Hydrogen Peroxide Modulates the Proliferation/Quiescence Switch in the Liver During Embryonic Development and Posthepatectomy Regeneration
Hydrogen Peroxide Modulates the Proliferation/Quiescence Switch in the Liver During Embryonic Development and Posthepatectomy Regeneration
复制标题
过氧化氢在胚胎发育和肝切除术后再生过程中调节肝脏的增殖/静止开关。
DOI：
10.1089/ars.2014.5960
复制
发表时间：
2015-04-10
影响因子：
6.6
通讯作者：
Hai, Chun-Xu
中科院分区：
文献类型：
--
作者：
Bai, Hua;Zhang, Wei;Hai, Chun-Xu
旨在
肝脏在正常发育和再生过程中通过许多信号通路的协调活动经历增殖速率的显著变化。然而，对这些信号通路上游的事件知之甚少。在这里，我们探讨过氧化氢（H2O2）对这些途径的调节作用，在肝脏发育和再生的背景下。
结果
我们发现，H2O2生产过程中的肝脏发育和部分肝切除术后，严格的时间调节特定的H2O2生产和清除蛋白和剂量依赖性触发两个不同的途径。持续升高的H2O2水平是激活ERK信号传导所必需的，并触发从静止到增殖的转变。相反，持续降低的H2O2水平是激活p38信号传导所必需的，并触发从增殖到静止的转变。这两种事件都影响细胞周期蛋白D和Rb途径，并参与肝脏发育和再生。药理学降低H2O2水平降低了胎肝细胞增殖的程度，并延迟了肝再生的开始。H2O2水平在成年肝细胞中的化学增强触发增殖并延迟肝再生的终止。
创新
我们的研究结果挑战了H2O2作为一种有害的应激源在肝损伤的传统观点，并确定了一个新的内源性H2O2在肝脏发育和再生的作用。
结论
内源性H2O2的产生在肝脏发育和再生过程中受到严格调节。H2 O2通过浓度依赖性激活ERK或p38途径，构成肝细胞增殖和静止转变的重要触发因素。
AIMS
The liver undergoes marked changes in the rate of proliferation during normal development and regeneration through the coordinated activity of numerous signaling pathways. Little is known, however, about the events that act upstream of these signaling pathways. Here, we explore the modulatory effects of hydrogen peroxide (H2O2) on these pathways in the context of liver development and regeneration.
RESULTS
We show that H2O2 production during liver development and after partial hepatectomy is tightly regulated in time by specific H2O2-producing and scavenging proteins and dose dependently triggers two distinct pathways. Sustained elevated H2O2 levels are required for the activation of ERK signaling and trigger a shift from quiescence to proliferation. Contrastingly, sustained decreased H2O2 levels are required for the activation of p38 signaling and trigger a shift from proliferation to quiescence. Both events impact the cyclin D and Rb pathways and are involved in liver development and regeneration. Pharmacological lowering of H2O2 levels reduces the extent of fetal hepatocyte proliferation and delays the onset of liver regeneration. Chemical augmentation of H2O2 levels in adult hepatocytes triggers proliferation and delays the termination of liver regeneration.
INNOVATION
Our results challenge the traditional view of H2O2 as a deleterious stressor in response to liver damage and identify a novel role of endogenous H2O2 in liver development and regeneration.
CONCLUSIONS
Endogenous H2O2 production is tightly regulated during liver development and regeneration. H2O2 constitutes an important trigger for the proliferation and quiescence transition in hepatocytes via the concentration-dependent activation of the ERK or p38 pathway.