Glucagon-like peptide-1 and its receptor agonist exendin-4 modulate cholangiocyte adaptive response to cholestasis

Gastroenterology. 2007 Jul;133(1):244-55. doi: 10.1053/j.gastro.2007.04.007.


Background & aims: Cholangiopathies are characterized by progressive dysregulation of the balance between proliferation and death of cholangiocytes. In the course of cholestasis, cholangiocytes undergo a neuroendocrine transdifferentiation and their biology is regulated by neuroendocrine hormones. Glucagon-like peptide-1 (GLP-1), secreted by neuroendocrine cells, sustains beta-cell survival in experimental diabetes and induces the neuroendocrine transdifferentiation of pancreatic ductal cells. GLP-1 receptor (GLP-1R) selective agonist exendin-4 is used in humans as a novel therapeutic tool for diabetes. The aim of this study was to define if GLP-1 modulates cholangiocyte biologic response to cholestasis.

Methods: Expression of GLP-1R in cholangiocytes was determined. Effects on cholangiocyte proliferation of the in vitro and in vivo exposure to GLP-1 or exendin-4, together with the intracellular signals, were then studied. Synthesis of GLP-1 by cholangiocytes and the effects of GLP-1R blockage on their growth were also determined.

Results: Cholangiocytes express the GLP-1 receptor, which is up-regulated in the course of cholestasis. GLP-1 and exendin-4 increase cholangiocyte growth both in vitro and in vivo. The GLP-1R signal is mediated by the phosphatidyl-inositol-3-kinase, cAMP/Protein Kinase A, and Ca(2+)-CamKIIalpha but not by the ERK1/2 and PKCalpha pathways. Proliferating cholangiocytes synthesize GLP-1: neutralization of its action by GLP-1R antagonist blunts cholangiocyte response to cholestasis.

Conclusions: GLP-1 is required for the cholangiocyte adaptive response to cholestasis. Cholangiocytes are susceptible to the activation of GLP-1R and respond with increased proliferation and functional activity. Exendin-4 availability for employment in humans and these data may open novel perspectives for the medical treatment of cholangiopathies.

Publication types

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

MeSH terms

  • Adaptation, Physiological / drug effects
  • Adaptation, Physiological / physiology
  • Animals
  • Bile Ducts / drug effects
  • Bile Ducts / metabolism
  • Bile Ducts / pathology
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cholestasis, Extrahepatic / drug therapy*
  • Cholestasis, Extrahepatic / metabolism
  • Cholestasis, Extrahepatic / pathology*
  • Exenatide
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents / pharmacology*
  • Male
  • Peptides / pharmacology*
  • Rats
  • Rats, Inbred F344
  • Receptors, Glucagon / agonists
  • Receptors, Glucagon / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Up-Regulation / drug effects
  • Up-Regulation / physiology
  • Venoms / pharmacology*


  • GLP1R protein, human
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Peptides
  • Receptors, Glucagon
  • Venoms
  • Glucagon-Like Peptide 1
  • Exenatide