Abstract：
Hepatocyte lipid and glucose metabolism is regulated not only by major hormones like insulin and glucagon but also by many other factors, including calcium ions. Recently, mitochondria-associated membrane (MAM) dysfunction combined with incorrect IP3-receptor regulation has been shown to result in abnormal calcium signaling in hepatocytes. This dysfunction could further lead to hepatic metabolism pathology. However, the exact contribution of MAM dysfunction, incorrect IP3-receptor regulation and insulin resistance to the calcium-insulin-glucagon interplay is not understood yet. In this work, we analyze the role of abnormal calcium signaling and insulin dysfunction in hepatocytes by proposing a model of hepatocyte metabolic regulatory network with a detailed focus on the model construction details besides the biological aspect. In this work, we analyze the role of abnormal calcium signaling and insulin dysfunction in hepatocytes by proposing a model of hepatocyte metabolic regulatory network. We focus on the model construction details, model validation, and predictions. We describe the dynamic regulation of signaling processes by sigmoid Hill function. In particular, we study the effect of both the Hill function slope and the distance between Hill function extremes on metabolic processes in hepatocytes as a model of nonspecific insulin dysfunction. We also address the significant time difference between characteristic time of glucose hepatic processing and a typical calcium oscillation period in hepatocytes. Our modeling results show that calcium signaling dysfunction results in an abnormal increase in postprandial glucose levels, an abnormal glucose decrease in fasting, and a decreased amount of stored glycogen. An insulin dysfunction of glucose phosphorylation, glucose dephosphorylation, and glycogen breakdown also cause a noticeable effect. We also get some insight into the so-called hepatic insulin resistance paradox, confirming the hypothesis regarding indirect insulin action on hepatocytes via dysfunctional adipocyte lipolysis.
摘要：
肝细胞的脂质和葡萄糖代谢不仅受胰岛素和胰高血糖素等主要激素的调节，而且还受许多其他因素的调节。包括钙离子。最近,线粒体相关膜（MAM）功能障碍与不正确的IP3受体调节已被证明会导致肝细胞中异常的钙信号传导。这种功能障碍可进一步导致肝代谢病理。然而,MAM功能障碍的确切贡献，不正确的IP3受体调节和对钙-胰岛素-胰高血糖素相互作用的胰岛素抵抗尚不清楚.在这项工作中,我们分析了异常钙信号和胰岛素功能障碍在肝细胞中的作用，提出了一个模型的肝细胞代谢调控网络，并详细关注模型的构建细节，除了生物学方面。在这项工作中,我们通过建立肝细胞代谢调节网络模型，分析了异常钙信号和胰岛素功能障碍在肝细胞中的作用。我们专注于模型构建细节，模型验证，和预测。我们描述了sigmoidHill函数对信号过程的动态调节。特别是,作为非特异性胰岛素功能障碍模型,我们研究了Hill功能斜率和Hill功能极值之间的距离对肝细胞代谢过程的影响.我们还解决了葡萄糖肝处理的特征时间与肝细胞中典型的钙振荡周期之间的显着时间差。我们的建模结果表明，钙信号功能障碍导致餐后葡萄糖水平异常增加，空腹血糖异常下降，和储存的糖原量减少。葡萄糖磷酸化的胰岛素功能障碍，葡萄糖去磷酸化，糖原分解也会引起明显的影响。我们还对所谓的肝胰岛素抵抗悖论有所了解，证实了关于胰岛素通过功能失调的脂肪细胞脂解作用对肝细胞的间接作用的假设。
