Farnesoid x Receptor Deficiency Promotes Hepatocytic Injury in Cyp2c70-Deficient Mice With a Human-Like Bile Acid...

Area of Science:

• Hepatology
• Molecular Biology
• Genetics

Background:

• Loss-of-function mutations in the farnesoid x receptor (FXR) lead to severe neonatal liver disease (PFIC5) in humans.
• FXR-deficient mice do not fully model human disease due to differences in bile acid pools.
• Cyp2c70-deficient mice possess a human-like bile acid composition, lacking muricholic acids.

Purpose of the Study:

• To investigate if FXR/Cyp2c70-double knockout (DKO) mice recapitulate the human FXR-deficiency phenotype.
• To assess the impact of combined FXR and Cyp2c70 deficiency on liver pathology and bile acid metabolism.

Main Methods:

• Assessment of bile acid metabolism and liver pathology in wild-type, Fxr-knockout, Cyp2c70-knockout, and DKO mice.
• Analysis of hepatocytic injury, inflammation, fibrosis, and ductular reactions.
• Gene Set Enrichment Analysis to evaluate molecular pathway alterations.

Main Results:

• DKO mice exhibited exacerbated hepatocytic injury and inflammation compared to Fxr-knockout mice.
• Female DKO mice showed reduced liver fibrosis and ductular reactions despite higher liver damage markers.
• Biliary bile acid hydrophobicity was altered by gene deficiencies, with complex sex-specific effects.

Conclusions:

• FXR/Cyp2c70-DKO mice present a more severe hepatocytic injury phenotype, closely mirroring human FXR deficiency.
• These findings underscore the critical role of bile acid composition in the etiology of cholestatic liver diseases.
• Studying cholestatic liver diseases requires consideration of human-like bile acid profiles.