RT Journal Article
SR Electronic
T1 TGR5-dependent hepatoprotection through the regulation of biliary epithelium barrier function
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP gutjnl-2018-316975
DO 10.1136/gutjnl-2018-316975
A1 Grégory Merlen
A1 Nicolas Kahale
A1 Jose Ursic-Bedoya
A1 Valeska Bidault-Jourdainne
A1 Hayat Simerabet
A1 Isabelle Doignon
A1 Zahra Tanfin
A1 Isabelle Garcin
A1 Noémie Péan
A1 Julien Gautherot
A1 Anne Davit-Spraul
A1 Catherine Guettier
A1 Lydie Humbert
A1 Dominique Rainteau
A1 Klaus Ebnet
A1 Christoph Ullmer
A1 Doris Cassio
A1 Thierry Tordjmann
YR 2019
UL http://gut.bmj.com/content/early/2019/02/05/gutjnl-2018-316975.abstract
AB 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.