The G Protein-Coupled Bile Acid Receptor TGR5 (Gpbar1) Modulates Endothelin-1 Signaling in Liver
Caroline Klindt,
Maria Reich,
Birte Hellwig,
Jan Stindt,
Jörg Rahnenführer,
Jan G. Hengstler,
Karl Köhrer,
Kristina Schoonjans,
Dieter Häussinger,
Verena Keitel
Affiliations
Caroline Klindt
Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Maria Reich
Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Birte Hellwig
Department of Statistics, TU Dortmund University, 44221 Dortmund, Germany
Jan Stindt
Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Jörg Rahnenführer
Department of Statistics, TU Dortmund University, 44221 Dortmund, Germany
Jan G. Hengstler
Leibniz Research Centre for Working Environment and Human Factors, TU Dortmund, 44139 Dortmund, Germany
Karl Köhrer
Genomics and Transcriptomics Laboratory, Biologisch-Medizinisches-Forschungszentrum (BMFZ), Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Kristina Schoonjans
Laboratory of Metabolic Signaling, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland
Dieter Häussinger
Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
Verena Keitel
Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
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.
