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

Standard

Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis. / Reich, Maria; Spomer, Lina; Klindt, Caroline; Fuchs, Katharina; Stindt, Jan; Deutschmann, Kathleen; Höhne, Johanna; Liaskou, Evaggelia; Hov, Johannes R; Karlsen, Tom H; Beuers, Ulrich; Verheij, Joanne; Ferreira-Gonzalez, Sofia; Hirschfield, Gideon; Forbes, Stuart J; Schramm, Christoph; Esposito, Irene; Nierhoff, Dirk; Fickert, Peter; Fuchs, Claudia Daniela; Trauner, Michael; García-Beccaria, María; Gabernet, Gisela; Nahnsen, Sven; Mallm, Jan-Philipp; Vogel, Marina; Schoonjans, Kristina; Lautwein, Tobias; Köhrer, Karl; Häussinger, Dieter; Luedde, Tom; Heikenwalder, Mathias; Keitel, Verena.

in: J HEPATOL, Jahrgang 75, Nr. 3, 09.2021, S. 634-646.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Reich, M, Spomer, L, Klindt, C, Fuchs, K, Stindt, J, Deutschmann, K, Höhne, J, Liaskou, E, Hov, JR, Karlsen, TH, Beuers, U, Verheij, J, Ferreira-Gonzalez, S, Hirschfield, G, Forbes, SJ, Schramm, C, Esposito, I, Nierhoff, D, Fickert, P, Fuchs, CD, Trauner, M, García-Beccaria, M, Gabernet, G, Nahnsen, S, Mallm, J-P, Vogel, M, Schoonjans, K, Lautwein, T, Köhrer, 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', J HEPATOL, Jg. 75, Nr. 3, S. 634-646. https://doi.org/10.1016/j.jhep.2021.03.029

APA

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., ... Keitel, V. (2021). Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis. J HEPATOL, 75(3), 634-646. https://doi.org/10.1016/j.jhep.2021.03.029

Vancouver

Reich M, Spomer L, Klindt C, Fuchs K, Stindt J, Deutschmann K et al. Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis. J HEPATOL. 2021 Sep;75(3):634-646. https://doi.org/10.1016/j.jhep.2021.03.029

Bibtex

@article{bf20c7cdc365402889502901c5dcbcf0,
title = "Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis",
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-/-/Tgr5Tg and ursodeoxycholic acid (UDCA)- or 24-norursodeoxycholic acid (norUDCA)-fed Abcb4-/- 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 Tgfβ2. 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.",
author = "Maria Reich and Lina Spomer and Caroline Klindt and Katharina Fuchs and Jan Stindt and Kathleen Deutschmann and Johanna H{\"o}hne and Evaggelia Liaskou and Hov, {Johannes R} and Karlsen, {Tom H} and Ulrich Beuers and Joanne Verheij and Sofia Ferreira-Gonzalez and Gideon Hirschfield and Forbes, {Stuart J} and Christoph Schramm and Irene Esposito and Dirk Nierhoff and Peter Fickert and Fuchs, {Claudia Daniela} and Michael Trauner and Mar{\'i}a Garc{\'i}a-Beccaria and Gisela Gabernet and Sven Nahnsen and Jan-Philipp Mallm and Marina Vogel and Kristina Schoonjans and Tobias Lautwein and Karl K{\"o}hrer and Dieter H{\"a}ussinger and Tom Luedde and Mathias Heikenwalder and Verena Keitel",
note = "Copyright {\textcopyright} 2021. Published by Elsevier B.V.",
year = "2021",
month = sep,
doi = "10.1016/j.jhep.2021.03.029",
language = "English",
volume = "75",
pages = "634--646",
journal = "J HEPATOL",
issn = "0168-8278",
publisher = "Elsevier",
number = "3",

}

RIS

TY - JOUR

T1 - Downregulation of TGR5 (GPBAR1) in biliary epithelial cells contributes to the pathogenesis of sclerosing cholangitis

AU - Reich, Maria

AU - Spomer, Lina

AU - Klindt, Caroline

AU - Fuchs, Katharina

AU - Stindt, Jan

AU - Deutschmann, Kathleen

AU - Höhne, Johanna

AU - Liaskou, Evaggelia

AU - Hov, Johannes R

AU - Karlsen, Tom H

AU - Beuers, Ulrich

AU - Verheij, Joanne

AU - Ferreira-Gonzalez, Sofia

AU - Hirschfield, Gideon

AU - Forbes, Stuart J

AU - Schramm, Christoph

AU - Esposito, Irene

AU - Nierhoff, Dirk

AU - Fickert, Peter

AU - Fuchs, Claudia Daniela

AU - Trauner, Michael

AU - García-Beccaria, María

AU - Gabernet, Gisela

AU - Nahnsen, Sven

AU - Mallm, Jan-Philipp

AU - Vogel, Marina

AU - Schoonjans, Kristina

AU - Lautwein, Tobias

AU - Köhrer, Karl

AU - Häussinger, Dieter

AU - Luedde, Tom

AU - Heikenwalder, Mathias

AU - Keitel, Verena

N1 - Copyright © 2021. Published by Elsevier B.V.

PY - 2021/9

Y1 - 2021/9

N2 - 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-/-/Tgr5Tg and ursodeoxycholic acid (UDCA)- or 24-norursodeoxycholic acid (norUDCA)-fed Abcb4-/- 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 Tgfβ2. 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.

AB - 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-/-/Tgr5Tg and ursodeoxycholic acid (UDCA)- or 24-norursodeoxycholic acid (norUDCA)-fed Abcb4-/- 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 Tgfβ2. 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.

U2 - 10.1016/j.jhep.2021.03.029

DO - 10.1016/j.jhep.2021.03.029

M3 - SCORING: Journal article

C2 - 33872692

VL - 75

SP - 634

EP - 646

JO - J HEPATOL

JF - J HEPATOL

SN - 0168-8278

IS - 3

ER -