ECE2016 Eposter Presentations Cardiovascular Endocrinology and Lipid Metabolism (51 abstracts)
The dual FXR/TGR5 agonist INT-767 counteracts nonalcoholic steatohepatitis in a rabbit model of high fat diet-induced metabolic syndrome
Linda Vignozzi 1 , Ilaria Cellai 1 , Sandra Filippi 2 , Paolo Comeglio 1 , Erica Sarchielli 3 , Annamaria Morelli 3 , Elena Maneschi 1 , Gabriella Barbara Vannelli 3 , Luciano Adorini 4 & Mario Maggi 1
1Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy; 2Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Department of Neuroscience, Drug Research and Child Care, University of Florence, Florence, Italy; 3Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; 4Intercept Pharmaceuticals, New York, NY 10011, New York, USA.
Farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) are interesting pharmacological targets for the treatment of liver and metabolic diseases. FXR-deficient mice on a high-fat diet (HFD) exhibit massive hepatic steatosis, necro-inflammation and fibrogenesis. Moreover, pharmacological activation of TGR5 in mice promotes protective mechanisms in biliary epithelial cells and inhibits hepatic and systemic inflammation. Thus, we hypothesized that a FXR/TGR5 dual agonist (INT-767) would ameliorate features of nonalcoholic steatohepatitis (NASH) in a rabbit model of metabolic syndrome (MetS). Treatment with increasing doses of INT-767 (3,10,30 mg/Kg/day for 12 weeks) in a rabbit model of HFD-induced MetS, characterized also by NASH, dose-dependently reduced several MetS-associated alterations, including hepatomegaly, insulin resistance, increase of ALT, glucose, cholesterol levels, while significantly increasing HDL levels. ALT was positively associated with all MetS parameters; however introducing all MetS factors in a multivariate analysis, only total cholesterol levels resulted positively associated with ALT level. High macrophage M1 pro-inflammatory/M2 anti-inflammatory ratio was observed in MetS-induced NASH, which was independently associated with serum ALT levels. HFD-induced increase in M1/M2 ratio was reduced by INT-767 treatment and M2 macrophage markers were increased. Genes related to neutrophil apoptosis/apoptotic-neutrophil clearance and to extracellular matrix degradation were also increased by INT-767 treatment. INT-767 also reduced liver expression of IL-6, which preferentially skews the Th cell response towards a Th17-phenotype, while increasing Foxp3 expression, a Treg cell marker. These data indicate that INT-767 can promote the neutrophil- and macrophage-driven resolution phase of inflammation and fibrosis regression. In addition, INT-767 increased genes related to hepatic fatty acid metabolism and lipid droplet formation, suggesting that INT-767 counteracts excess fatty acid mediated lipotoxicity in the liver. Genes related to insulin signaling were also increased by INT-767. Finally, immunohistochemical studies demonstrated that INT-767 treatment significantly reduced both HFD-induced liver inflammation and fibrosis.
In conclusion, INT-767 treatment counteracts NASH in a rabbit model of HFD-induced MetS by promoting insulin sensitivity, resolution of inflammation and fibrosis regression.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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