Targeting FXR in hepatocytes: a promising approach to enhance fibrinolysis and reduce deep vein thrombosis risk.

Summary

In murine obesity models, hepatocyte FXR activation directly repressed Serpine1/PAI-1 transcription, improving fibrinolysis and reducing DVT burden. Loss of hepatocyte FXR increased circulating PAI-1 and worsened thrombosis, and the FXR agonist tropifexor lowered PAI-1 and thrombus load, supporting FXR as a hepatocentric, druggable regulator of fibrinolysis.

Key Findings

• Hepatocyte FXR activation directly represses Serpine1/PAI-1 transcription (dual-luciferase and ChIP evidence).
• FXR-null and hepatocyte-specific Fxr-deleted mice have elevated plasma PAI-1, impaired fibrinolysis, and increased DVT burden.
• Tropifexor treatment in obese mice lowers plasma PAI-1 and reduces thrombus load, improving fibrinolysis.
• Human single-cell liver transcriptomes from obesity suggest reduced hepatocyte FXR signaling associates with higher PAI-1.

Clinical Implications

If translated to humans, FXR agonists could reduce PAI-1 and enhance fibrinolysis in high-risk obese patients, potentially lowering DVT risk. This supports clinical testing of FXR-targeted therapies and monitoring PAI-1 as a pharmacodynamic biomarker.

Limitations

• Preclinical models; human causal validation and dose–response/safety of FXR agonists for thrombosis are untested.
• Potential pleiotropic effects of FXR agonism and context-dependent metabolic actions may complicate translation.

Future Directions

Prospective human studies to correlate FXR activity and PAI-1 with fibrinolytic capacity and DVT outcomes; early-phase trials of FXR agonists (e.g., tropifexor) in obesity-related hypercoagulability with PAI-1-guided dosing.