Ciliary subcellular localization of TGR5 determines the cholangiocyte functional response to bile acid signaling

Am J Physiol Gastrointest Liver Physiol. 2013 Jun 1;304(11):G1013-24. doi: 10.1152/ajpgi.00383.2012. Epub 2013 Apr 11.


TGR5, the G protein-coupled bile acid receptor that transmits bile acid signaling into a cell functional response via the intracellular cAMP signaling pathway, is expressed in human and rodent cholangiocytes. However, detailed information on the localization and function of cholangiocyte TGR5 is limited. We demonstrated that in human (H69 cells) and rat cholangiocytes, TGR5 is localized to multiple, diverse subcellular compartments, with its strongest expression on the apical plasma, ciliary, and nuclear membranes. To evaluate the relationship between ciliary TGR5 and the cholangiocyte functional response to bile acid signaling, we used a model of ciliated and nonciliated H69 cells and demonstrated that TGR5 agonists induce opposite changes in cAMP and ERK levels in cells with and without primary cilia. The cAMP level was increased in nonciliated cholangiocytes but decreased in ciliated cells. In contrast, ERK signaling was induced in ciliated cholangiocytes but suppressed in cells without cilia. TGR5 agonists inhibited proliferation of ciliated cholangiocytes but activated proliferation of nonciliated cells. The observed differential effects of TGR5 agonists were associated with the coupling of TGR5 to Gαi protein in ciliated cells and Gαs protein in nonciliated cholangiocytes. The functional responses of nonciliated and ciliated cholangiocytes to TGR5-mediated bile acid signaling may have important pathophysiological significance in cilia-related liver disorders (i.e., cholangiociliopathies), such as polycystic liver disease. In summary, TGR5 is expressed on diverse cholangiocyte compartments, including a primary cilium, and its ciliary localization determines the cholangiocyte functional response to bile acid signaling.

Keywords: G protein-coupled bile acid receptor; TGR5; bile acid signaling; cholangiocytes; primary cilia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / metabolism
  • Bile Acids and Salts / pharmacology*
  • Bile Ducts, Intrahepatic / cytology
  • Bile Ducts, Intrahepatic / metabolism*
  • Cell Line
  • Cell Membrane / metabolism
  • Cell Proliferation / drug effects
  • Cilia / metabolism
  • Cilia / ultrastructure
  • Cyclic AMP / metabolism
  • Epithelial Cells / metabolism
  • Exosomes / metabolism
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Protein Transport
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / metabolism*


  • Bile Acids and Salts
  • GPBAR1 protein, human
  • Gpbar1 protein, rat
  • Receptors, G-Protein-Coupled
  • Cyclic AMP
  • Mitogen-Activated Protein Kinase 3