Melatonin inhibits cholangiocyte hyperplasia in cholestatic rats by interaction with MT1 but not MT2 melatonin receptors

• DOI: 10.1152/ajpgi.00206.2011
• Publication Date: 2011-07-15T02:47:36Z
• Authors: Anastasia Renzi; Shannon Glaser; Sharon DeMorrow; Romina Mancinelli; Fanyin Meng; Antonio Franchitto; Julie Venter; Mellanie White; Heather Francis; Yuyan Han; Domenico Alvaro; Eugenio Gaudio; Guido Carpino; Yoshiyuki Ueno; Paolo Onori; Gianfranco Alpini
• Keywords: Luzindole; PER1; Cholangiocyte

In bile duct-ligated (BDL) rats, large cholangiocytes proliferate by activation of cAMP-dependent signaling. Melatonin, which is secreted from pineal gland as well extrapineal tissues, regulates cell mitosis interacting with melatonin receptors (MT1 and MT2) modulating cAMP clock genes. the liver, suppresses oxidative damage ameliorates fibrosis. No information exists regarding role in regulation biliary hyperplasia. We evaluated mechanisms action growth cholangiocytes. normal BDL we determined hepatic distribution MT1, MT2, genes, CLOCK, BMAL1, CRY1, PER1. Normal (immediately after BDL) rats were treated vivo before evaluating 1) serum levels melatonin, bilirubin, transaminases; 2) intrahepatic duct mass (IBDM) liver sections; 3) expression MT1 PKA phosphorylation. vitro, stimulated absence/presence luzindole (MT1/MT2 antagonist) 4-phenyl-2-propionamidotetralin (MT2 proliferation, levels, Cholangiocytes express PER1 that all upregulated following BDL. Administration to decreased IBDM, bilirubin transaminases phosphorylation phosphorylation, decreases blocked luzindole. Melatonin may be important management hyperplasia human cholangiopathies.