Exploring novel therapies for cholestatic liver disease in ‘humanized’ mouse models

Exploring novel therapies for cholestatic liver disease in ‘humanized’ mouse models

Bile and its main constituent, bile acids, have important functions in the human body. These functions become especially evident in cholestatic liver disorders when there is a disruption of normal bile  formation. Mice have a different bile acid pool composition with different properties than the bile acid species present in humans which complicates translation of preclinical findings in the field of liver research. The hydrophilic muricholic acids (MCAs) that are abundant in mice are less cytotoxic and exhibit different signalling effects than the more hydrophobic human bile acids. 

The work presented in this thesis of Esther Verkade focuses on the development and characterization of mice with a more human-like bile acid pool and applies these models to study novel treatment modalities for cholestatic liver disease. It is shown that the enzyme CYP2C70 is responsible for the synthesis of MCAs. This led to the generation of Cyp2c70-knock out (Cyp2c70-/-) mice which have a human-like hydrophobic bile acid pool and which responded differently to pharmacological FXR activation and gut microbiome removal. The human-like bile acid pool of Cyp2c70-/- mice increased its potential to develop a model for the cholestatic liver disease progressive familial intrahepatic cholestasis type 2 (PFIC2). However, regardless of their hydrophobic bile acids, Cyp2c70-/- mice with a deficiency in the bile salt export pump (BSEP) do not develop severe progressive cholestasis like PFIC2 patients. Lastly, the Cyp2c70-/- mice were also applied to study the underlying mechanisms and metabolic effects of two novel potential therapeutics for cholestatic liver disease, namely pemafibrate and norUDCA.

Proefschrift: https://hdl.handle.net/11370/a5d3fd71-3ecf-41a2-8a12-59053b275e32