TGR5-dependent hepatoprotection through the regulation of biliary epithelium barrier function. Issue 1 (5th February 2019)

• Record Type: Journal Article
• Authors: Merlen, Grégory; Kahale, Nicolas; Ursic-Bedoya, Jose; Bidault-Jourdainne, Valeska; Simerabet, Hayat; Doignon, Isabelle; Tanfin, Zahra; Garcin, Isabelle; Péan, Noémie; Gautherot, Julien; Davit-Spraul, Anne; Guettier, Catherine; Humbert, Lydie; Rainteau, Dominique; Ebnet, Klaus; Ullmer, Christoph; Cassio, Doris; Tordjmann, Thierry
• Is Part Of: Gut. Volume 69:Issue 1(2020)
• Page Start: 146
• Page End: 157
• Publication Date: 2019-02-05
• Subjects: bile acid -- tight junction -- biliary epithelium -- cholestaticliver diseases; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2018-316975
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Objective: We explored the hypothesis that TGR5, the bile acid (BA) G-protein-coupled receptor highly expressed in biliary epithelial cells, protects the liver against BA overload through the regulation of biliary epithelium permeability. Design: Experiments were performed under basal and TGR5 agonist treatment. In vitro transepithelial electric resistance (TER) and FITC-dextran diffusion were measured in different cell lines. In vivo FITC-dextran was injected in the gallbladder (GB) lumen and traced in plasma. Tight junction proteins and TGR5-induced signalling were investigated in vitro and in vivo (wild-type [WT] and TGR5-KO livers and GB). WT and TGR5-KO mice were submitted to bile duct ligation or alpha-naphtylisothiocyanate intoxication under vehicle or TGR5 agonist treatment, and liver injury was studied. Results: In vitro TGR5 stimulation increased TER and reduced paracellular permeability for dextran. In vivo dextran diffusion after GB injection was increased in TGR5-knock-out (KO) as compared with WT mice and decreased on TGR5 stimulation. In TGR5-KO bile ducts and GB, junctional adhesion molecule A (JAM-A) was hypophosphorylated and selectively downregulated among TJP analysed. TGR5 stimulation induced JAM-A phosphorylation and stabilisation both in vitro and in vivo, associated with protein kinase C-ζ activation. TGR5 agonist-induced TER increase as well as JAM-A protein stabilisation was dependent on JAM-A Ser285 phosphorylation. TGR5 agonist-treated mice were protected from cholestasis-induced liver injury, and this protection was significantly impaired in JAM-A-KO mice. Conclusion: The BA receptor TGR5 regulates biliary epithelial barrier function in vitro and in vivo through an impact on JAM-A expression and phosphorylation, thereby protecting liver parenchyma against bile leakage.