P1 - Metabolic profiling of the hepatic sinusoid

点击翻译按钮获取中文摘要

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.