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Dabigatran reduces liver fibrosis in thioacetamide-injured rats
POSTER PRESENTATIONS that after 2 weeks scaffold implant, the mRNA expression for AFP, CK18, CD26 and CX32 increased in Foxa2 over-expressed group. Moreover, Foxa2 over-expressed ADSCs treatment group attenuated liver injury in thioacetamide induced acute liver injury model. Conclusions: Foxa2 over-expression strengthened hepatic differentiation and function. Scaffold system using Foxa2 over-expression attenuated acute liver damage in acute liver injury model. SAT-458 Dabigatran reduces liver fibrosis in thioacetamide-injured rats Y.-C. Hsieh1, K.-C. Lee1, Y.-Y. Yang1, Y.-H. Huang1, W.-F. Hsu2, H.-C. Lin1. 1 Division of Gastroenterology & Hepatology, Department of Medicine, Taipei Veterans General Hospital; 2Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan E-mail: [email protected] Background and Aims: Liver fibrosis can progress to liver cirrhosis, hepatocellular carcinoma, or liver failure. Unfortunately, the clinical benefits of antifibrotic therapy are limited. Thrombin activates hepatic stellate cells (HSCs), which contribute to liver fibrosis. The thrombin receptor protease-activated receptor 1 (PAR1) is constitutively expressed in HSCs. Thus, we investigated the effects of a direct thrombin inhibitor, dabigatran, on liver fibrosis. Methods: Adult male Sprague-Dawley rats were injected intraperitoneally with thioacetamide (TAA, 200 mg/kg twice per week) for 8 weeks to induce liver fibrosis. The injured rats were then assigned to oral gavage of dabigatran (30 mg/kg/day) or vehicle for the next 4 weeks. Rats receiving an injection of normal saline and subsequent oral gavage of dabigatran or vehicle served as controls. Results: In TAA-injured rats, dabigatran treatment ameliorated fibrosis, fibrin deposition, and phosphorylated ERK1/2 in liver, without altering transcript expression of PAR1. In vitro, dabigatran inhibited thrombin-induced HSC activation. In addition, dabigatran reduced intrahepatic angiogenesis and portal hypertension in TAAinjured rats.
Conclusions: By inhibiting thrombin activity, dabigatran reduced liver fibrosis in vivo and in vitro and may thus be a useful antifibrotic agent for treatment of early fibrosis. SAT-459 A novel FXR agonist EDP-305 potently suppresses liver injury and fibrosis in mouse models of biliary and metabolic liver disease P. An1, K. Vaid2, G. Wei2, Y. Lin2, M. Chau3, Y. Li3, Y.S. Or3, L.-J. Yang3, Y. Popov1. 1Gastroenterology and Hepatology; 2Beth Israel Deaconess Medical Center, Harvard Medical School; 3Enanta Pharmaceuticals, Inc, Boston, United States E-mail: [email protected] Background and Aims: EDP-305 is a novel and potent FXR agonist with a single-digit nanomolar affinity in vitro, with no/minimal cross-reactivity to the G protein-coupled bile acid receptor 1 (TGR5) or other nuclear receptors. Herein we report therapeutic efficacy of EDP-305 in two mouse models representing biliary and metabolically-induced liver disease, in direct comparison with the first-in-class FXR agonist, obeticholic acid (OCA). Methods: Delayed therapy with EDP-305 (10 and 30 mg/kg/day) was tested in mouse models of pre-stablished (i) biliary fibrosis (BALBc. Mdr2-/-, 6 through 12 weeks of age, n = 9–11/group) and (ii) steatohepatitis induced by methionine/choline-deficient diet (MCD, week 4 through 8, n = 8–12/group). Parallel groups received either no treatment as control or OCA (30 mg/kg/day p.o.) as a comparator. Results: In BALBc.Mdr2-/- model of biliary fibrosis, 10 and 30 mg/kg of EDP-305 significantly reduced serum transaminase (ALT) levels by 30% and 53%, respectively compared to controls. Histologically, untreated group developed severe periportal and perisinusoidal fibrosis with bridging, which was markedly attenuated in BALBc. Mdr2-/- mice receiving EDP-305 at both doses, with up to 39% reduction in hepatic collagen content in high-dose EDP-305 ( p < 0.05, ANOVA). OCA at 30 mg/kg did not improve fibrosis histologically, and had no significant impact on hepatic collagen levels or serum ALT in the BALBc.Mdr2-/- model compared to control group. In MCD-fed mice with steatohepatitis, serum ALT were significantly decreased by 62% in the 30 mg/kg EDP-305-treated group compared to controls. 10 mg/kg EDP-305 and obeticholic acid (30 mg/kg) showed only a trend towards lower ALT levels (not significant). EDP305 at both doses profoundly inhibited MCD-induced liver fibrosis, with up to 70% reduction in hepatic collagen deposition ( p < 0.05, ANOVA). Histologically, MCD-fed control mice developed the advanced perisinusoidal “chicken wire” fibrosis, which was markedly reduced by EDP-305 compared to the control group. OCA (30 mg/kg) did not have an appreciable effect on hepatic hydroxyproline levels and connective tissue histology in the MCD model. Conclusions: Treatment with the novel FXR agonist EDP-305 potently improved pre-established liver injury and hepatic fibrosis in both biliary (BALBc.Mdr2-/-) and metabolic (MCD) models of liver disease in mice. In both models and by all studied parameters of liver injury and fibrosis, EDP-305 outperformed the first-in-class FXR agonist, obeticholic acid.
Non-invasive assessment of liver disease SAT-460 Morphology based assessment of liver fibrosis using a new quantitative metric in abdominal CT scans V.C. Obmann1, N. Mertineit1, J.T. Heverhagen1, A. Christe1, A.T. Huber1. 1 Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital Bern, Bern, Switzerland E-mail: [email protected]
Journal of Hepatology 2017 vol. 66 | S543–S750
S657
Conclusions: By inhibiting thrombin activity, dabigatran reduced liver fibrosis in vivo and in vitro and may thus be a useful antifibrotic agent for treatment of early fibrosis. SAT-459 A novel FXR agonist EDP-305 potently suppresses liver injury and fibrosis in mouse models of biliary and metabolic liver disease P. An1, K. Vaid2, G. Wei2, Y. Lin2, M. Chau3, Y. Li3, Y.S. Or3, L.-J. Yang3, Y. Popov1. 1Gastroenterology and Hepatology; 2Beth Israel Deaconess Medical Center, Harvard Medical School; 3Enanta Pharmaceuticals, Inc, Boston, United States E-mail: [email protected] Background and Aims: EDP-305 is a novel and potent FXR agonist with a single-digit nanomolar affinity in vitro, with no/minimal cross-reactivity to the G protein-coupled bile acid receptor 1 (TGR5) or other nuclear receptors. Herein we report therapeutic efficacy of EDP-305 in two mouse models representing biliary and metabolically-induced liver disease, in direct comparison with the first-in-class FXR agonist, obeticholic acid (OCA). Methods: Delayed therapy with EDP-305 (10 and 30 mg/kg/day) was tested in mouse models of pre-stablished (i) biliary fibrosis (BALBc. Mdr2-/-, 6 through 12 weeks of age, n = 9–11/group) and (ii) steatohepatitis induced by methionine/choline-deficient diet (MCD, week 4 through 8, n = 8–12/group). Parallel groups received either no treatment as control or OCA (30 mg/kg/day p.o.) as a comparator. Results: In BALBc.Mdr2-/- model of biliary fibrosis, 10 and 30 mg/kg of EDP-305 significantly reduced serum transaminase (ALT) levels by 30% and 53%, respectively compared to controls. Histologically, untreated group developed severe periportal and perisinusoidal fibrosis with bridging, which was markedly attenuated in BALBc. Mdr2-/- mice receiving EDP-305 at both doses, with up to 39% reduction in hepatic collagen content in high-dose EDP-305 ( p < 0.05, ANOVA). OCA at 30 mg/kg did not improve fibrosis histologically, and had no significant impact on hepatic collagen levels or serum ALT in the BALBc.Mdr2-/- model compared to control group. In MCD-fed mice with steatohepatitis, serum ALT were significantly decreased by 62% in the 30 mg/kg EDP-305-treated group compared to controls. 10 mg/kg EDP-305 and obeticholic acid (30 mg/kg) showed only a trend towards lower ALT levels (not significant). EDP305 at both doses profoundly inhibited MCD-induced liver fibrosis, with up to 70% reduction in hepatic collagen deposition ( p < 0.05, ANOVA). Histologically, MCD-fed control mice developed the advanced perisinusoidal “chicken wire” fibrosis, which was markedly reduced by EDP-305 compared to the control group. OCA (30 mg/kg) did not have an appreciable effect on hepatic hydroxyproline levels and connective tissue histology in the MCD model. Conclusions: Treatment with the novel FXR agonist EDP-305 potently improved pre-established liver injury and hepatic fibrosis in both biliary (BALBc.Mdr2-/-) and metabolic (MCD) models of liver disease in mice. In both models and by all studied parameters of liver injury and fibrosis, EDP-305 outperformed the first-in-class FXR agonist, obeticholic acid.
Non-invasive assessment of liver disease SAT-460 Morphology based assessment of liver fibrosis using a new quantitative metric in abdominal CT scans V.C. Obmann1, N. Mertineit1, J.T. Heverhagen1, A. Christe1, A.T. Huber1. 1 Department of Diagnostic, Interventional and Pediatric Radiology, Inselspital Bern, Bern, Switzerland E-mail: [email protected]
Journal of Hepatology 2017 vol. 66 | S543–S750
S657