1. INT-767 improves histopathological features in a diet-induced ob/ob mouse model of biopsy-confirmed non-alcoholic steatohepatitis.
- Author
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Roth JD, Feigh M, Veidal SS, Fensholdt LK, Rigbolt KT, Hansen HH, Chen LC, Petitjean M, Friley W, Vrang N, Jelsing J, and Young M
- Subjects
- Animals, Bile Acids and Salts metabolism, Chromatography, High Pressure Liquid, Disease Models, Animal, Dose-Response Relationship, Drug, Gene Expression Regulation, Liver metabolism, Liver pathology, Liver Cirrhosis etiology, Liver Cirrhosis metabolism, Liver Cirrhosis pathology, Liver Cirrhosis prevention & control, Mice, Inbred C57BL, Mice, Obese, Microscopy, Fluorescence, Multiphoton, Non-alcoholic Fatty Liver Disease etiology, Non-alcoholic Fatty Liver Disease metabolism, Non-alcoholic Fatty Liver Disease pathology, Obesity etiology, Obesity metabolism, Obesity pathology, Proof of Concept Study, Receptors, Cytoplasmic and Nuclear agonists, Receptors, Cytoplasmic and Nuclear metabolism, Receptors, G-Protein-Coupled agonists, Receptors, G-Protein-Coupled metabolism, Signal Transduction drug effects, Tandem Mass Spectrometry, Time Factors, Bile Acids and Salts pharmacology, Diet, High-Fat, Liver drug effects, Non-alcoholic Fatty Liver Disease prevention & control, Obesity drug therapy
- Abstract
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 trans-fat, cholesterol and fructose). In a proof-of-concept study, Lepob/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 C57Bl/6 mice on standard chow. C57Bl/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., Competing Interests: Conflict-of-interest statement: Jonathan Roth and Mark Young are employed by and hold equity in Intercept Pharmaceuticals, Inc. All other authors have nothing to disclose.- Published
- 2018
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