Clinic for Gastroenterology, Hepatology, and Infectiology, Heinrich Heine University, Düsseldorf, Germany.
Hepatology. 2014 Dec;60(6):2040-51. doi: 10.1002/hep.27136. Epub 2014 May 12.
The impairment of hepatic metabolism due to liver injury has high systemic relevance. However, it is difficult to calculate the impairment of metabolic capacity from a specific pattern of liver damage with conventional techniques. We established an integrated metabolic spatial-temporal model (IM) using hepatic ammonia detoxification as a paradigm. First, a metabolic model (MM) based on mass balancing and mouse liver perfusion data was established to describe ammonia detoxification and its zonation. Next, the MM was combined with a spatial-temporal model simulating liver tissue damage and regeneration after CCl4 intoxication. The resulting IM simulated and visualized whether, where, and to what extent liver damage compromised ammonia detoxification. It allowed us to enter the extent and spatial patterns of liver damage and then calculate the outflow concentrations of ammonia, glutamine, and urea in the hepatic vein. The model was validated through comparisons with (1) published data for isolated, perfused livers with and without CCl4 intoxication and (2) a set of in vivo experiments. Using the experimentally determined portal concentrations of ammonia, the model adequately predicted metabolite concentrations over time in the hepatic vein during toxin-induced liver damage and regeneration in rodents. Further simulations, especially in combination with a simplified model of blood circulation with three ammonia-detoxifying compartments, indicated a yet unidentified process of ammonia consumption during liver regeneration and revealed unexpected concomitant changes in amino acid metabolism in the liver and at extrahepatic sites.
The IM of hepatic ammonia detoxification considerably improves our understanding of the metabolic impact of liver disease and highlights the importance of integrated modeling approaches on the way toward virtual organisms.
由于肝损伤导致的肝代谢损伤具有很高的全身相关性。然而，使用传统技术很难从特定的肝损伤模式计算代谢能力的损伤。我们使用肝氨解毒作为范例，建立了一个综合代谢时空模型（IM）。首先，我们建立了一个基于质量平衡和小鼠肝灌注数据的代谢模型（MM），以描述氨解毒及其分区。接下来，将 MM 与模拟 CCl4 中毒后肝组织损伤和再生的时空模型相结合。由此产生的 IM 模拟并可视化了肝损伤在何处以及在何种程度上损害了氨解毒。它允许我们输入肝损伤的程度和空间模式，然后计算出肝静脉中氨、谷氨酰胺和尿素的流出浓度。该模型通过与（1）具有和不具有 CCl4 中毒的离体灌注肝脏的已发表数据以及（2）一组体内实验进行比较来验证。使用实验确定的门静脉氨浓度，该模型可以在啮齿动物中毒性肝损伤和再生过程中，充分预测时间依赖性肝静脉中代谢物浓度。进一步的模拟，特别是与具有三个氨解毒隔室的简化血液循环模型结合使用，表明在肝再生过程中存在一个尚未确定的氨消耗过程，并揭示了在肝脏和肝外部位氨基酸代谢的意外伴随变化。
肝氨解毒的 IM 大大提高了我们对肝病代谢影响的理解，并强调了综合建模方法在虚拟生物发展道路上的重要性。
