Effects of apical sodium-bile acid transporter inhibitor and obeticholic acid co-treatment in experimental non-alcoholic steatohepatitis
Background and aims: Several bile acids-based monotherapies have been developed for non-alcoholic steatohepatitis (NASH) treatment but clinical trial findings suggest that they do not satisfactorily improve NASH and liver fibrosis in many patients. Recently, we have shown that combining a gut-restri...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
KeAi Communications Co., Ltd.
2022-12-01
|
| Series: | Liver Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2542568422000617 |
| _version_ | 1797975208079917056 |
|---|---|
| author | David J. Matye Xuan Qin Mohammad Nazmul Hasan Lijie Gu Yung Dai Clayton Feng Li Tiangang Li |
| author_facet | David J. Matye Xuan Qin Mohammad Nazmul Hasan Lijie Gu Yung Dai Clayton Feng Li Tiangang Li |
| author_sort | David J. Matye |
| collection | DOAJ |
| description | Background and aims: Several bile acids-based monotherapies have been developed for non-alcoholic steatohepatitis (NASH) treatment but clinical trial findings suggest that they do not satisfactorily improve NASH and liver fibrosis in many patients. Recently, we have shown that combining a gut-restricted apical sodium-bile acid transporter (ASBT) inhibitor GSK2330672 (GSK) with adeno-associated virus (AAV)-mediated liver fibroblast growth factor 15 (FGF15) overexpression provides significantly improved efficacy than either single treatment against NASH and liver fibrosis in a high fat, cholesterol, and fructose (HFCFr) diet-induced NASH mouse model. The beneficial effects of the combined treatment can be attributed to the markedly reduced bile acid pool that reduces liver bile acid burden and intestinal lipid absorption. The aim of this study is to further investigate if combining GSK treatment with the orally bioavailable obeticholic acid (OCA), which induces endogenous FGF15 and inhibits hepatic bile acid synthesis, can achieve similar anti-NASH effect as the GSK + AAV-FGF15 co-treatment in HFCFr-diet-fed mice. Materials and methods: Male C57BL/6J mice were fed HFCFr diet to induce NASH and liver fibrosis. The effect of GSK, OCA, and GSK + OCA treatments on NASH development was compared and contrasted among all groups. Results: Findings from this study showed that the GSK + OCA co-treatment did not cause persistent reduction of obesity over a 12-week treatment period. Neither single treatment nor the GSK + OCA co-treatment reduce hepatic steatosis, but all three treatments reduced hepatic inflammatory cytokines and fibrosis by a similar magnitude. The GSK + OCA co-treatment caused a higher degree of total bile acid pool reduction (∼55%) than either GSK or OCA treatment alone. However, such bile acid pool reduction was insufficient to cause increased fecal lipid loss. The GSK + OCA co-treatment prevented GSK-mediated induction of hepatic cholesterol 7alpha-hydroxylase but failed to induce ileal FGF15 expression. GSK did not reduce gallbladder OCA amount in the GSK + OCA group compared to the OCA group, suggesting that ASBT inhibition does not reduce hepatic OCA distribution. Conclusions: Unlike the GSK + AAV-FGF15 co-treatment, the GSK + OCA co-treatment does not provide improved efficacy against NASH and liver fibrosis than either single treatment in mice. The lack of synergistic effect may be partly attributed to the moderate reduction of total bile acid pool and the lack of high level of FGF15 exposure as seen in the GSK + AAV-FGF15 co-treatment. |
| first_indexed | 2024-04-11T04:31:51Z |
| format | Article |
| id | doaj.art-beea8ecf722143c8bf8cb6f59073c383 |
| institution | Directory Open Access Journal |
| issn | 2542-5684 |
| language | English |
| last_indexed | 2024-04-11T04:31:51Z |
| publishDate | 2022-12-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Liver Research |
| spelling | doaj.art-beea8ecf722143c8bf8cb6f59073c3832022-12-29T04:13:49ZengKeAi Communications Co., Ltd.Liver Research2542-56842022-12-0164276283Effects of apical sodium-bile acid transporter inhibitor and obeticholic acid co-treatment in experimental non-alcoholic steatohepatitisDavid J. Matye0Xuan Qin1Mohammad Nazmul Hasan2Lijie Gu3Yung Dai Clayton4Feng Li5Tiangang Li6Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USADepartment of Pathology and Immunology, Baylor College of Medicine, Houston, TX, 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, USADepartment of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA; NMR and Drug Metabolism Core, Baylor College of Medicine, Houston, TX, USAHarold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Corresponding author. Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.Background and aims: Several bile acids-based monotherapies have been developed for non-alcoholic steatohepatitis (NASH) treatment but clinical trial findings suggest that they do not satisfactorily improve NASH and liver fibrosis in many patients. Recently, we have shown that combining a gut-restricted apical sodium-bile acid transporter (ASBT) inhibitor GSK2330672 (GSK) with adeno-associated virus (AAV)-mediated liver fibroblast growth factor 15 (FGF15) overexpression provides significantly improved efficacy than either single treatment against NASH and liver fibrosis in a high fat, cholesterol, and fructose (HFCFr) diet-induced NASH mouse model. The beneficial effects of the combined treatment can be attributed to the markedly reduced bile acid pool that reduces liver bile acid burden and intestinal lipid absorption. The aim of this study is to further investigate if combining GSK treatment with the orally bioavailable obeticholic acid (OCA), which induces endogenous FGF15 and inhibits hepatic bile acid synthesis, can achieve similar anti-NASH effect as the GSK + AAV-FGF15 co-treatment in HFCFr-diet-fed mice. Materials and methods: Male C57BL/6J mice were fed HFCFr diet to induce NASH and liver fibrosis. The effect of GSK, OCA, and GSK + OCA treatments on NASH development was compared and contrasted among all groups. Results: Findings from this study showed that the GSK + OCA co-treatment did not cause persistent reduction of obesity over a 12-week treatment period. Neither single treatment nor the GSK + OCA co-treatment reduce hepatic steatosis, but all three treatments reduced hepatic inflammatory cytokines and fibrosis by a similar magnitude. The GSK + OCA co-treatment caused a higher degree of total bile acid pool reduction (∼55%) than either GSK or OCA treatment alone. However, such bile acid pool reduction was insufficient to cause increased fecal lipid loss. The GSK + OCA co-treatment prevented GSK-mediated induction of hepatic cholesterol 7alpha-hydroxylase but failed to induce ileal FGF15 expression. GSK did not reduce gallbladder OCA amount in the GSK + OCA group compared to the OCA group, suggesting that ASBT inhibition does not reduce hepatic OCA distribution. Conclusions: Unlike the GSK + AAV-FGF15 co-treatment, the GSK + OCA co-treatment does not provide improved efficacy against NASH and liver fibrosis than either single treatment in mice. The lack of synergistic effect may be partly attributed to the moderate reduction of total bile acid pool and the lack of high level of FGF15 exposure as seen in the GSK + AAV-FGF15 co-treatment.http://www.sciencedirect.com/science/article/pii/S2542568422000617Bile acidsFarnesoid X receptor (FXR)Fibroblast growth factor 15 (FGF15)Apical sodium-bile acid transporter (ASBT)Non-alcoholic steatohepatitis (NASH)Liver fibrosis |
| spellingShingle | David J. Matye Xuan Qin Mohammad Nazmul Hasan Lijie Gu Yung Dai Clayton Feng Li Tiangang Li Effects of apical sodium-bile acid transporter inhibitor and obeticholic acid co-treatment in experimental non-alcoholic steatohepatitis Liver Research Bile acids Farnesoid X receptor (FXR) Fibroblast growth factor 15 (FGF15) Apical sodium-bile acid transporter (ASBT) Non-alcoholic steatohepatitis (NASH) Liver fibrosis |
| title | Effects of apical sodium-bile acid transporter inhibitor and obeticholic acid co-treatment in experimental non-alcoholic steatohepatitis |
| title_full | Effects of apical sodium-bile acid transporter inhibitor and obeticholic acid co-treatment in experimental non-alcoholic steatohepatitis |
| title_fullStr | Effects of apical sodium-bile acid transporter inhibitor and obeticholic acid co-treatment in experimental non-alcoholic steatohepatitis |
| title_full_unstemmed | Effects of apical sodium-bile acid transporter inhibitor and obeticholic acid co-treatment in experimental non-alcoholic steatohepatitis |
| title_short | Effects of apical sodium-bile acid transporter inhibitor and obeticholic acid co-treatment in experimental non-alcoholic steatohepatitis |
| title_sort | effects of apical sodium bile acid transporter inhibitor and obeticholic acid co treatment in experimental non alcoholic steatohepatitis |
| topic | Bile acids Farnesoid X receptor (FXR) Fibroblast growth factor 15 (FGF15) Apical sodium-bile acid transporter (ASBT) Non-alcoholic steatohepatitis (NASH) Liver fibrosis |
| url | http://www.sciencedirect.com/science/article/pii/S2542568422000617 |
| work_keys_str_mv | AT davidjmatye effectsofapicalsodiumbileacidtransporterinhibitorandobeticholicacidcotreatmentinexperimentalnonalcoholicsteatohepatitis AT xuanqin effectsofapicalsodiumbileacidtransporterinhibitorandobeticholicacidcotreatmentinexperimentalnonalcoholicsteatohepatitis AT mohammadnazmulhasan effectsofapicalsodiumbileacidtransporterinhibitorandobeticholicacidcotreatmentinexperimentalnonalcoholicsteatohepatitis AT lijiegu effectsofapicalsodiumbileacidtransporterinhibitorandobeticholicacidcotreatmentinexperimentalnonalcoholicsteatohepatitis AT yungdaiclayton effectsofapicalsodiumbileacidtransporterinhibitorandobeticholicacidcotreatmentinexperimentalnonalcoholicsteatohepatitis AT fengli effectsofapicalsodiumbileacidtransporterinhibitorandobeticholicacidcotreatmentinexperimentalnonalcoholicsteatohepatitis AT tiangangli effectsofapicalsodiumbileacidtransporterinhibitorandobeticholicacidcotreatmentinexperimentalnonalcoholicsteatohepatitis |