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


CONCLUSIONS
Local modulation of melatonin synthesis may be important for management of the balance between biliary proliferation/damage that is typical of cholangiopathies. (HEPATOLOGY 2013).
Central Texas Veterans Health Care System, Temple, TX 76504, USA.
Anastasia
A
Renzi
Sharon
S
DeMorrow
Paolo
P
Onori
Guido
G
Carpino
Romina
R
Mancinelli
Fanyin
F
Meng
Julie
J
Venter
Mellanie
M
White
Antonio
A
Franchitto
Heather
H
Francis
Yuyan
Y
Han
Yoshiyuki
Y
Ueno
Giuseppina
G
Dusio
Kendal J
KJ
Jensen
John J
JJ
Greene
Shannon
S
Glaser
Eugenio
E
Gaudio
Gianfranco
G
Alpini
D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D017920:Antiporters / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D047068:Arylalkylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology*; D001653:Bile Ducts, Intrahepatic / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002779:Cholestasis / Q000378:metabolism* / Q000473:pathology*; D055785:Gene Knockdown Techniques; D008297:Male; D008550:Melatonin / Q000097:blood / Q000494:pharmacology; D051379:Mice; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism; D064606:SLC4A Proteins
D027321:Anion Transport Proteins; D000975:Antioxidants; D017920:Antiporters; D018809:Proliferating Cell Nuclear Antigen; D011985:Receptors, Serotonin; D064606:SLC4A Proteins; C520223:Aanat protein, rat; D047068:Arylalkylamine N-Acetyltransferase; D008550:Melatonin