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Gastroenterology. 2007 Jul;133(1):244-55.

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

Author information

1
Department of Gastroenterology, Università Politecnica delle Marche, Ancona, Italy. m.marzioni@univpm.it <m.marzioni@univpm.it>

Abstract

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.

PMID:
17631146
DOI:
10.1053/j.gastro.2007.04.007
[Indexed for MEDLINE]

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