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

BACKGROUND AND AIMS: Loss-of-function mutations in bile acid (BA)-activated farnesoid x receptor (FXR/NR1H4) cause severe neonatal liver pathology in humans, earlier referred to as progressive familial intrahepatic cholestasis type 5 (PFIC5). However, Fxr-deficient mice do not develop early-onset liver disease, possibly due to the predominance of hydrophilic muricholic acids (MCAs) in their BA pool. Mice lacking Cyp2c70 display a human-like BA composition, lacking MCAs. This study aimed to evaluate whether Fxr/Cyp2c70-double knockout (DKO) mice recapitulate the pathophysiology of human FXR-deficiency.

METHODS: BA metabolism and liver pathology were assessed in wild-type (WT), Fxr-knockout (KO), Cyp2c70-KO and DKO mice of both sexes.

RESULTS: Fxr-deficiency markedly reduced the amounts of bile salt export pump (BSEP/ABCB11), but did not affect biliary BA secretion. DKO mice showed exacerbated hepatocytic injury and inflammation compared to Fxr-KO mice of both sexes. Surprisingly, despite higher alanine aminotransferase levels that indicate hepatocellular damage, female DKO mice showed much less liver fibrosis and ductular reactions than female Cyp2c70-KO mice. Gene Set Enrichment Analysis suggested that epithelial-mesenchymal transition was upregulated in Cyp2c70-KO livers compared to WT mice but downregulated particularly in livers of female DKO mice compared to Cyp2c70-KO. Biliary BA hydrophobicity was increased by the deletion of Cyp2c70, yet reduced by simultaneous absence of Fxr in female mice.

CONCLUSIONS: Fxr/Cyp2c70-DKO mice exhibit more severe hepatocytic injury than Fxr-KO mice, mirroring the clinical phenotype of FXR deficiency. These data highlight the importance of studying the aetiology of cholestatic liver diseases in the context of a human-like BA composition.