{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T18:47:19Z","timestamp":1788115639781,"version":"build-2803163510"},"reference-count":60,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,11,19]],"date-time":"2019-11-19T00:00:00Z","timestamp":1574121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC 974"],"award-info":[{"award-number":["CRC 974"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cells8111467","type":"journal-article","created":{"date-parts":[[2019,11,19]],"date-time":"2019-11-19T11:30:17Z","timestamp":1574163017000},"page":"1467","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["The G Protein-Coupled Bile Acid Receptor TGR5 (Gpbar1) Modulates Endothelin-1 Signaling in Liver"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7161-6123","authenticated-orcid":false,"given":"Caroline","family":"Klindt","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty of Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Reich","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty of Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2806-7250","authenticated-orcid":false,"given":"Birte","family":"Hellwig","sequence":"additional","affiliation":[{"name":"Department of Statistics, TU Dortmund University, 44221 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Stindt","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty of Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Rahnenf\u00fchrer","sequence":"additional","affiliation":[{"name":"Department of Statistics, TU Dortmund University, 44221 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan G.","family":"Hengstler","sequence":"additional","affiliation":[{"name":"Leibniz Research Centre for Working Environment and Human Factors, TU Dortmund, 44139 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"K\u00f6hrer","sequence":"additional","affiliation":[{"name":"Genomics and Transcriptomics Laboratory, Biologisch-Medizinisches-Forschungszentrum (BMFZ), Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Schoonjans","sequence":"additional","affiliation":[{"name":"Laboratory of Metabolic Signaling, \u00c9cole Polytechnique F\u00e9d\u00e9rale de Lausanne, CH-1015 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter","family":"H\u00e4ussinger","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty of Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Keitel","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Medical Faculty of Heinrich Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1002\/hep.21458","article-title":"The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells","volume":"45","author":"Keitel","year":"2007","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.cmet.2011.11.006","article-title":"TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading","volume":"14","author":"Pols","year":"2011","journal-title":"Cell Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1016\/j.bbadis.2017.08.021","article-title":"Bile acid receptors in the biliary tree: TGR5 in physiology and disease","volume":"1864","author":"Deutschmann","year":"2018","journal-title":"Biochim. 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