Premium
Reticulon 4B (Nogo‐B) is a novel regulator of hepatic fibrosis
Author(s) -
Zhang Dahai,
Utsumi Teruo,
Huang HuiChun,
Gao Lili,
Sangwung Panjamaporn,
Chung Chuhan,
Shibao Kazunori,
Okamoto Kohji,
Yamaguchi Koji,
Groszmann Roberto J.,
Jozsef Levente,
Hao Zhengrong,
Sessa William C.,
Iwakiri Yasuko
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24200
Subject(s) - cirrhosis , hepatic stellate cell , fibrosis , portal venous pressure , hepatic fibrosis , knockout mouse , portal hypertension , pathology , medicine , endocrinology , chemistry , receptor
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). Conclusion: 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. (H EPATOLOGY 2011;)