Potential conflict of interest: Nothing to report.
Reticulon 4B (Nogo-B) facilitates hepatocyte proliferation and liver regeneration in mice†
Article first published online: 19 MAR 2013
Copyright © 2013 American Association for the Study of Liver Diseases
Volume 57, Issue 5, pages 1992–2003, May 2013
How to Cite
Gao, L., Utsumi, T., Tashiro, K., Liu, B., Zhang, D., Swenson, E. S. and Iwakiri, Y. (2013), Reticulon 4B (Nogo-B) facilitates hepatocyte proliferation and liver regeneration in mice. Hepatology, 57: 1992–2003. doi: 10.1002/hep.26235
These authors contributed equally to this work.
- Issue published online: 22 APR 2013
- Article first published online: 19 MAR 2013
- Accepted manuscript online: 8 JAN 2013 05:29PM EST
- Manuscript Accepted: 28 NOV 2012
- Manuscript Received: 17 JUN 2012
- National Institutes of Health. Grant Numbers: R01-DK082600, K08-DK073404
- Yale Liver Center Morphology and Cell Isolation Cores and a Pilot Project Award. Grant Number: P30-34989
Nogo-B, also known as reticulon 4B, promotes liver fibrosis and cirrhosis by facilitating the transforming growth factor β (TGF-β) signaling pathway in activated hepatic stellate cells. The aim of this study was to determine the role of Nogo-B in hepatocyte proliferation and liver regeneration. Partial hepatectomy (PHx, 70% resection) was performed in male wild-type (WT) and Nogo-A/B knockout mice (referred to as Nogo-B KO mice). Remnant livers were isolated 2 hours, 5 hours, and 1, 2, 3, 7, and 14 days after PHx. Hepatocyte proliferation was assessed by Ki67 labeling index. Quantitative real-time polymerase chain reaction was performed for genes known to be involved in liver regeneration. Hepatocytes isolated from WT and Nogo-B KO mice were used to examine the role of Nogo-B in interleukin-6 (IL-6), hepatocyte growth factor (HGF), epidermal growth factor (EGF), and TGF-β signaling. Nogo-B protein levels increased in the regenerating livers in a time-dependent manner after PHx. Specifically, Nogo-B expression in hepatocytes gradually spread from the periportal toward the central areas by 7 days after PHx, but receded notably by 14 days. Nogo-B facilitated IL-6/signal transducer and activator of transcription 3 signaling, increased HGF-induced but not EGF-induced hepatocyte proliferation, and tended to reduce TGF-β1–induced suppression of hepatocyte proliferation in cultured hepatocytes. Lack of Nogo-B significantly induced TGF-β1 and inhibitor of DNA binding expression 1 day after PHx and IL-6 and EGF expression 2 days after PHx. Lack of Nogo-B delayed hepatocyte proliferation but did not affect the liver-to-body ratio in the regenerative process. Conclusion: Nogo-B expression in hepatocytes facilitates hepatocyte proliferation and liver regeneration. (HEPATOLOGY 2013)