Background & Aims
Reactive cholangiocytes acquire a neuroendocrine-like phenotype, with synthesis and
local release of neuropeptides and hormones. The mechanism that drives such phenotypical
changes is still undefined. Pancreatic Duodenal Homeobox-1 (PDX-1) is a transcription
factor required for pancreatic development, that sustains pancreatic beta-cell response
to injury and insulin synthesis. PDX-1 induces neuroendocrine-like transition of pancreatic
ductal cells. Cholangiocyte response to injury is modulated by Glucagon-Like Peptide-1
Receptor (GLP-1R), which, in the pancreas, activates PDX-1. We wanted to verify whether
PDX-1 plays any role in cholangiocyte neuroendocrine-like transdifferentiation in
response to injury.
Methods
PDX-1 expression was assessed in cholangiocytes from normal and one week bile duct
ligated (BDL) rats. Changes in PDX-1 expression and activation upon GLP-1R activation
were then assayed. The effects of the lack of PDX-1 in cholangiocytes were studied
in vitro by siRNA and in vivo by the employment of PDX-1-deficient (+/−) mice.
Results
BDL but not normal cholangiocytes express PDX-1. GLP-1R activation elicits, in a PI3K-dependent
fashion, PDX-1 expression, together with its nuclear translocation. In vitro, GLP-1R-induced increases in VEGF and IGF-1 mRNA expression were blunted in cells
with PDX-1 siRNA. In vivo, the VEGF and IGF-1 mRNA expression in the liver after one week BDL was markedly
reduced in PDX-1-deficient mice, together with reduced bile duct mass.
Conclusions
In response to injury, reactive cholangiocytes de novo express PDX-1, the activation of which allows cholangiocytes to synthesize IGF-1
and VEGF. These findings suggest that PDX-1 drives the acquisition of the neuroendocrine-like
phenotype by cholangiocytes in response to cholestatic injury.
Abbreviations:
PDX-1 (Pancreatic Duodenal Homeobox-1), NRC (normal rat cultured cholangiocytes), BDL (bile duct ligation), cAMP (cyclic adenosine 3′,5′-monophosphate), FBS (fetal bovine serum), PKA (protein kinase A), PI3K (phosphatidyl-inositol-3-kinase), PCNA (proliferating cell nuclear antigen)Keywords
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Article info
Publication history
Published online: June 25, 2010
Accepted:
April 12,
2010
Received in revised form:
April 10,
2010
Received:
October 25,
2009
Identification
Copyright
© 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
