title: Neuropeptide Y inhibits biliary hyperplasia of cholestatic rats by paracrine and autocrine mechanisms.
abstract: Neuropeptide Y (NPY) exerts its functions through six subtypes of receptors (Y₁-Y₆). Biliary homeostasis is regulated by several factors through autocrine/paracrine signaling. NPY inhibits cholangiocarcinoma growth; however, no information exists regarding the autocrine/paracrine role of NPY on biliary hyperplasia during cholestasis. The aims of this study were to determine: 1) the expression of NPY and Y₁-Y₅ in cholangiocytes and 2) the paracrine/autocrine effects of NPY on cholangiocyte proliferation. Normal or bile duct ligation (BDL) rats were treated with NPY, neutralizing anti-NPY antibody, or vehicle for 7 days. NPY and NPY receptor (NPYR) expression was assessed in liver sections and isolated cholangiocytes. NPY secretion was assessed in serum and bile from normal and BDL rats, as well as supernatants from normal and BDL cholangiocytes and normal rat cholangiocyte cell line [intrahepatic normal cholangiocyte culture (NRICC)]. We evaluated intrahepatic bile ductal mass (IBDM) in liver sections and proliferation in cholangiocytes. With the use of NRICC, the effects of NPY or anti-NPY antibody on cholangiocyte proliferation were determined. The expression of NPY and all NPYR were increased after BDL. NPY levels were lower in serum and cholangiocyte supernatant from BDL compared with normal rats. NPY secretion from NRICC was detected at both the basolateral and apical domains. Chronic NPY treatment decreased proliferating cellular nuclear antigen (PCNA) expression and IBDM in BDL rats. Administration of anti-NPY antibody to BDL rats increased cholangiocyte proliferation and IBDM. NPY treatment of NRICC decreased PCNA expression and increased the cell cycle arrest, whereas treatment with anti-NPY antibody increased proliferation. Therapies targeting NPY-mediated signaling may prove beneficial for the treatment of cholangiopathies.
authors.affiliation: Research, Central Texas Veterans Health Care System, Temple, TX 76504, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: DeMorrow
authors.forename: Fanyin
authors.initials: F
authors.lastname: Meng
authors.forename: Julie
authors.initials: J
authors.lastname: Venter
authors.forename: Dinorah
authors.initials: D
authors.lastname: Leyva-Illades
authors.forename: Heather
authors.initials: H
authors.lastname: Francis
authors.forename: Gabriel
authors.initials: G
authors.lastname: Frampton
authors.forename: Hae Yong
authors.initials: HY
authors.lastname: Pae
authors.forename: Matthew
authors.initials: M
authors.lastname: Quinn
authors.forename: Paolo
authors.initials: P
authors.lastname: Onori
authors.forename: Shannon
authors.initials: S
authors.lastname: Glaser
authors.forename: Kelly
authors.initials: K
authors.lastname: McDaniel
authors.forename: Romina
authors.initials: R
authors.lastname: Mancinelli
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
authors.forename: Antonio
authors.initials: A
authors.lastname: Franchitto
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D019898:Autocrine Communication / Q000502:physiology*; D001653:Bile Ducts, Intrahepatic / Q000737:chemistry / Q000473:pathology* / Q000503:physiopathology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002779:Cholestasis / Q000473:pathology* / Q000503:physiopathology; D006706:Homeostasis; D006965:Hyperplasia; D008297:Male; D009478:Neuropeptide Y / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D019899:Paracrine Communication / Q000502:physiology*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D017476:Receptors, Neuropeptide Y / Q000032:analysis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D057134:Antibodies, Neutralizing; D009478:Neuropeptide Y; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D017476:Receptors, Neuropeptide Y
keywords: biliary epithelium; cell cycle; neurotransmitters; proliferation