P1 - Metabolic profiling of the hepatic sinusoid

研究单位“QualiPerF”的全面目标是编制一个计算模型，在肝脏手术的背景下包含肝脏血流和代谢功能之间的定量关系。从长远来看，这将支持手术计划和风险分层。可以认为，肝脏手术引起的血流灌注紊乱可能会影响肝脏的代谢功能。然而，整体功能可能不能反映细胞水平的情况，因为代谢途径沿肝窦呈带状分布在肝实质中。因此，在器官水平上了解肝脏的功能需要在细胞水平上的了解，以建立一个多尺度的计算模型来预测手术引起的血流灌注和功能变化。然而，虽然代谢区带本身已经被很好地记录下来，但在正弦水平上的血流灌注变化和代谢控制之间的定量关系以及它们之间的相互作用到目前为止还不清楚。我们假设肝细胞的代谢功能最终依赖于线粒体的氧化能力，为术后器官再生提供能量。然而，线粒体功能可能会因阈值灌流限制而耗尽，最终导致肝细胞功能障碍和代谢损伤。我们的项目“肝窦的代谢图谱”旨在将脂肪变性和手术诱导的肝脏血流灌注变化与肝细胞代谢控制的变化联系起来，并在正弦水平上耦合线粒体功能。我们将提供尚不为人所知的关于碳水化合物和脂肪代谢的带状分布和动态的定量数据，这些数据由脂质过载和肝脏手术引起的血流灌注变化来调节。此外，我们将定义未知的区带线粒体活性作为碳水化合物和脂肪代谢的函数，并将血流限制导致的线粒体功能障碍确定为术后肝功能衰竭的潜在病理机制。最后，我们将为在组织和细胞尺度上模拟碳水化合物和脂肪代谢的模型提供定量数据。因此，该项目为研究股联合项目在组织和细胞层面上的计算建模提供了数据，并支持在肝脏手术的背景下阐明代谢分区的灌流控制的生物学机制。研究股项目的相互迭代互动将支持实验的模型验证和文本改进，以改进模型预测和实验战略。

The comprehensive aim of the Research Unit “QualiPerF” is to compile a computational model encompassing the quantitative relationship between liver perfusion and metabolic functions in the context of liver surgery. In the long-term range this will support surgical planning and risk stratification. It may be assumed that liver surgery-induced perfusion perturbation may impact on hepatic metabolic functions. However, global function may not reflect the situation on the cellular level, since metabolic pathways are heterogeneously distributed in the liver parenchyma in a zonal pattern along the hepatic sinusoids. Therefore, the understanding of liver function on the organ level requires the understanding on the cellular level to establish a multi-scale computational model for the prediction of surgery-induced perfusion and function changes. Yet, while metabolic zonation per se is well documented, the quantitative relationship between perfusion changes and metabolic control on the sinusoidal level and their mutual interactions are unknown so far. We hypothesize that metabolic functions of the hepatocytes ultimately depend on the mitochondrial oxidative capacity providing energy for post-surgery organ regeneration. Yet, mitochondrial function may be exhausted by threshold perfusion restrictions, eventually causing hepatocyte dysfunction and metabolic impairment.Our project “Metabolic profiling of the hepatic sinusoid” aims to correlate steatosis- and surgery-induced changes in liver perfusion with changes of hepatocyte metabolic control coupled to mitochondrial function on the sinusoidal level in the rat model. We will provide as yet unknown quantitative data on the zonal distribution and dynamics of carbohydrate and lipid metabolism regulated by perfusion changes as induced by lipid overload and liver surgery. Further, we will define as yet unknown zonal mitochondrial activity as a function of carbohydrate and lipid metabolism, and identify mitochondrial dysfunction induced by flow restrictions as a potential pathomechanism in post-surgery liver failure. Finally, we will provide quantitative data for input into models of simulation of carbohydrate and lipid metabolism on the tissue and cellular scale. Thus, the project contributes data for computational modelling in joint projects of the Research Unit on the tissue and cellular level, and supports elucidation of biological mechanisms of perfusion control of metabolic zonation in the context of liver surgery. Mutual iterative interactions of the projects in the Research Unit will support model validation and textual refinement of experiments in order to improve model predictions as well as experimental strategies.