title: Reticulon 4B (Nogo-B) is a novel regulator of hepatic fibrosis.
abstract: Nogo-B, also known as Reticulon 4B, plays important roles in vascular injuries. Its function in the liver is not understood. The aim of this study was to characterize Nogo-B in liver fibrosis and cirrhosis. Nogo-B distribution was assessed in normal and cirrhotic human liver sections. We also determined the levels of liver fibrosis in wild-type (WT) and Nogo-A/B knockout (NGB KO) mice after sham operation or bile duct ligation (BDL). To investigate the mechanisms of Nogo-B's involvement in fibrosis, hepatic stellate cells were isolated from WT and NGB KO mice and transformed into myofibroblasts. Portal pressure was measured to test whether Nogo-B gene deletion could ameliorate portal hypertension. In normal livers, Nogo-B expression was found in nonparenchymal cells, whereas its expression in hepatocytes was minimal. Nogo-B staining was significantly elevated in cirrhotic livers. Fibrosis was significantly increased in WT mice 4 weeks after BDL compared with NGB KO mice. The absence of Nogo-B significantly reduced phosphorylation of Smad2 levels upon transforming growth factor β (TGF-β) stimulation. Reconstitution of the Nogo-B gene into NGB KO fibroblasts restored Smad2 phosphorylation. Four weeks after BDL, portal pressure was significantly increased in WT mice by 47%, compared with sham-operated controls (P = 0.03), whereas such an increase in portal pressure was not observed in NGB KO mice (P = NS).
  
  
  CONCLUSIONS
  Nogo-B regulates liver fibrosis, at least in part, by facilitating the TGFβ/Smad2 signaling pathway in myofibroblasts. Because absence of Nogo-B ameliorates liver fibrosis and portal hypertension, Nogo-B blockade may be a potential therapeutic target in fibrosis/cirrhosis.
authors.affiliation: Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Dahai
authors.initials: D
authors.lastname: Zhang
authors.forename: Teruo
authors.initials: T
authors.lastname: Utsumi
authors.forename: Hui-Chun
authors.initials: HC
authors.lastname: Huang
authors.forename: Lili
authors.initials: L
authors.lastname: Gao
authors.forename: Panjamaporn
authors.initials: P
authors.lastname: Sangwung
authors.forename: Chuhan
authors.initials: C
authors.lastname: Chung
authors.forename: Kazunori
authors.initials: K
authors.lastname: Shibao
authors.forename: Kohji
authors.initials: K
authors.lastname: Okamoto
authors.forename: Koji
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Roberto J
authors.initials: RJ
authors.lastname: Groszmann
authors.forename: Levente
authors.initials: L
authors.lastname: Jozsef
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Hao
authors.forename: William C
authors.initials: WC
authors.lastname: Sessa
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Iwakiri
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D006975:Hypertension, Portal / Q000517:prevention & control; D008099:Liver / Q000737:chemistry; D008103:Liver Cirrhosis / Q000209:etiology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000235:genetics / Q000502:physiology*; D000070798:Nogo Proteins; D051381:Rats; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D009185:Myelin Proteins; D000070798:Nogo Proteins; C000603199:RTN4 protein, human; C000603201:Rtn4 protein, mouse; C000603197:Rtn4 protein, rat; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta