Circadian clock core component Bmal1 dictates cell cycle rhythm of proliferating hepatocytes during liver regeneration.
Circadian clock core component Bmal1 dictates cell cycle rhythm of proliferating hepatocytes during liver regeneration.
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生物钟核心成分 Bmal1 决定肝脏再生过程中肝细胞增殖的细胞周期节律。
DOI：
10.1152/ajpgi.00204.2021
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Dai,Guoli
中科院分区：
文献类型：
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作者：
Jiang,Huaizhou;Garcia,Veronica;Yanum,JenniferAbla;Lee,Joonyong;Dai,Guoli
在部分肝切除术（PH）后，大多数残余肝细胞同步进入并有节奏地通过细胞周期进行三个主要回合，以恢复失去的肝脏质量。生物钟的核心成分Bmal1是否以及如何调节这一过程仍然难以捉摸。我们对Bmal1 +/+和肝细胞特异性Bmal1敲除（Bmal1hep −/−）小鼠进行了PH，并比较了肝细胞周期的启动和进展。PH后，Bmal1 +/+肝细胞核DNA合成出现三个主要波。相反，在Bmal1hep −/−肝细胞中，核DNA合成的第一波延迟了12小时，第三波丢失。PH后，Bmal1 +/+肝细胞经历了三次主要的有丝分裂波，而Bmal1hep −/−肝细胞完全消除了有丝分裂振荡。PH后肝细胞周期节律性的这些Bmal1依赖性破坏伴随着一组细胞周期组分和调节剂的表达峰值抑制以及促有丝分裂信号分子c-Met和表皮生长因子受体的激活模式失调。此外，Bmal1 +/+肝细胞在PH后扩张时有节奏地积累脂肪，而这种现象在Bmal1hep −/−肝细胞中受到很大程度的抑制。此外，在肝再生的晚期阶段，肝细胞中Bmal 1的缺失导致氧化还原传感器Nrf2的激活，表明再生肝组织中的氧化应激状态。总的来说，我们证明了在肝再生过程中，Bmal1部分调节S期进展的振荡，完全控制M期进展的节律性，并在很大程度上控制复制肝细胞中脂肪代谢的波动，以及最终决定再生肝脏的氧化还原状态。新&值得注意的是，我们证明Bmal1在肝再生过程中集中控制细胞周期的同步性和节律性以及复制肝细胞中的脂质积累。Bmal1至少部分地通过确保细胞周期组分和调节剂的表达峰的形成以及促有丝分裂信号传导分子的激活的时间和水平来发挥这些作用。
After partial hepatectomy (PH), the majority of remnant hepatocytes synchronously enter and rhythmically progress through the cell cycle for three major rounds to regain lost liver mass. Whether and how the circadian clock core component Bmal1 modulates this process remains elusive. We performed PH onBmal1+/+and hepatocyte-specificBmal1knockout (Bmal1hep−/−) mice and compared the initiation and progression of the hepatocyte cell cycle. After PH,Bmal1+/+hepatocytes exhibited three major waves of nuclear DNA synthesis. In contrast, inBmal1hep−/−hepatocytes, the first wave of nuclear DNA synthesis was delayed by 12 h, and the third such wave was lost. Following PH,Bmal1+/+hepatocytes underwent three major waves of mitosis, whereasBmal1hep−/−hepatocytes fully abolished mitotic oscillation. These Bmal1-dependent disruptions in the rhythmicity of hepatocyte cell cycle after PH were accompanied by suppressed expression peaks of a group of cell cycle components and regulators and dysregulated activation patterns of mitogenic signaling molecules c-Met and epidermal growth factor receptor. Moreover,Bmal1+/+hepatocytes rhythmically accumulated fat as they expanded following PH, whereas this phenomenon was largely inhibited inBmal1hep−/−hepatocytes. In addition, during late stages of liver regrowth, Bmal1 absence in hepatocytes caused the activation of redox sensor Nrf2, suggesting an oxidative stress state in regenerated liver tissue. Collectively, we demonstrated that during liver regeneration, Bmal1 partially modulates the oscillation of S-phase progression, fully controls the rhythmicity of M-phase advancement, and largely governs fluctuations in fat metabolism in replicating hepatocytes, as well as eventually determines the redox state of regenerated livers.NEW & NOTEWORTHYWe demonstrated that Bmal1 centrally controls the synchronicity and rhythmicity of the cell cycle and lipid accumulation in replicating hepatocytes during liver regeneration. Bmal1 plays these roles, at least in part, by ensuring formation of the expression peaks of cell cycle components and regulators, as well as the timing and levels of activation of mitogenic signaling molecules.