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INT-767 improves histopathological features in a diet-induced ob/ob mouse model of biopsy-confirmed non-alcoholic steatohepatitis.
- Source :
-
World journal of gastroenterology [World J Gastroenterol] 2018 Jan 14; Vol. 24 (2), pp. 195-210. - Publication Year :
- 2018
-
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).<br />Methods: The effects of INT-767 on histological features of NASH were assessed in two studies using Lep <superscript>ob/ob</superscript> ( ob/ob ) NASH mice fed the AMLN diet (high fat with trans-fat, cholesterol and fructose). In a proof-of-concept study, Lep <superscript>ob/ob</superscript> ( 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.<br />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.<br />Conclusion: These findings confirm the potential utility of FXR and dual FXR/TGR5 activation as disease intervention strategies in NASH.<br />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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 2219-2840
- Volume :
- 24
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- World journal of gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 29375205
- Full Text :
- https://doi.org/10.3748/wjg.v24.i2.195