Reich, Maria, Spomer, Lina, Klindt, Caroline, Fuchs, Katharina, Stindt, Jan, Deutschmann, Kathleen, Hohne, Johanna, Liaskou, Evaggelia, Hov, Johannes R., Karlsen, Tom H., Beuers, Ulrich, Verheij, Joanne ORCID: 0000-0003-1283-630X, Ferreira-Gonzalez, Sofia ORCID: 0000-0001-7776-287X, Hirschfield, Gideon, Forbes, Stuart J., Schramm, Christoph, Esposito, Irene, Nierhoff, Dirk, Fickert, Peter, Fuchs, Claudia Daniela, Trauner, Michael, Garcia-Beccaria, Maria, Gabernet, Gisela ORCID: 0000-0001-7049-9474, Nahnsen, Sven, Mallm, Jan-Philipp, Vogel, Marina, Schoonjans, Kristina, Lautwein, Tobias, Koehrer, Karl, Haeussinger, Dieter, Luedde, Tom, Heikenwalder, Mathias and Keitel, Verena ORCID: 0000-0003-1383-7662 (2021). Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis. J. Hepatol., 75 (3). S. 634 - 648. AMSTERDAM: ELSEVIER. ISSN 1600-0641

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Abstract

Background & Aims: Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and progressive fibrosis of the biliary tree. The bile acid receptor TGR5 (GPBAR1) is found on biliary epithelial cells (BECs), where it promotes secretion, proliferation and tight junction integrity. Thus, we speculated that changes in TGR5-expression in BECs may contribute to PSC pathogenesis. Methods: TGR5-expression and-localization were analyzed in PSC livers and liver tissue, isolated bile ducts and BECs from Abcb4(-/-) , Abcb4(-/-)/Tgr5(Tg) and ursodeoxycholic acid (UDCA)-or 24-norursodeoxycholic acid (norUDCA)-fed Abcb(4-/-) mice. The effects of IL8/IL8 homologues on TGR5 mRNA and protein levels were studied. BEC gene expression was analyzed by single-cell transcriptomics (scRNA-seq) from distinct mouse models. Results: TGR5 mRNA expression and immunofluorescence staining intensity were reduced in BECs of PSC and Abcb4(-/-) livers, in Abcb4(-/-) extrahepatic bile ducts, but not in intrahepatic macrophages. No changes in TGR5 BEC fluorescence intensity were detected in liver tissue of other liver diseases, including primary biliary cholangitis. Incubation of BECs with IL8/IL8 homologues, but not with other cytokines, reduced TGR5 mRNA and protein levels. BECs from Abcb4(-/-) mice had lower levels of phosphorylated Erk and higher expression levels of Icam1, Vcam1 and Tgfb2. Overexpression of Tgr5 abolished the activated inflammatory phenotype characteristic of Abcb4(-/-) BECs. NorUDCA-feeding restored TGR5-expression levels in BECs in Abcb4(-/-) livers. Conclusions: Reduced TGR5 levels in BECs from patients with PSC and Abcb4(-/-) mice promote development of a reactive BEC phenotype, aggravate biliary injury and thus contribute to the pathogenesis of sclerosing cholangitis. Restoration of biliary TGR5-expression levels represents a previously unknown mechanism of action of norUDCA. Lay summary: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease-associated with progressive inflammation of the bile duct, leading to fibrosis and end-stage liver disease. Bile acid (BA) toxicity may contribute to the development and disease progression of PSC. TGR5 is a membrane-bound receptor for BAs, which is found on bile ducts and protects bile ducts from BA toxicity. In this study, we show that TGR5 levels were reduced in bile ducts from PSC livers and in bile ducts from a genetic mouse model of PSC. Our investigations indicate that lower levels of TGR5 in bile ducts may contribute to PSC development and progression. Furthermore, treatment with norUDCA, a drug currently being tested in a phase III trial for PSC, restored TGR5 levels in biliary epithelial cells. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Reich, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spomer, LinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klindt, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fuchs, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stindt, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deutschmann, KathleenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hohne, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liaskou, EvaggeliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hov, Johannes R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karlsen, Tom H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beuers, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Verheij, JoanneUNSPECIFIEDorcid.org/0000-0003-1283-630XUNSPECIFIED
Ferreira-Gonzalez, SofiaUNSPECIFIEDorcid.org/0000-0001-7776-287XUNSPECIFIED
Hirschfield, GideonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Forbes, Stuart J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schramm, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Esposito, IreneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nierhoff, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fickert, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fuchs, Claudia DanielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trauner, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia-Beccaria, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gabernet, GiselaUNSPECIFIEDorcid.org/0000-0001-7049-9474UNSPECIFIED
Nahnsen, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mallm, Jan-PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogel, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schoonjans, KristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lautwein, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koehrer, KarlUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haeussinger, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luedde, TomUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heikenwalder, MathiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keitel, VerenaUNSPECIFIEDorcid.org/0000-0003-1383-7662UNSPECIFIED
URN: urn:nbn:de:hbz:38-604353
DOI: 10.1016/j.jhep.2021.03.029
Journal or Publication Title: J. Hepatol.
Volume: 75
Number: 3
Page Range: S. 634 - 648
Date: 2021
Publisher: ELSEVIER
Place of Publication: AMSTERDAM
ISSN: 1600-0641
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
BILE-ACID RECEPTOR; NORURSODEOXYCHOLIC ACID; HCO3-UMBRELLA; MURINE MODEL; INTERLEUKIN-8; EXPRESSION; CHOLANGIOCYTES; DETERMINES; DISEASEMultiple languages
Gastroenterology & HepatologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60435

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