TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro

Reich, Maria; Deutschmann, K; Sommerfeld, Annika; Klindt, Caroline; Kluge, Stefanie; Kubitz, Ralf; Ullmer, Christoph; Knoefel, Wolfram Trudo; Herebian, Diran; Mayatepek, Ertan; Häussinger, Dieter; Keitel, Verena

doi:10.1136/gutjnl-2015-309458

Cited by 168 publications

(168 citation statements)

References 84 publications

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“…The results showed that these markers were significantly decreased, suggesting that murine cholangiocyte proliferation was inhibited. In addition, expression of the transmembrane-bound G protein-coupled receptor (Tgr5) that is activated by bile acids (especially tLCA and tDCA) (Keitel and Haussinger, 2013;Duboc et al, 2014;Reich et al, 2016) and localized in cholangiocytes and modulates cholangiocyte proliferation and bile flow, was lower (Fig. 3B).…”

Section: Instability Of the Chimeric Humanized Liver Mouse Modelmentioning

confidence: 99%

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Chow

Quach

Zhang

et al. 2016

J Pharmacol Exp Ther

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The humanized liver mouse model is being exploited increasingly for human drug metabolism studies. However, its model stability, intercommunication between human hepatocytes and mouse nonparenchymal cells in liver and murine intestine, and changes in extrahepatic transporter and enzyme expressions have not been investigated. We examined these issues in FRGN [fumarylacetoacetate hydrolase (Fah2/2), recombination activating gene 2 (Rag22/2), and interleukin 2 receptor subunit gamma (IL-2rg 2/2) triple knockout] on nonobese diabetic (NOD) background] and chimeric mice: mFRGN and hFRGN (repopulated with mouse or human hepatocytes, respectively). hFRGN mice showed markedly higher levels of liver cholesterol, biliary bilirubin, and bile acids (liver, bile, and plasma; mainly human forms, but also murine bile acids) but lower transforming growth factor beta receptor 2 (TGFBR2) mRNA expression levels (10%) in human hepatocytes and other proliferative markers in mouse nonparenchymal cells (Tgf-b1) and cholangiocytes [plasma membrane-bound, G protein-coupled receptor for bile acids (Tgr5)], suggestive of irregular regeneration processes in hFRGN livers. Changes in gene expression in murine intestine, kidney, and brain of hFRGN mice, in particular, induction of intestinal farnesoid X receptor (Fxr) genes: fibroblast growth factor 15 (Fgf15), mouse ileal bile acid binding protein (Ibabp), small heterodimer partner (Shp), and the organic solute transporter alpha (Osta), were observed. Proteomics revealed persistence of remnant murine proteins (cyotchrome P450 7a-hydroxylase (Cyp7a1) and other enzymes and transporters) in hFRGN livers and suggest the likelihood of mouse activity. When compared with normal human liver tissue, hFRGN livers showed lower SHP mRNA and higher CYP7A1 (300%) protein expression, consequences of tb-and ta-muricholic acid-mediated inhibition of the FXR-SHP cascade and miscommunication between intestinal Fgf15 and human liver fibroblast growth factor receptor 4 (FGFR4), as confirmed by the unchanged hepatic pERK/total ERK ratio. Dysregulation of hepatocyte proliferation and bile acid homeostasis in hFRGN livers led to hepatotoxicity, gallbladder distension, liver deformity, and other extrahepatic changes, making questionable the use of the preparation for drug metabolism studies.

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Section: Instability Of the Chimeric Humanized Liver Mouse Modelmentioning

confidence: 99%

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Chow

Quach

Zhang

et al. 2016

J Pharmacol Exp Ther

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“…Bile acids have been shown to alter platelet activation [35] and aggregation [26] and are elevated in BDL mice and in mice fed with a cholic acid diet [36]. To test, if bile acids account for the observed activation defects of BDL platelets, a chow enriched with 0.5% cholic acid, a physiological bile acid in the mouse, was given ad libitum for 7 days.…”

Section: Resultsmentioning

confidence: 99%

Defective Platelet Activation and Bleeding Complications upon Cholestasis in Mice

Gowert

Klier

Reich

et al. 2017

Cell Physiol Biochem

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Background/Aims: Platelets are essential mediators of hemostasis to avoid excessive blood loss. Cirrhosis and chronic liver diseases are characterized by alterations in hemostasis. Alterations in the secondary hemostasis have been well studied, while defects in primary hemostasis, especially the consequences of cholestatic liver disease on platelet function are not well defined. Methods: After bile duct ligation (BDL) platelet activation and thrombus formation were analyzed in mice. Results: BDL in mice had a moderate effect on platelet counts; however, intrinsic platelet activation was strongly reduced upon activation of the collagen receptor GPVI at early time points. 7 days after bile duct ligation, platelets displayed an almost complete loss of activation with reduced agonist-triggered release of alpha and dense granules and expression of integrin α_IIbβ₃ on the platelet surface. This activation defects resulted in strongly reduced thrombus formation under flow, reduced platelet adhesion to fibrinogen and bleeding complications in BDL mice as measured by tail bleeding experiments. Mechanistically, elevated nitric oxide and prostacyclin levels induced phosphorylation of Vasodilator-stimulated phosphoprotein (VASP), an established inhibitor of platelet activation. Furthermore increased tissue plasminogen activator in plasma of BDL mice led to enhanced plasmin levels that might be responsible for reduced glycoprotein expression of BDL platelets. Besides, high amounts of bile acids contribute to defective signal transduction as shown in platelets from mice fed with a cholic acid diet. Conclusions: Cholestatic liver disease induces multiple platelet activation defects and impairs thrombus formation responsible for bleeding complications at least in mice.

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“…L'activation de TGR5 par les acides biliaires secondaires stimule la prolifération et inhibe l'apoptose des cholangiocytes [5]. Au niveau des macrophages, TGR5 limite la production de cytokines pro-inflammatoires [6].…”

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Les lésions hépatiques induites par la cholestase : le rôle de S1PR2

et al. 2017

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TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro

Cited by 168 publications

References 84 publications

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Defective Platelet Activation and Bleeding Complications upon Cholestasis in Mice

Les lésions hépatiques induites par la cholestase : le rôle de S1PR2

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