Modeling the pathogenesis of pericentral steatosis Influence of oxygen on fat accumulation and production of reactive oxygen species
Bioinformatics and Theoretical Biology
Final Report Abstract
What role does oxygen supply play in fatty liver disease, also known as steatosis? We addressed this question in the present DFG project. First, we addressed the basic mechanisms of steatosis and the causes of its zonation (i.e., spatial heterogeneous fat storage in liver cells along blood vessels). Second, we addressed the question of how to explain the reduced ischemic tolerance (i.e., ability to cope with the loss of blood supply) of fatty livers compared with nonfatty organs. Interruption of oxygen supply (hypoxia), which occurs during liver transplantation, leads to the formation of reactive oxygen species (ROS), which damage liver cells. Experimental possibilities for detecting oxidative processes are limited, suggesting the use of mathematical modeling to address our question. Two specific sub-objectives were pursued using mathematical modeling: (I) verify basic mechanisms in the pathogenesis of zonated steatosis and (II) evaluate the importance of altered oxygen conditions in steatotic livers for ROS production under normal and hypoxic conditions. Using a mathematical model, we demonstrated that the oxygen gradient, but not the fatty acid gradient, contributes significantly to pericentral steatosis under a high-fat diet. Oxidative processes in lipid metabolism play a crucial role. In addition, the uptake process of fatty acids from the blood into liver cells was shown to play a crucial role in the zonation of steatosis. Thus, we were able to reveal a mechanism in zonation that has hardly been considered so far. Based on our model results, it seems essential for a deeper understanding of steatosis formation to direct more research toward evaluating the uptake capacities of fatty acids in liver cells. Using immunohistochemical staining of liver sections, we were able to show that the molecule CD36, which is involved in fatty acid transport, does not follow a zonal distribution pattern, but is expressed homogeneously along the sinusoids in human liver tissue. This homogeneity is also observed in the presence of fibrosis or steatosis. Furthermore, we investigated the cause of reduced ischemia tolerance in severe hepatic steatosis. By establishing a mathematical model, we aimed to predict cell injury after oxygen deprivation and during reperfusion. Using this modeling approach, we predict a possible underlying interaction network for high oxidative stress. A bistable behavior conditioned by the interactions between the production of ROS and the extent of cellular damage is revealed. Here, we uncovered the basic structural elements to generate the bistability.
Publications
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(2017). "Computational modeling in liver surgery." Frontiers in Physiology 8: 906
Christ, B., U. Dahmen, K.-H. Herrmann, M. König, J. R. Reichenbach, T. Ricken, J. Schleicher, L. O. Schwen, S. Vlaic and N. Waschinsky
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(2017). "Zonation of hepatic fat accumulation: insights from mathematical modelling of nutrient gradients and fatty acid uptake." Journal of the Royal Society Interface 14(133)
Schleicher, J., U. Dahmen, R. Guthke and S. Schuster
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(2018). "Computational modeling of oxidative stress in fatty livers elucidates the underlying mechanism of the increased susceptibility to ischemia/reperfusion injury." Computational and Structural Biotechnology Journal 16: 511-522
Schleicher, J. and U. Dahmen
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(2021). Introduction to In Silico Modeling to Study ROS Dynamics. In: Methods in Molecular Biology 2202: 1-32, Springer Nature
Schleicher, J.
