Fen Zhang1, Jinglong Zhang2, Xiao Li1, Bowei Li3, Kaishan Tao1, Shuqiang Yue1. 1. Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China. 2. Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China. 3. Department of 2nd Surgery, Baoji City Chinese Medicine Hospital, Baoji, Shanxi, China.
Abstract
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.
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/AktAkt/Hif-1α pathway.
Authors: Nuria Oliva-Vilarnau; Simona Hankeova; Sabine U Vorrink; Souren Mkrtchian; Emma R Andersson; Volker M Lauschke Journal: Front Med (Lausanne) Date: 2018-07-04
Authors: Yana V Kiseleva; Sevak Z Antonyan; Tatyana S Zharikova; Kirill A Tupikin; Dmitry V Kalinin; Yuri O Zharikov Journal: World J Hepatol Date: 2021-03-27