Correnti Jason M, Cook Daniel, Aksamitiene Edita, Swarup Aditi, Ogunnaike Babatunde, Vadigepalli Rajanikanth, Hoek Jan B
MitoCare Center for Mitochondrial Research, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
J Physiol. 2015 Jan 15;593(2):365-83. doi: 10.1113/jphysiol.2014.284109.
Following partial hepatectomy, the liver initiates a regenerative programme involving hepatocyte priming and replication driven by the coordinated actions of cytokine and growth factors. We investigated the mechanisms underlying adiponectin's (Adn) regulation of liver regeneration through modulation of these mediators. Adn(-/-) mice showed delayed onset of hepatocyte replication, but accelerated cell cycle progression relative to wild-type mice, suggesting Adn has multiple effects fine-tuning the kinetics of liver regeneration. We developed a computational model describing the molecular and physiological kinetics of liver regeneration in Adn(-/-) mice. We employed this computational model to evaluate the underlying regulatory mechanisms. Our analysis predicted that Adn is required for an efficient early cytokine response to partial hepatectomy, but is inhibitory to later growth factor actions. Consistent with this prediction, Adn knockout reduced hepatocyte responses to interleukin-6 during the priming phase, but enhanced growth factor levels through peak hepatocyte replication. By contrast, supraphysiological concentrations of Adn resulting from rosiglitazone treatment suppressed regeneration by reducing growth factor levels during S phase, consistent with computational predictions. Together, these results revealed that Adn fine-tunes the progression of liver regeneration through dynamically modulating molecular mediator networks and cellular interactions within the liver.
部分肝切除术后，肝脏启动一个再生程序，该程序涉及由细胞因子和生长因子的协同作用驱动的肝细胞启动和复制。我们研究了脂联素（Adn）通过调节这些介质来调控肝脏再生的潜在机制。与野生型小鼠相比，Adn基因敲除（Adn(-/-)）小鼠的肝细胞复制起始延迟，但细胞周期进程加速，这表明Adn对肝脏再生动力学具有多种微调作用。我们建立了一个计算模型，描述Adn(-/-)小鼠肝脏再生的分子和生理动力学。我们使用这个计算模型来评估潜在的调控机制。我们的分析预测，Adn是肝脏对部分肝切除产生有效早期细胞因子反应所必需的，但对后期生长因子的作用具有抑制性。与这一预测一致，Adn基因敲除降低了启动阶段肝细胞对白介素-6的反应，但在肝细胞复制高峰期提高了生长因子水平。相比之下，罗格列酮治疗导致的超生理浓度的Adn通过在S期降低生长因子水平来抑制再生，这与计算预测一致。这些结果共同表明，Adn通过动态调节肝脏内的分子介质网络和细胞相互作用来微调肝脏再生的进程。
