Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 KO mice

• DOI: 10.1016/j.jlr.2023.100340
• Publication Date: 2023-02-03T06:49:37Z
• Authors: Mohammad Nazmul H...; Jianglei Chen; David Matye; Huaiwen Wang; Wenyi Luo; Lijie Gu; Yung Dai Clayton; Yanhong Du; Tiangang Li
• Keywords: Ursodeoxycholic acid; Deoxycholic acid; Taurocholic acid; Chenodeoxycholic acid; Enterohepatic circulation

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