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VPAC1 expression is regulated by FXR agonists in the human gallbladder epithelium
Author(s) -
Chignard Nicolas,
Mergey Martine,
Barbu Véronique,
Finzi Laetitia,
Tiret Emmanuel,
Paul Annick,
Housset Chantal
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20806
Subject(s) - farnesoid x receptor , vasoactive intestinal peptide , medicine , endocrinology , biology , receptor , agonist , g protein coupled bile acid receptor , gallbladder , secretion , bile acid , nuclear receptor , biochemistry , transcription factor , neuropeptide , gene
Vasoactive intestinal peptide receptor‐1 (VPAC1) is the high‐affinity receptor of vasoactive intestinal peptide (VIP), a major regulator of bile secretion. To better define the level at which VPAC1 stimulates bile secretion, we examined its expression in the different cell types participating in bile formation ( i.e. , hepatocytes, bile duct, and gallbladder epithelial cells). Because VPAC1 expression was previously shown to be regulated by nuclear receptors, we tested the hypothesis that it may be regulated by the farnesoid X receptor (FXR). Quantitative RT‐PCR and immunoblot analyses of cell isolates indicated that VPAC1 is expressed in all three cell types lining the human biliary tree, with predominant expression in the gallbladder. In primary cultures of human gallbladder epithelial cells, VIP induced cAMP production and chloride secretion. Analysis of the VPAC1 gene revealed the presence of potential FXR response element sequences, and both FXR and RXRα expressions were detected in gallbladder epithelial cells. In these cells, the FXR pharmacological agonist GW4064 upregulated VPAC1 expression in a dose‐dependent manner, and this effect was antagonized by the RXRα ligand, 9‐cis retinoic acid. Chenodeoxycholate activated endogenous FXR in gallbladder epithelial cells, as ascertained by electromobility shift assay and upregulation of the FXR target gene, small heterodimer partner. Chenodeoxycholate also provoked an increase in VPAC1 mRNA and protein content in these cells. In conclusion , FXR agonists may increase gallbladder fluid secretion through transcriptional activation of VPAC1, which may contribute to the regulation of bile secretion by bile salts and to a protective effect of FXR pharmacological agonists in gallstone disease. (H EPATOLOGY 2005.)