Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
Gut ; 69(1): 146-157, 2020 01.
Article in English | MEDLINE | ID: mdl-30723104

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.


Subject(s)
Biliary Tract/physiopathology , Cholestasis, Intrahepatic/prevention & control , Receptors, G-Protein-Coupled/physiology , Animals , Bile/metabolism , Bile Acids and Salts/metabolism , Cell Adhesion Molecules/metabolism , Cells, Cultured , Cholestasis, Intrahepatic/metabolism , Electric Impedance , Epithelium/physiopathology , Isonipecotic Acids/pharmacology , Isonipecotic Acids/therapeutic use , Mice, Inbred C57BL , Mice, Knockout , Oximes/pharmacology , Oximes/therapeutic use , Permeability , Phosphorylation/physiology , Receptors, Cell Surface/metabolism , Receptors, G-Protein-Coupled/agonists , Signal Transduction/physiology , Tight Junction Proteins/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...