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Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis

التفاصيل البيبلوغرافية
العنوان: Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis
المؤلفون: Dirk Nierhoff, Marina Vogel, Tom H. Karlsen, Jan-Philipp Mallm, Katharina Fuchs, Gisela Gabernet, Caroline Klindt, Karl Köhrer, Michael Trauner, Dieter Häussinger, Tom Luedde, Claudia D. Fuchs, Irene Esposito, Jan Stindt, Kristina Schoonjans, María García-Beccaria, Peter Fickert, Johanna Höhne, Tobias Lautwein, Evaggelia Liaskou, Sofia Ferreira-Gonzalez, M Reich, Joanne Verheij, Lina Spomer, Johannes R. Hov, Ulrich Beuers, Verena Keitel, Mathias Heikenwalder, Stuart J. Forbes, Sven Nahnsen, Christoph Schramm, K Deutschmann, Gideon M. Hirschfield
المساهمون: Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Pathology
المصدر: Journal of hepatology, 75(3), 634-646. Elsevier
Reich, M, Spomer, L, Klindt, C, Fuchs, K, Stindt, J, Deutschmann, K, Höhne, J, Liaskou, E, Hov, J R, Karlsen, T H, Beuers, U, Verheij, J, Ferreira-Gonzalez, S, Hirschfield, G, Forbes, S J, Schramm, C, Esposito, I, Nierhoff, D, Fickert, P, Fuchs, C D, Trauner, M, García-Beccaria, M, Gabernet, G, Nahnsen, S, Mallm, J-P, Vogel, M, Schoonjans, K, Lautwein, T, Koehrer, K, Häussinger, D, Luedde, T, Heikenwalder, M & Keitel, V 2021, ' Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis ', Journal of Hepatology . https://doi.org/10.1016/j.jhep.2021.03.029
سنة النشر: 2021
مصطلحات موضوعية: 0301 basic medicine, Pathology, medicine.medical_specialty, Virulence Factors, medicine.drug_class, Cholangitis, Sclerosing, education, Down-Regulation, determines, digestive system, Receptors, G-Protein-Coupled, Primary sclerosing cholangitis, murine model, Biliary injury, Pathogenesis, scrna-seq, Mice, 03 medical and health sciences, 0302 clinical medicine, biliary damage, Fibrosis, expression, parasitic diseases, medicine, Animals, Interleukin 8, cholangiocytes, Biliary Tract, norursodeoxycholic acid, health care economics and organizations, disease, Hepatology, Bile acid, biliary organoids, Chemistry, Bile duct, interleukin-8, Epithelial Cells, hco3-umbrella, medicine.disease, G protein-coupled bile acid receptor, bile acid receptor, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, bile-acid receptor, Liver, norudca, 030211 gastroenterology & hepatology
الوصف: 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.
وصف الملف: application/vnd.openxmlformats-officedocument.wordprocessingml.document
تدمد: 0168-8278
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d02c374f29995d64c84328b525e4acb7
http://hdl.handle.net/10852/92295
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....d02c374f29995d64c84328b525e4acb7
قاعدة البيانات: OpenAIRE
الوصف
تدمد:01688278