Modeling the pathogenesis of pericentral steatosis Influence of oxygen on fat accumulation and production of reactive oxygen species

• Applicants: Professorin Dr. Uta Dahmen; Dr. Jana Schleicher
• Subject Area: Gastroenterology ; Bioinformatics and Theoretical Biology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 282224468

A shortage of donor organs for liver transplantation demands the extension of donor organ criteria, so that also suboptimal organs, such as steatotic livers, can be used for liver transplantation. However, transplanting steatotic livers is accompanied by an increased rate of complications and rejections. Steatotic livers suffer from ischemia-reperfusion injury due to reinforced production of reactive oxygen species (ROS). The degree of ROS production depends strongly on the metabolism and oxygen supply in the steatotic liver. In our project, we want to evaluate the relationship between ROS production, fat accumulation and oxygen supply by the use of mathematical modeling. In doing so, we focus on the hardly addressed role of metabolic zonation along the hepatic blood vessels, because it determines the spatial arrangement of oxygen supply and the development of hypoxia.We will verify the general mechanisms in the pathogenesis of zonated fat accumulation and uncover the role of the altered oxygen supply in steatotic livers for the production of ROS. The project is aimed to propose specific hypotheses in regard to a reduced ROS burden during ischemia of steatotic livers. This ought to happen through an iterative cycle of modeling and experiments. In a first step, we implement models (ordinary differential equations) of hepatic lipid metabolism and ROS production for the fat-induced and the alcohol-induced fatty liver pathogenesis. Here the already implemented single-cell model of hepatic fat accumulation (Schleicher et al. 2014) will be expanded towards a zonated multi-cell model. In the next step, the developed models will be calibrated and validated by experimental data. The analysis of the models under different parameter sets allows the evaluation of the role of oxygen for fat accumulation and ROS production. Based on the results, we will propose hypotheses in regard to a reduced ROS production in steatotic livers and test them in silico. Subsequently, the hypotheses will be transferred to ischemia-reperfusion experiments. Finally, the project will provide working points to increase the tolerance of steatotic livers to ischemia.

• DFG Programme: Research Grants