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Modulation of the biliary expression of arylalkylamine N-acetyltransferase alters the autocrine proliferative responses of cholangiocytes in rats
- Source :
- Hepatology. 57:1130-1141
- Publication Year :
- 2013
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2013.
-
Abstract
- Secretin stimulates ductal secretion by interacting with secretin receptor (SR) activating cyclic adenosine 3',5'-monophosphate/cystic fibrosis transmembrane conductance regulator/chloride bicarbonate anion exchanger 2 (cAMP⇒CFTR⇒Cl(-) /HCO 3- AE2) signaling that is elevated by biliary hyperplasia. Cholangiocytes secrete several neuroendocrine factors regulating biliary functions by autocrine mechanisms. Melatonin inhibits biliary growth and secretin-stimulated choleresis in cholestatic bile-duct-ligated (BDL) rats by interaction with melatonin type 1 (MT1) receptor through down-regulation of cAMP-dependent signaling. No data exist regarding the role of melatonin synthesized locally by cholangiocytes in the autocrine regulation of biliary growth and function. In this study, we evaluated the (1) expression of arylalkylamine N-acetyltransferase (AANAT; the rate-limiting enzyme for melatonin synthesis from serotonin) in cholangiocytes and (2) effect of local modulation of biliary AANAT expression on the autocrine proliferative/secretory responses of cholangiocytes. In the liver, cholangiocytes (and, to a lesser extent, BDL hepatocytes) expressed AANAT. AANAT expression and melatonin secretion (1) increased in BDL, compared to normal rats and BDL rats treated with melatonin, and (2) decreased in normal and BDL rats treated with AANAT Vivo-Morpholino, compared to controls. The decrease in AANAT expression, and subsequent lower melatonin secretion by cholangiocytes, was associated with increased biliary proliferation and increased SR, CFTR, and Cl(-) /HCO 3- AE2 expression. Overexpression of AANAT in cholangiocyte cell lines decreased the basal proliferative rate and expression of SR, CFTR, and Cl(-) /HCO 3- AE2 and ablated secretin-stimulated biliary secretion in these cells.Local modulation of melatonin synthesis may be important for management of the balance between biliary proliferation/damage that is typical of cholangiopathies. (HEPATOLOGY 2013).
- Subjects :
- Male
medicine.medical_specialty
AANAT
SLC4A Proteins
Anion Transport Proteins
Apoptosis
Arylalkylamine N-Acetyltransferase
digestive system
Antioxidants
Antiporters
Article
Cholangiocyte
Secretin
Melatonin
Mice
Proliferating Cell Nuclear Antigen
Internal medicine
medicine
Animals
Autocrine signalling
Cell Line, Transformed
Cell Proliferation
Cholestasis
Hepatology
biology
Biliary hyperplasia
Rats, Inbred F344
digestive system diseases
Cystic fibrosis transmembrane conductance regulator
Rats
Autocrine Communication
Bile Ducts, Intrahepatic
Endocrinology
Gene Knockdown Techniques
Receptors, Serotonin
biology.protein
Secretin receptor
hormones, hormone substitutes, and hormone antagonists
medicine.drug
Subjects
Details
- ISSN :
- 02709139
- Volume :
- 57
- Database :
- OpenAIRE
- Journal :
- Hepatology
- Accession number :
- edsair.doi.dedup.....eb2fef97ac5817934593a9f64f8263c4