INT-767 improves histopathological features in a diet-inducedob/obmouse model of biopsy-confirmed non-alcoholic steatohepatitis

Abstract

AIMTo 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).METHODSThe effects of INT-767 on histological features of NASH were assessed in two studies using Lepob/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.RESULTSINT-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.CONCLUSIONThese findings confirm the potential utility of FXR and dual FXR/TGR5 activation as disease intervention strategies in NASH.

Obeticholic Acid Modulates Serum Metabolites and Gene Signatures Characteristic of Human NASH and Attenuates Inflammation and Fibrosis Progression in Ldlr‐/‐.Leiden Mice

“…We show that OCA quantitatively reduces hepatic fibrosis as measured by traditional picrosirius red staining, as well as biochemically measured collagen levels. This is in line with the findings of others, who report reduced hepatic collagen content after OCA treatment in chemically induced liver fibrosis and in AMLN diet (high trans‐fat and fructose diet supplemented with 2% cholesterol)–fed ob/ob mice . In addition to the observed reduction in the level of collagen in the liver in the present study, OCA also lowered the degree of reticulation of collagen (of both thin and aggregated collagen fibers) as assessed by multiphoton imaging, a technology that allows the dissection of fibrosis stages in human biopsies .…”

Ratio of Conjugated Chenodeoxycholic to Muricholic Acids is Associated with Severity of Nonalcoholic Steatohepatitis

“…BAs may function as signaling molecules through a variety of receptors, such as members of the nuclear receptor superfamily (farnesoid X nuclear receptor [FXR], vitamin D receptor, and pregnane X receptor) and members of the G‐protein‐coupled receptor superfamily (G‐protein‐coupled bile acid receptor 1 and sphingosine‐1‐phosphate receptor 2), among which FXR seems to have evolved as one of most promising avenues for the treatment of metabolic diseases, including NAFLD . A growing body of studies has shown benefits from FXR agonism treatment both in animals and in the clinic . Nonetheless, inhibition of FXR signaling by a specific FXR antagonist or elimination of BAs was also capable of improving hepatic steatosis and NASH in mouse experiments .…”

Novel Targets in the Immune Microenvironment of the Hepatic Sinusoids for Treating Liver Diseases

“…Treatment of mice with the dual FXR/TGR5 agonist INT-767 induced a restorative intrahepatic macrophage phenotype (Ly6C l°C D206 hi and expression of Retnla and Clec7a). 121 Provision of agonists for FXR and TGR5 have been suggested as potential therapeutics during liver regeneration, where there is an excess bile acid pool 122 in NASH 123 or in cholestatic liver diseases, 124 although some caution is required given the pleiotropic effects of these receptors, such as the role of TGR5 in the development of cholangiocarcinoma. 125 During acute liver failure (ALF), a marked increase in inflammatory macrophages, is observed in areas of necrosis.…”