The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism--insights from mathematical modeling.
The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism--insights from mathematical modeling.
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DOI：
10.1186/s12915-016-0237-6
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发表时间：
2016-03-02
期刊：
影响因子：
5.4
通讯作者：
Berndt N
中科院分区：
文献类型：
--
作者：
Bulik S;Holzhütter HG;Berndt N
细胞代谢对变化的外部条件的适应是通过酶和转运蛋白活性的调节变化来实现的。激素依赖性可逆酶磷酸化和反应物和变构效应物的浓度变化是快速动力学酶调节的主要类型，而在较长的时间尺度上，蛋白质丰度的变化也可能起作用。在这里，我们使用了一个全面的数学模型，大鼠肝细胞的肝葡萄糖代谢，以破译不同的监管模式的相对重要性和它们之间的相互依赖性，在肝脏控制血糖稳态。模型模拟揭示了在不同的生理环境（饥饿，随意营养供应，糖尿病）的肝脏代谢的能力，以抵消血浆葡萄糖的变化显着差异。酶丰度的变化调整代谢输出预期的生理需求，但可能会变成一个监管不利，如果突然发生意外的外部条件的变化。酶活性的变构和激素控制使肝脏能够呈现广泛的代谢状态，甚至可以完全逆转仅由酶丰度变化引起的通量变化。代谢控制分析表明，肝脏葡萄糖代谢的控制主要是由酶单独发挥，这是不同的酶丰度，可逆磷酸化和变构效应的改变控制。在肝脏葡萄糖代谢中，通过反应物的变化、变构效应和可逆磷酸化来调节酶活性与关键调节酶的蛋白质丰度的变化同样重要。本文的在线版本（doi：10.1186/s12915-016-0237-6）包含补充材料，可供授权用户使用。
Adaptation of the cellular metabolism to varying external conditions is brought about by regulated changes in the activity of enzymes and transporters. Hormone-dependent reversible enzyme phosphorylation and concentration changes of reactants and allosteric effectors are the major types of rapid kinetic enzyme regulation, whereas on longer time scales changes in protein abundance may also become operative. Here, we used a comprehensive mathematical model of the hepatic glucose metabolism of rat hepatocytes to decipher the relative importance of different regulatory modes and their mutual interdependencies in the hepatic control of plasma glucose homeostasis. Model simulations reveal significant differences in the capability of liver metabolism to counteract variations of plasma glucose in different physiological settings (starvation, ad libitum nutrient supply, diabetes). Changes in enzyme abundances adjust the metabolic output to the anticipated physiological demand but may turn into a regulatory disadvantage if sudden unexpected changes of the external conditions occur. Allosteric and hormonal control of enzyme activities allow the liver to assume a broad range of metabolic states and may even fully reverse flux changes resulting from changes of enzyme abundances alone. Metabolic control analysis reveals that control of the hepatic glucose metabolism is mainly exerted by enzymes alone, which are differently controlled by alterations in enzyme abundance, reversible phosphorylation, and allosteric effects. In hepatic glucose metabolism, regulation of enzyme activities by changes of reactants, allosteric effects, and reversible phosphorylation is equally important as changes in protein abundance of key regulatory enzymes. The online version of this article (doi:10.1186/s12915-016-0237-6) contains supplementary material, which is available to authorized users.