Therapeutic reduction of hydrophobic
bile acids exposure is considered beneficial in
cholestasis. The Cyp2c70 KO mice lack hydrophilic muricholic
acids and have a human-like hydrophobic
bile acid pool resulting in hepatobiliary injury. This study investigates if combining an
apical sodium-dependent bile acid transporter inhibitor
GSK2330672 (GSK) and fibroblast growth factor-15 (FGF15) overexpression, via simultaneous inhibition of
bile acid synthesis and gut
bile acid uptake, achieves enhanced therapeutic efficacy in alleviating hepatobiliary injury in Cyp2c70 KO mice. The effects of GSK, adeno-associated virus (AAV)-FGF15, and the combined treatment on
bile acid metabolism and cholangiopathy were compared in Cyp2c70 KO mice. In female Cyp2c70 KO mice with more severe cholangiopathy than male Cyp2c70 KO mice, the combined treatment was more effective in reversing portal
inflammation, ductular reaction, and
fibrosis than AAV-FGF15, while GSK was largely ineffective. The combined treatment reduced
bile acid pool by ∼80% compared to ∼50% reduction by GSK or AAV-FGF15, and enriched tauro-conjugated
ursodeoxycholic acid in the bile. Interestingly, the male Cyp2c70 KO mice treated with AAV-FGF15 or GSK showed attenuated cholangiopathy and portal
fibrosis but the combined treatment was ineffective despite reducing
bile acid pool. Both male and female Cyp2c70 KO mice showed impaired gut barrier integrity. AAV-FGF15 and the combined treatment, but not GSK, reduced gut exposure to
lithocholic acid and improved gut barrier function. In conclusion, the combined treatment improved therapeutic efficacy against cholangiopathy than either single treatment in the female but not male Cyp2c70 KO mice by reducing
bile acid pool size and hydrophobicity.