Melatonin inhibits cholangiocyte hyperplasia in cholestatic rats by interaction with MT1 but not MT2 melatonin receptors
| Autor: | Paolo Onori, Romina Mancinelli, Domenico Alvaro, Gianfranco Alpini, Anastasia Renzi, Yoshiyuki Ueno, Fanyin Meng, Mellanie White, Shannon Glaser, Heather Francis, Guido Carpino, Yuyan Han, Sharon DeMorrow, Julie Venter, Antonio Franchitto, Eugenio Gaudio |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Male
endocrine system medicine.medical_specialty Physiology CLOCK Proteins camp Biology secretin Cholangiocyte Secretin Melatonin Mice Pineal gland Cholestasis Proliferating Cell Nuclear Antigen Physiology (medical) Internal medicine Cyclic AMP medicine Animals Receptor Ligation Cell Proliferation mitosis Hyperplasia Hepatology Receptor Melatonin MT2 Cell growth Receptor Melatonin MT1 cholestasis pka Gastroenterology ARNTL Transcription Factors Period Circadian Proteins medicine.disease Rats Inbred F344 Rats Cryptochromes Bicarbonates Liver and Biliary Tract Endocrinology medicine.anatomical_structure Bile Ducts hormones hormone substitutes and hormone antagonists medicine.drug |
| Zdroj: | American Journal of Physiology-Gastrointestinal and Liver Physiology. 301:G634-G643 |
| ISSN: | 1522-1547 0193-1857 |
| DOI: | 10.1152/ajpgi.00206.2011 |
| Popis: | In bile duct-ligated (BDL) rats, large cholangiocytes proliferate by activation of cAMP-dependent signaling. Melatonin, which is secreted from pineal gland as well as extrapineal tissues, regulates cell mitosis by interacting with melatonin receptors (MT1 and MT2) modulating cAMP and clock genes. In the liver, melatonin suppresses oxidative damage and ameliorates fibrosis. No information exists regarding the role of melatonin in the regulation of biliary hyperplasia. We evaluated the mechanisms of action by which melatonin regulates the growth of cholangiocytes. In normal and BDL rats, we determined the hepatic distribution of MT1, MT2, and the clock genes, CLOCK, BMAL1, CRY1, and PER1. Normal and BDL (immediately after BDL) rats were treated in vivo with melatonin before evaluating 1) serum levels of melatonin, bilirubin, and transaminases; 2) intrahepatic bile duct mass (IBDM) in liver sections; and 3) the expression of MT1 and MT2, clock genes, and PKA phosphorylation. In vitro, large cholangiocytes were stimulated with melatonin in the absence/presence of luzindole (MT1/MT2 antagonist) and 4-phenyl-2-propionamidotetralin (MT2 antagonist) before evaluating cell proliferation, cAMP levels, and PKA phosphorylation. Cholangiocytes express MT1 and MT2, CLOCK, BMAL1, CRY1, and PER1 that were all upregulated following BDL. Administration of melatonin to BDL rats decreased IBDM, serum bilirubin and transaminases levels, the expression of all clock genes, cAMP levels, and PKA phosphorylation in cholangiocytes. In vitro, melatonin decreased the proliferation, cAMP levels, and PKA phosphorylation, decreases that were blocked by luzindole. Melatonin may be important in the management of biliary hyperplasia in human cholangiopathies. |
| Databáze: | OpenAIRE |
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