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Notch signaling pathway regulates cell cycle in proliferating hepatocytes involved in liver regeneration
Author(s) -
Zhang Fen,
Zhang Jinglong,
Li Xiao,
Li Bowei,
Tao Kaishan,
Yue Shuqiang
Publication year - 2018
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/jgh.14110
Subject(s) - notch signaling pathway , liver regeneration , hepatocyte , protein kinase b , regeneration (biology) , microbiology and biotechnology , cell cycle , signal transduction , cell growth , cancer research , biology , cell , biochemistry , in vitro
Background and Aim It has been well documented that Notch signaling is involved in liver regeneration. However, the exact molecular mechanism mediating this process is not fully elucidated. The current study aimed to investigate the role of Notch signaling regulating cell cycle in proliferating hepatocytes in liver regeneration after partial hepatectomy (PHx, 67% resection) and the related molecular mechanism. Methods Partial hepatectomy was performed in Sprague Dawley rats, and remnant livers were harvested 0, 1, 3, 5, and 7 days after operation, and primary hepatocytes were isolated to investigate the molecular mechanism. Results Notch signaling activation and hepatocyte proliferation were significantly increased after PHx, while treatment with FLI‐06, the inhibitor of γ‐secreting enzyme, blocked these trends. Besides, inhibition of Notch signaling led to dysregulation of cell cycle and cell‐cycle components. Furthermore, Akti‐1/2 (a selective Akt inhibitor) and PX‐478 (a selective Hif‐1α inhibitor) inhibited hepatocyte proliferation and liver regeneration after PHx, and the effect of downstream molecules activation by Jagged‐1 (Notch‐1 ligand) in hepatocytes was abolished by FLI‐06, Akti‐1/2, and PX‐478. Conclusion The current study demonstrated for the first time that Notch signaling regulated cell cycle in proliferating hepatocytes involved in liver regeneration through NICD/Akt Akt/Hif‐1α pathway.