The G Protein‐Coupled Receptor TGR5 Plays a Protective Role Against the Development of Non‐Alcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of conditions which ranges from simple steatosis to non‐alcoholic steayohepatitis (NASH) and liver cirrhosis. Although only a small percentage of people with steatosis develop serious liver disease, NAFLD is often associated with obesity and insulin resistance. The aim of this study is to establish that activation of the G‐protein coupled receptor TGR5 by its synthetic ligand INT‐777 leads to a reduction in hepatic lipid accumulation. TGR5+/+ mice were treated with either vehicle or INT‐777 for 7 days and then sacrificed. Hepatic lipid analysis revealed that administration of INT‐777 led to a significant reduction in liver triglycerides and cholesterol. In addition, TGR5+/+ LDLr‐/‐ and TGR5‐/‐ LDLr‐/‐ mice were fed a methionine choline‐deficient diet for induction of fibrosis. Hepatic lipid analysis of these mice showed that liver and plasma triglycerides were significantly higher in TGR5‐/‐ LDLr‐/‐ mice. Furthermore, hematoxylin and eosin (H and E) of liver sections from these mice displayed higher lipid droplet deposition compared to TGR5+/+ LDLr‐/‐ mice. Also, qPCR analysis of liver gene expression revealed a marginal yet significant increase in some fibrosis genes in the TGR5‐/‐ LDLr‐/‐ mice indicating that TGR5 may have a protective role in liver fibrosis. These results point to the possibility that TGR5 could be a potential therapeutic target for the treatment of NAFLD, even in its advanced stages.