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

Autor: 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
Přispěvatelé: Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Pathology
Rok vydání: 2021
Předmět:
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
Zdroj: 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
ISSN: 0168-8278
Popis: 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.
Databáze: OpenAIRE
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