Transcriptome Analysis of Dual FXR and GPBAR1 Agonism in Rodent Model of NASH Reveals Modulation of Lipid Droplets Formation.

Adriana Carino,Cristina Di Giorgio,Silvia Marchianò,Maria Chiara Monti,Rosalinda Roselli,Patrizia Ricci,Angela Zampella,Chiara Fiorucci,Eleonora Distrutti,Elva Morretta,Martina Bordoni,Michele Biagioli,Stefano Fiorucci

doi:10.3390/nu11051132

Abstract

Non-alcoholic steatohepatitis (NASH) is a progressive, chronic, liver disease whose prevalence is growing worldwide. Despite several agents being under development for treating NASH, there are no drugs currently approved. The Farnesoid-x-receptor (FXR) and the G-protein coupled bile acid receptor 1 (GPBAR1), two bile acid activated receptors, have been investigated for their potential in treating NASH. Here we report that BAR502, a steroidal dual ligand for FXR/GPBAR1, attenuates development of clinical and liver histopathology features of NASH in mice fed a high fat diet (HFD) and fructose (F). By RNAseq analysis of liver transcriptome we found that BAR502 restores FXR signaling in the liver of mice feed HFD–F, and negatively regulates a cluster of genes including Srebf1 (Srepb1c) and its target genes—fatty acid synthase (Fasn) and Cell death-inducing DFF45-like effector (CIDE) genes, Cidea and Cidec—involved in lipid droplets formation and triglycerides storage in hepatocytes. Additionally, BAR502 increased the intestinal expression of Fgf15 and Glp1 and energy expenditure by white adipose tissues. Finally, exposure to BAR502 reshaped the intestinal microbiota by increasing the amount of Bacteroidaceae. In conclusion, we have shown that dual FXR/GPBAR1 agonism might have utility in treatment of NASH.

Highlights

Non-alcoholic Fatty Liver Disease (NAFLD) is a highly prevalent liver disorder worldwide [1].NAFLD refers to a spectrum of conditions ranging from fatty liver disease, a relatively benign rarely progressive disease, to non-alcoholic steatohepatitis (NASH), a potentially progressive disease that carries a substantial risk of development of severe fibrosis, cirrhosis, and hepatocellular carcinoma [2].While the pathogenesis of Non-alcoholic steatohepatitis (NASH) is multifactorial, an excessive caloric intake is common among patients with NASH and, its prevalence is elevated in obesity, type II diabetes, and metabolic syndrome [3,4]
Our results demonstrated that BAR502 functions as a negative regulator for a cluster of genes including Srebf1 (Srepb1c) and its target genes, fatty acid synthase (Fasn) and Cell death-inducing DFF45-like effector (CIDE) genes, Cidea and Cidec, involved in lipid droplets formation and triglycerides storage [30,31,32,33,34]
We have first investigated whether treating mice with BAR502 rescues high fat diet (HFD)–F mice from NASH-like features

Summary

Introduction

Non-alcoholic Fatty Liver Disease (NAFLD) is a highly prevalent liver disorder worldwide [1].NAFLD refers to a spectrum of conditions ranging from fatty liver disease, a relatively benign rarely progressive disease, to non-alcoholic steatohepatitis (NASH), a potentially progressive disease that carries a substantial risk of development of severe fibrosis, cirrhosis, and hepatocellular carcinoma [2].While the pathogenesis of NASH is multifactorial, an excessive caloric intake is common among patients with NASH and, its prevalence is elevated in obesity, type II diabetes, and metabolic syndrome [3,4]. The Farnesoid-x-receptor (FXR) and the G-protein coupled receptor (GPBAR1 known as TGR5), are the two best characterized receptors of the BARs family [8,9,10]. These receptors are mainly expressed in entero-hepatic tissues and by cells of innate immunity, adipocytes, muscles, and vessels [6,7,8,9,10,11,12], and when activated by natural or synthetic ligands they regulate essential checkpoint in lipid, glucose, and protein metabolism. FXR deficient mice spontaneously develop liver inflammation and fibrosis, due to impaired bile acid metabolism, while

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