Data_Sheet_3_Network Modeling of Liver Metabolism to Predict Plasma Metabolite Changes During Short-Term Fasting in the Laboratory Rat.ZIP

The liver—a central metabolic organ that integrates whole-body metabolism to maintain glucose and fatty-acid regulation, and detoxify ammonia—is susceptible to injuries induced by drugs and toxic substances. Although plasma metabolite profiles are increasingly investigated for their potential to detect liver injury earlier than current clinical markers, their utility may be compromised because such profiles are affected by the nutritional state and the physiological state of the animal, and by contributions from extrahepatic sources. To tease apart the contributions of liver and non-liver sources to alterations in plasma metabolite profiles, here we sought to computationally isolate the plasma metabolite changes originating in the liver during short-term fasting. We used a constraint-based metabolic modeling approach to integrate central carbon fluxes measured in our study, and physiological flux boundary conditions gathered from the literature, into a genome-scale model of rat liver metabolism. We then measured plasma metabolite profiles in rats fasted for 5–7 or 10–13 h to test our model predictions. Our computational model accounted for two-thirds of the observed directions of change (an increase or decrease) in plasma metabolites, indicating their origin in the liver. Specifically, our work suggests that changes in plasma lipid metabolites, which are reliably predicted by our liver metabolism model, are key features of short-term fasting. Our approach provides a mechanistic model for identifying plasma metabolite changes originating in the liver.

肝脏是整合全身代谢以维持葡萄糖与脂肪酸稳态、执行氨解毒功能的核心代谢器官，易受药物与有毒物质诱导的损伤。尽管血浆代谢物谱（plasma metabolite profiles）的检测潜力日益受到关注，有望比现有临床标志物更早检出肝损伤，但其应用价值可能受限——此类谱图会受动物营养状态与生理状态，以及肝外来源贡献的影响。为厘清肝脏与肝外来源对血浆代谢物谱改变的贡献，本研究尝试通过计算方法分离短期禁食过程中源自肝脏的血浆代谢物变化。本研究采用约束基代谢建模 (constraint-based metabolic modeling) 方法，将本研究实测的中心碳通量与从文献中获取的生理通量边界条件，整合至大鼠肝脏代谢的基因组规模模型 (genome-scale model) 中。随后，我们对禁食5~7小时或10~13小时的大鼠进行血浆代谢物谱检测，以验证模型预测结果。我们的计算模型可解释三分之二的血浆代谢物观测变化方向（上调或下调），表明这些变化源自肝脏。具体而言，本研究显示，血浆脂质代谢物的变化可通过我们的肝脏代谢模型可靠预测，且该变化是短期禁食的关键特征。本研究提出的方法可为识别源自肝脏的血浆代谢物变化提供机制性模型。