title: Knockout of alpha-calcitonin gene-related peptide reduces cholangiocyte proliferation in bile duct ligated mice.
abstract: The role of sensory innervation in the regulation of liver physiology and the pathogenesis of cholestatic liver disease are undefined. Biliary proliferation has been shown to be coordinately controlled by parasympathetic and sympathetic innervation of the liver. The aim of our study was to address the role of the sensory neuropeptide calcitonin gene-related peptide (alpha-CGRP) in the regulation of cholangiocyte proliferation during cholestasis induced by extrahepatic bile duct obstruction (BDL). Our study utilized a knockout (KO) mouse model, which lacks the sensory neuropeptide alpha-CGRP. Wild-type (WT) and alpha-CGRP KO mice were subjected to sham surgery or BDL for 3 and 7 days. In addition, immediately after BDL, WT and KO mice were administered the CGRP receptor antagonist (CGRP(8-37)) for 3 and 7 days by osmotic minipumps. Liver sections and isolated cholangiocytes were evaluated for proliferation markers. Isolated WT BDL (3 days) cholangiocytes were stimulated with alpha- and beta-CGRP and evaluated for proliferation and cAMP-mediated signaling. Lack of alpha-CGRP inhibits cholangiocyte proliferation induced by BDL at both 3 and 7 days. BDL-induced cholangiocyte proliferation in WT mice was associated with increases of circulating alpha-CGRP levels. In vitro, alpha- and beta-CGRP stimulated proliferation in purified BDL cholangiocytes, induced elevation of cAMP levels, and stimulated the activation of cAMP-dependent protein kinase A and cAMP response element binding protein DNA binding. In conclusion, sensory innervation of the liver and biliary expression of alpha-CGRP play an important role in the regulation of cholangiocyte proliferation during cholestasis.
authors.affiliation: Department of Medicine, Scott & White Hospital, The Texas A&M University System Health Science Center, College of Medicine, Temple, TX 76504, USA.
authors.forename: Shannon S
authors.initials: SS
authors.lastname: Glaser
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ueno
authors.forename: Sharon
authors.initials: S
authors.lastname: DeMorrow
authors.forename: Valorie L
authors.initials: VL
authors.lastname: Chiasson
authors.forename: Khurshed A
authors.initials: KA
authors.lastname: Katki
authors.forename: Julie
authors.initials: J
authors.lastname: Venter
authors.forename: Heather L
authors.initials: HL
authors.lastname: Francis
authors.forename: Ian M
authors.initials: IM
authors.lastname: Dickerson
authors.forename: Donald J
authors.initials: DJ
authors.lastname: DiPette
authors.forename: Scott C
authors.initials: SC
authors.lastname: Supowit
authors.forename: Gianfranco D
authors.initials: GD
authors.lastname: Alpini
mesh_terms: D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001659:Biliary Tract / Q000166:cytology; D015740:Calcitonin Gene-Related Peptide / Q000097:blood / Q000378:metabolism*; D049109:Cell Proliferation; D002761:Cholangitis / Q000378:metabolism / Q000503:physiopathology*; D001651:Cholestasis, Extrahepatic / Q000503:physiopathology*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D015740:Calcitonin Gene-Related Peptide