Modulation of the biliary expression of arylalkylamine N-acetyltransferase alters the autocrine proliferative responses of cholangiocytes

Background & Aims: Secretin stimulates ductal secretion by interacting with secretin receptor (SR) activating 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 via downregulation of cAMP-dependent signaling. No data exists regarding the role of melatonin synthesized locally by cholangiocytes in the autocrine regulation of biliary growth and function.Methods: In this study, we evaluated: (i) the expression of arylalkylamine N-acetyltransferase (AANAT, the rate-limiting enzyme for melatonin synthesis from serotonin) in cholangiocytes; and (ii) the effect of local modulation of biliary AANAT expression on the autocrine proliferative/secretory responses of cholangiocytes. Results: In the liver, cholangiocytes (and to lower extent BDL hepatocytes) expressed AANAT. AANAT expression and melatonin secretion: (i) increased in BDL compared to normal rats and BDL rats treated with melatonin; and (ii) 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 the management of the balance between biliary proliferation/damage that is typical of cholangiopathies.