Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 KO mice
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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-03-01
|
| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227523000135 |
| _version_ | 1827979285838692352 |
|---|---|
| author | Mohammad Nazmul Hasan Jianglei Chen David Matye Huaiwen Wang Wenyi Luo Lijie Gu Yung Dai Clayton Yanhong Du Tiangang Li |
| author_facet | Mohammad Nazmul Hasan Jianglei Chen David Matye Huaiwen Wang Wenyi Luo Lijie Gu Yung Dai Clayton Yanhong Du Tiangang Li |
| author_sort | Mohammad Nazmul Hasan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T21:34:52Z |
| format | Article |
| id | doaj.art-897440a21bd44797a0f914ca459f29f9 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-04-09T21:34:52Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-897440a21bd44797a0f914ca459f29f92023-03-27T04:02:48ZengElsevierJournal of Lipid Research0022-22752023-03-01643100340Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 KO miceMohammad Nazmul Hasan0Jianglei Chen1David Matye2Huaiwen Wang3Wenyi Luo4Lijie Gu5Yung Dai Clayton6Yanhong Du7Tiangang Li8Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USAHarold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USAHarold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USALaboratory for Molecular Biology and Cytometry Research, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USADepartment of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USAHarold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USAHarold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USAHarold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USAHarold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; For correspondence: Tiangang LiTherapeutic 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.http://www.sciencedirect.com/science/article/pii/S0022227523000135bile acidASBTCYP7A1FXRcholestasisCYP2C70 |
| spellingShingle | Mohammad Nazmul Hasan Jianglei Chen David Matye Huaiwen Wang Wenyi Luo Lijie Gu Yung Dai Clayton Yanhong Du Tiangang Li Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 KO mice Journal of Lipid Research bile acid ASBT CYP7A1 FXR cholestasis CYP2C70 |
| title | Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 KO mice |
| title_full | Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 KO mice |
| title_fullStr | Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 KO mice |
| title_full_unstemmed | Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 KO mice |
| title_short | Combining ASBT inhibitor and FGF15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male Cyp2c70 KO mice |
| title_sort | combining asbt inhibitor and fgf15 treatments enhances therapeutic efficacy against cholangiopathy in female but not male cyp2c70 ko mice |
| topic | bile acid ASBT CYP7A1 FXR cholestasis CYP2C70 |
| url | http://www.sciencedirect.com/science/article/pii/S0022227523000135 |
| work_keys_str_mv | AT mohammadnazmulhasan combiningasbtinhibitorandfgf15treatmentsenhancestherapeuticefficacyagainstcholangiopathyinfemalebutnotmalecyp2c70komice AT jiangleichen combiningasbtinhibitorandfgf15treatmentsenhancestherapeuticefficacyagainstcholangiopathyinfemalebutnotmalecyp2c70komice AT davidmatye combiningasbtinhibitorandfgf15treatmentsenhancestherapeuticefficacyagainstcholangiopathyinfemalebutnotmalecyp2c70komice AT huaiwenwang combiningasbtinhibitorandfgf15treatmentsenhancestherapeuticefficacyagainstcholangiopathyinfemalebutnotmalecyp2c70komice AT wenyiluo combiningasbtinhibitorandfgf15treatmentsenhancestherapeuticefficacyagainstcholangiopathyinfemalebutnotmalecyp2c70komice AT lijiegu combiningasbtinhibitorandfgf15treatmentsenhancestherapeuticefficacyagainstcholangiopathyinfemalebutnotmalecyp2c70komice AT yungdaiclayton combiningasbtinhibitorandfgf15treatmentsenhancestherapeuticefficacyagainstcholangiopathyinfemalebutnotmalecyp2c70komice AT yanhongdu combiningasbtinhibitorandfgf15treatmentsenhancestherapeuticefficacyagainstcholangiopathyinfemalebutnotmalecyp2c70komice AT tiangangli combiningasbtinhibitorandfgf15treatmentsenhancestherapeuticefficacyagainstcholangiopathyinfemalebutnotmalecyp2c70komice |