title: Gonadotropin-releasing hormone stimulates biliary proliferation by paracrine/autocrine mechanisms.
abstract: During cholestatic liver disease, there is dysregulation in the balance between biliary growth and loss in bile duct-ligated (BDL) rats modulated by neuroendocrine peptides via autocrine/paracrine pathways. Gonadotropin-releasing hormone (GnRH) is a trophic peptide hormone that modulates reproductive function and proliferation in many cell types. We evaluated the autocrine role of GnRH in the regulation of cholangiocyte proliferation. The expression of GnRH receptors was assessed in a normal mouse cholangiocyte cell line (NMC), sham, and BDL rats. The effect of GnRH administration was evaluated in normal rats and in NMC. GnRH-induced biliary proliferation was evaluated by changes in intrahepatic bile duct mass and the expression of proliferation and function markers. The expression and secretion of GnRH in NMC and isolated cholangiocytes was assessed. GnRH receptor subtypes GnRHR1 and GnRHR2 were expressed in cholangiocytes. Treatment with GnRH increased intrahepatic bile duct mass as well as proliferation and function markers in cholangiocytes. Transient knockdown and pharmacologic inhibition of GnRHR1 in NMC decreased proliferation. BDL cholangiocytes had increased expression of GnRH compared with normal rats, accompanied by increased GnRH secretion. In vivo and in vitro knockdown of GnRH decreased intrahepatic bile duct mass/cholangiocyte proliferation and fibrosis. GnRH secreted by cholangiocytes promotes biliary proliferation via an autocrine pathway. Disruption of GnRH/GnRHR signaling may be important for the management of cholestatic liver diseases.
authors: Department of Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas.
authors: Debolina
authors: D
authors: Ray
authors: Department of Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas.
authors: Yuyan
authors: Y
authors: Han
authors: Department of Anatomical, Histological, Forensic Medicine, and Orthopedics Sciences, Sapienza, Rome, Italy; Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy.
authors: Antonio
authors: A
authors: Franchitto
authors: Department of Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas; Scott & White Digestive Disease Research Center, Texas A&M Health Science Center College of Medicine, Temple, Texas.
authors: Sharon
authors: S
authors: DeMorrow
authors: Department of Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas; Scott & White Digestive Disease Research Center, Texas A&M Health Science Center College of Medicine, Temple, Texas; Department of Research, Central Texas Veterans Health Care System, Texas A&M Health Science Center College of Medicine, Temple, Texas.
authors: Fanyin
authors: F
authors: Meng
authors: Department of Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas.
authors: Julie
authors: J
authors: Venter
authors: Department of Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas; Scott & White Digestive Disease Research Center, Texas A&M Health Science Center College of Medicine, Temple, Texas.
authors: Matthew
authors: M
authors: McMillin
authors: Department of Research, Central Texas Veterans Health Care System, Texas A&M Health Science Center College of Medicine, Temple, Texas.
authors: Lindsey
authors: L
authors: Kennedy
authors: Department of Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas; Scott & White Digestive Disease Research Center, Texas A&M Health Science Center College of Medicine, Temple, Texas; Department of Research, Central Texas Veterans Health Care System, Texas A&M Health Science Center College of Medicine, Temple, Texas.
authors: Heather
authors: H
authors: Francis
authors: Department of Anatomical, Histological, Forensic Medicine, and Orthopedics Sciences, Sapienza, Rome, Italy.
authors: Paolo
authors: P
authors: Onori
authors: Department of Anatomical, Histological, Forensic Medicine, and Orthopedics Sciences, Sapienza, Rome, Italy.
authors: Romina
authors: R
authors: Mancinelli
authors: Department of Anatomical, Histological, Forensic Medicine, and Orthopedics Sciences, Sapienza, Rome, Italy.
authors: Eugenio
authors: E
authors: Gaudio
authors: Department of Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas; Scott & White Digestive Disease Research Center, Texas A&M Health Science Center College of Medicine, Temple, Texas; Department of Research, Central Texas Veterans Health Care System, Texas A&M Health Science Center College of Medicine, Temple, Texas. Electronic address: galpini@tamu.edu.
authors: Gianfranco
authors: G
authors: Alpini
authors: Department of Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas; Scott & White Digestive Disease Research Center, Texas A&M Health Science Center College of Medicine, Temple, Texas; Department of Research, Central Texas Veterans Health Care System, Texas A&M Health Science Center College of Medicine, Temple, Texas. Electronic address: sglaser@tamu.edu.
authors: Shannon S
authors: SS
authors: Glaser
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D001653:Bile Ducts, Intrahepatic / Q000166:cytology* / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008103:Liver Cirrhosis / Q000473:pathology; D008297:Male; D051379:Mice; D060172:Morpholinos / Q000008:administration & dosage / Q000494:pharmacology; D019899:Paracrine Communication / Q000187:drug effects; D011916:Rats, Inbred F344; D011966:Receptors, LHRH / Q000378:metabolism
chemical_list: D060172:Morpholinos; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP