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| 1 | INT-767 improves histopathological features in a dietinduced ob/ob mouse model of biopsy-confirmed nonalcoholic steatohepatitis显示文摘AIM To characterize the efficacy of the dual FXR/TGR5 receptor agonist INT-767 upon histological endpoints in a rodent model of diet-induced and biopsy-confirmed non-alcoholic steatohepatitis(NASH).METHODS The effects of INT-767 on histological features of NASH were assessed in two studies using Lep^(ob/ob)(ob/ob) NASH mice fed the AMLN diet(high fat with transfat, cholesterol and fructose). In a proof-of-conceptstudy, Lep^(ob/ob)(ob/ob) NASH mice were first dosed with INT-767(3 or 10 mg/kg for 8 wk). A second ob/ob NASH study compared INT-767(3 and 10 mg/kg) to obeticholic acid(OCA)(10 or 30 mg/kg; 16 wk). Primary histological endpoints included qualitative and quantitative assessments of NASH. Other metabolic and plasma endpoints were also assessed. A comparative assessment of INT-767 and OCA effects on drug distribution and hepatic gene expression was performed in C57 Bl/6 mice on standard chow. C57 Bl/6 mice were orally dosed with INT-767 or OCA(1-30 mg/kg) for 2 wk, and expression levels of candidate genes were assessed by RNA sequencing and tissue drug levels were measured by liquid chromatography tandem-mass spectrometry.RESULTS INT-767 dose-dependently(3 and 10 mg/kg, PO, QD, 8 wk) improved qualitative morphometric scores on steatohepatitis severity, inflammatory infiltrates and fibrosis stage. Quantitative morphometric analyses revealed that INT-767 reduced parenchymal collagen area, collagen fiber density, inflammation(assessed by Galectin-3 immunohistochemistry) and hepatocyte lipid droplet area following INT-767 treatment. In a comparative study(16 wk), the FXR agonists OCA(10 and 30 mg/kg) and INT-767(3 and 10 mg/kg) both improved NASH histopathology, with INT-767 exerting greater therapeutic potency and efficacy than OCA. Mechanistic studies suggest that both drugs accumulate similarly within the liver and ileum, however, the effects of INT-767 may be driven by enhanced hepatic, but not ileal, FXR function. CONCLUSION These findings confirm the potential utility of FXR and dual FXR/TGR5 activation as disease intervention strategies in NASH. | Jonathan D Roth Michael Feigh Sanne S Veidal Louise KD Fensholdt Kristoffer T Rigbolt Henrik H Hansen Li C Chen Mathieu Petitjean Weslyn Friley Niels Vrang Jacob Jelsing Mark Young | 2018 | World Journal of Gastroenterology2018，24，2： | 7 |
| 2 | Ordered mesoporous molecular sieves synthesized by a liquid crystal templates mechanism显示文摘 | Kresge C T Leonowicz M E Roth W J | 1992 | Nature1992，359，6397： | 1 |
| 3 | Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism显示文摘 | Kressge C T Leonowicz M E Roth W J | 1992 | Nature1992，359，： | 1 |
| 4 | Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism 显示文摘 | Kresge C T Leonowicz M E Roth W J | 1992 | Nature1992，359，： | 1 |
| 5 | Ordered mesoporous molecular sieves syntherized by a liquid-crystal template mechanism显示文摘 | KRESGE C T LEONOWlCZ M E ROTH W J | 1992 | Nature1992，359，6397： | 1 |
| 6 | Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism显示文摘 | KRESEGE C T LEONNWICZ M E ROTH W J | 1992 | Nature1992，359，： | 1 |
| 7 | Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism 显示文摘 | KRESGE C T LEONOWICZ M E ROTH W J | 1992 | Nature1992，359，6397： | 1 |
| 8 | Ordered mesoporous molecular-sieves synthesized by a liquid-crystal template mechanism显示文摘 | Leonowicz M E Roth W J | 1992 | Nature1992，56，359： | 1 |
| 9 | Ordered mesoporous molecular-sieves synthesized by a liquid-crystal template mechanism 显示文摘 | Kresge C T Leonowicz M E Roth W J | 1992 | Nature1992，359，6397： | 1 |
| 10 | Rosai-Dorfman disease mimicking parasagittal meningioma: case presentation and review of literature显示文摘 | Kattner K A Stroink A R Roth T C | 2000 | Surg Neurol2000，53，5： | 1 |
| 11 | Ordered mesoporous molecular sieves synthesized by a liquid - crystal template mechanism显示文摘 | C T Kresge M E Leonowicz W J Roth | 1992 | Nature1992，359，22： | 1 |
| 12 | Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism显示文摘 | Leonowiez M E Roth W J | 1992 | Nature1992，359，6397： | 1 |
| 13 | Ordered mesoporous molecular sieves synthesized by a liquid-crystal templated mechanism显示文摘 | Kresge C T Leonowicz M E Roth W J | 1992 | Nature1992，359，： | 1 |
| 14 | Ordered mcsoporous molecular sieves synthesized by a liquid - crystal template mechanism显示文摘 | Kresge C T Leonowicz M E Roth W J | 1992 | Nature1992，359，： | 1 |
| 15 | Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechani- sm 显示文摘 | Kresge C T Leonowicz M E Roth W J | 1992 | Nature1992，359，6397： | 1 |
| 16 | Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism显示文摘 | Kresge C T Leonowicz M E Roth W J | 1992 | Nature1992，359，6397： | 1 |
| 17 | Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism显示文摘 | Kresge C T Leonowicz M E Roth W J | | 0，，6397： | 1 |
| 18 | Ordered Meso- porous Molecular Sieves Synthesized by a Liquid-Crystal Template Mechanism显示文摘 | Kresge C T Leonowicz M E Roth W J | 1992 | Nature1992，359，： | 1 |
| 19 | Ordered mesoporous molecular sieves synthesized by a liquid template mechanism显示文摘 | Kresge C T Leonowicz M E Roth W J | 1992 | Nature1992，359，6397： | 1 |
| 20 | Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism显示文摘 | Leonowicz M E Roth W J | 1992 | Nature1992，359，： | 1 |
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