Researchers at the Spanish National Cancer Research Centre (CNIO) have identified a molecular mechanism in bile duct cells that regulates liver fibrosis. The study, published in Nature Metabolism, shows that biliary epithelial cells (BEC) act as active barriers, preventing bile acid leakage and subsequent scar formation.
The Molecular Mechanism
- A Critical Barrier Role: The protein FXR receptor in BEC cells detects bile acids and activates YAP protein, which maintains cell adhesion and limits excessive proliferation. This process keeps the bile duct lining intact.
- When the System Fails: When FXR function is lost, BEC cells proliferate excessively, the barrier weakens, and bile acids leak into liver tissue. This leakage activates stellate cells, which produce scar tissue (fibrosis).
- Accelerated Progression: This mechanism accelerates the progression from fibrosis to cirrhosis, a finding demonstrated in both mouse models and human liver samples.
Clinical Implications
- Improving Treatment Selection: The findings may improve patient selection for FXR-targeted therapies, such as obeticholic acid (OCA).
- Explaining Drug Failures: The study helps explain why OCA can worsen fibrosis in some patients. When FXR signaling is lost in BEC cells, the drug may exacerbate damage rather than repair it.
- Current Status: OCA has been withdrawn from the US market, and its European authorization is currently under review.
Funding
This research was supported by the Spanish Ministry of Science, Innovation and Universities, European Regional Development Funds, the Madrid regional government, the Spanish Cancer Association, and other foundations.