51. Modulation of the biliary expression of arylalkylamine N-acetyltransferase alters the autocrine proliferative responses of cholangiocytes in rats.
- Author
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Renzi A, DeMorrow S, Onori P, Carpino G, Mancinelli R, Meng F, Venter J, White M, Franchitto A, Francis H, Han Y, Ueno Y, Dusio G, Jensen KJ, Greene JJ Jr, Glaser S, Gaudio E, and Alpini G
- Subjects
- Animals, Anion Transport Proteins genetics, Anion Transport Proteins metabolism, Antioxidants metabolism, Antioxidants pharmacology, Antiporters genetics, Antiporters metabolism, Apoptosis drug effects, Apoptosis physiology, Arylalkylamine N-Acetyltransferase genetics, Autocrine Communication drug effects, Bile Ducts, Intrahepatic drug effects, Cell Line, Transformed, Cell Proliferation, Gene Knockdown Techniques, Male, Melatonin blood, Melatonin pharmacology, Mice, Proliferating Cell Nuclear Antigen genetics, Proliferating Cell Nuclear Antigen metabolism, Rats, Rats, Inbred F344, Receptors, Serotonin genetics, Receptors, Serotonin metabolism, SLC4A Proteins, Arylalkylamine N-Acetyltransferase metabolism, Autocrine Communication physiology, Bile Ducts, Intrahepatic cytology, Bile Ducts, Intrahepatic enzymology, Cholestasis metabolism, Cholestasis pathology
- Abstract
Unlabelled: 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., Conclusion: Local modulation of melatonin synthesis may be important for management of the balance between biliary proliferation/damage that is typical of cholangiopathies. (HEPATOLOGY 2013)., (Copyright © 2012 American Association for the Study of Liver Diseases.)
- Published
- 2013
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