The G Protein-Coupled Bile Acid Receptor TGR5 (Gpbar1) Modulates Endothelin-1 Signaling in Liver.

Caroline Klindt,Kristina Schoonjans,Dieter Häussinger,Jan Stindt,Birte Hellwig,Jan G Hengstler,Maria Reich,Jörg Rahnenführer,Verena Keitel,Karl Köhrer

doi:10.3390/cells8111467

Abstract

TGR5 (Gpbar1) is a G protein-coupled receptor responsive to bile acids (BAs), which is expressed in different non-parenchymal cells of the liver, including biliary epithelial cells, liver-resident macrophages, sinusoidal endothelial cells (LSECs), and activated hepatic stellate cells (HSCs). Mice with targeted deletion of TGR5 are more susceptible towards cholestatic liver injury induced by cholic acid-feeding and bile duct ligation, resulting in a reduced proliferative response and increased liver injury. Conjugated lithocholic acid (LCA) represents the most potent TGR5 BA ligand and LCA-feeding has been used as a model to rapidly induce severe cholestatic liver injury in mice. Thus, TGR5 knockout (KO) mice and wildtype (WT) littermates were fed a diet supplemented with 1% LCA for 84 h. Liver injury and gene expression changes induced by the LCA diet revealed an enrichment of pathways associated with inflammation, proliferation, and matrix remodeling. Knockout of TGR5 in mice caused upregulation of endothelin-1 (ET-1) expression in the livers. Analysis of TGR5-dependent ET-1 signaling in isolated LSECs and HSCs demonstrated that TGR5 activation reduces ET-1 expression and secretion from LSECs and triggers internalization of the ET-1 receptor in HSCs, dampening ET-1 responsiveness. Thus, we identified two independent mechanisms by which TGR5 inhibits ET-1 signaling and modulates portal pressure.

Highlights

TGR5 (Gpbar1) is a G protein-coupled bile acid receptor expressed in various cell types, including macrophages, as well as non-parenchymal liver cells such as activated hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs) [1,2,3,4,5]
Disturbances of the intercellular crosstalk within the sinusoids, especially between LSECs and HSCs, contribute to fibrosis development and microvascular dysfunction [24,43,44]
Gene expression analysis of liver tissue following lithocholic acid (LCA) feeding for 84 h revealed an enrichment in signaling pathways related to inflammation, proliferation, and matrix remodeling, which was in line with histological analysis of the livers

Summary

Introduction

TGR5 (Gpbar1) is a G protein-coupled bile acid receptor expressed in various cell types, including macrophages, as well as non-parenchymal liver cells such as activated hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs) [1,2,3,4,5]. Activation of TGR5 occurs after binding of bile acids (BAs), leading to an intracellular increase of cyclic AMP (cAMP) as second messenger and to the activation of further downstream signaling [6,7,8]. TGR5 KO are more susceptible towards cholestatic and inflammatory liver injury [17,18,19]. Using mice deficient for either the intercellular adhesion molecule-1 (ICAM-1 KO mice) or the catalytic subunit of NADPH oxidase (gp91phox KO mice), it was demonstrated that the contribution of neutrophils to liver injury following LCA feeding is negligible. The hepatotoxicity stems from LCA and its metabolites directly, and this model can be used to rapidly induce severe cholestatic liver injury, which shows characteristics of sclerosing cholangitis [21,22]

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Results

Conclusion