte specific Cebpb knockout at the time of alcohol cessation | increase | fibrosis resolution | mice | - | promoted | #1 |
C/EBPβ | decrease | expression of CYP3A family of enzymes in hepatocytes | mice | - | suppressed | #2 |
C/EBPβ | decrease | downstream macrophage collagen degradation ability | mice | - | suppressed | #3 |
Cebpb knockout in hepatocytes | increase | pro-resolving phenotype in liver macrophages | mice | - | promoted | #4 |
alcohol | increase | C/EBPβ | mice | - | induced | #5 |
angiopoietin-1 supplementation | decrease | C/EBPβ | mice | - | reduced | #6 |
angiopoietin-1 supplementation | increase | fibrosis resolution | mice | - | promoted | #7 |
BACKGROUND: Abstinence is an important therapeutic intervention for patients with alcohol-associated liver disease (ALD). However, fibrosis improvement after cessation is not uniform and some patients do not improve. METHODS: Mice were fed high fat diet with 20% alcohol in the drinking water for 20 weeks (ALD) followed by 4 weeks of chow diet with plain water (resolution). scATAC-seq dataset was analyzed using Signac R package. Cebpb floxed mice received AAV-TBG-Cre or AAV-control at the time of alcohol cessation. Hepatocyte-macrophage and endothelial cell-hepatocytes crosstalk was investigated using a transwell co-culture system. To test the role of angiopoietin mice were treated with recombinant ANG-1 one week after alcohol cessation. RESULTS: We analyzed differentially accessible regions in hepatocytes from control, ALD, or 4 weeks post alcohol cessation mice and identified transcription factors activated in ALD that remained activated after alcohol withdrawal. The top hit was C/EBPβ. We found that hepatocyte specific Cebpb knockout at the time of alcohol cessation promoted fibrosis resolution. The resolution was mediated by altered hepatocyte-macrophage crosstalk. C/EBPβ suppressed the expression of CYP3A family of enzymes in hepatocytes and downstream macrophage collagen degradation ability. Cebpb knockout in hepatocytes promoted a pro-resolving phenotype in liver macrophages. We further identified upstream events leading to persistent C/EBPβ activation. C/EBPβ was induced by alcohol-mediated endothelial changes both during ALD development and resolution. Restoring endothelial cell function with angiopoietin-1 supplementation reduced C/EBPβ and promoted fibrosis resolution. CONCLUSION: Taken together, alcohol-induced C/EBPβ activation is a key driver of poor disease resolution in ALD and a promising target for patients who fail to recover after alcohol abstinence.