{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:06:01Z","timestamp":1760241961039,"version":"build-2065373602"},"reference-count":44,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2018,10,20]],"date-time":"2018-10-20T00:00:00Z","timestamp":1539993600000},"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":["PA 2365\/1-1"],"award-info":[{"award-number":["PA 2365\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Medical Faculty of University of Heidelberg","award":["Olympia Morata Postdoctoral Fellowship"],"award-info":[{"award-number":["Olympia Morata Postdoctoral Fellowship"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a synthetic bile acid-phospholipid conjugate with profound hepatoprotective and anti-fibrogenic functions in vitro and in vivo. Herein, we aimed to demonstrate the inhibitory effects of UDCA-LPE on pro-fibrogenic integrin signalling. UDCA-LPE treatment of human embryonic liver cell line CL48 and primary human hepatic stellate cells induced a non-classical internalization of integrin \u03b21 resulting in dephosphorylation and inhibition of SRC and focal adhesion kinase (FAK). Signalling analyses suggested that UDCA-LPE may act as a heterobivalent ligand for integrins and lysophospholipid receptor1 (LPAR1) and co-immunoprecipitation demonstrated the bridging effect of UDCA-LPE on integrin \u03b21 and LPAR1. The disruption of either the UDCA-moiety binding to integrins by RGD-containing peptide GRGDSP or the LPE-moiety binding to LPAR1 by LPAR1 antagonist Ki16425 reversed inhibitory functions of UDCA-LPE. The lack of inhibitory functions of UDCA-PE and UDCA-LPE derivatives (14:0 and 12:0, LPE-moiety containing shorter fatty acid chain) as well as the consistency of the translocation of UDCA-LPE and integrins, which co-fractionated with LPE but not UDCA, suggested that the observed UDCA-LPE-induced translocation of integrins was mediated by LPE endocytic transport pathway.<\/jats:p>","DOI":"10.3390\/ijms19103254","type":"journal-article","created":{"date-parts":[[2018,10,23]],"date-time":"2018-10-23T08:43:36Z","timestamp":1540284216000},"page":"3254","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Bivalent Ligand UDCA-LPE Inhibits Pro-Fibrogenic Integrin Signalling by Inducing Lipid Raft-Mediated Internalization"],"prefix":"10.3390","volume":"19","author":[{"given":"Jie","family":"Su","sequence":"first","affiliation":[{"name":"Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany"},{"name":"Department of Biology, Southern University of Science and Technology, Shenzhen 518055, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongying","family":"Gan-Schreier","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Goeppert","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walee","family":"Chamulitrat","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang","family":"Stremmel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3670-8209","authenticated-orcid":false,"given":"Anita","family":"Pathil","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1055\/s-2001-17556","article-title":"Matrix as a modulator of hepatic fibrogenesis","volume":"21","author":"Schuppan","year":"2001","journal-title":"Semin. 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