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TGR5-dependent hepatoprotection through the regulation of biliary epithelium barrier function
  1. Grégory Merlen1,2,
  2. Nicolas Kahale1,2,
  3. Jose Ursic-Bedoya1,2,
  4. Valeska Bidault-Jourdainne1,2,
  5. Hayat Simerabet1,2,
  6. Isabelle Doignon1,2,
  7. Zahra Tanfin1,2,
  8. Isabelle Garcin1,2,
  9. Noémie Péan1,2,
  10. Julien Gautherot1,2,
  11. Anne Davit-Spraul3,4,
  12. Catherine Guettier4,5,
  13. Lydie Humbert6,
  14. Dominique Rainteau7,
  15. Klaus Ebnet8,
  16. Christoph Ullmer9,
  17. Doris Cassio1,2,
  18. Thierry Tordjmann1,2
  1. 1U1174, INSERM, Orsay, France
  2. 2Université Paris-Sud, Orsay, France
  3. 3Service de Biochimie, Hopital Bicêtre, Le Kremlin-Bicêtre, France
  4. 4Université Paris Sud Faculte de Medecine, Le Kremlin-Bicêtre, France
  5. 5Service d’Anatomie Pathologique, Hopital Bicêtre, Le Kremlin-Bicêtre, France
  6. 6ER7, Université Pierre et Marie Curie-Paris-6, Paris, France
  7. 7ERL U1057/UMR 7203 Inserm, University Paris VI, Paris, France
  8. 8Institute-associated Research Group ’Cell adhesion and cell polarity', Institute of Medical Biochemistry, ZMBE, Münster, University of Münster, Münster, Germany
  9. 9Roche Pharmaceutical Research and Early Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland
  1. Correspondence to Dr Thierry Tordjmann, U1174, INSERM, Orsay, 91405, France; thierry.tordjmann{at}


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.

  • bile acid
  • tight junction
  • biliary epithelium
  • cholestaticliver diseases
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  • NK and JU-B contributed equally.

  • Contributors JU-B and NK contributed equally to this work. TT: study concept and design, obtained funding, wrote the manuscript and study supervision; GM, JU-B, NK, HS, VB-J, ID, ZT, NP, JG, DC and TT: acquisition, data analysis and interpretation; GM, JU-B, DC, ZT and KE: critical revision of the manuscript for important intellectual content; CU, KE, AD-S and CG: technical and material support.

  • Funding This study was funded by Institut National de la Santé et de la Recherche Médicale, Université Paris-Sud and Agence Nationale de la Recherche (Grant Number:15-CE14-0007-01).

  • Competing interests None declared.

  • Patient consent This manuscript does not contain identifiable patients data.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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