Systems Biology of Cell Death in Hepatocytes
The processes of liver regeneration and liver disease are regulated by a complex network of soluble and cell-associated apoptotic and inflammatory signals. To obtain insights into the mechanistic interplay of these signals and to define new therapeutic strategies, the combination of experimental data and mathematical modeling is a promising systems biological approach. Here, we review recent results in death receptor-mediated hepatocyte apoptosis focusing on Fas/CD95 and TNFα-mediated cell death. In this context, we present two complementary approaches of modeling death receptor-mediated cell death in hepatocytes. On the one hand we describe an ODE model of TNFα and FasL sensitising, which was extended by adding the regulation of pJNK and the generation of ROS after combined TNFα and ActD treatment and in which a published NF-κB model was integrated. This model is suitable for the integration of further pathway models, thus contributing to a better understanding of the network. On the other hand a literature-based and in parts experimentally validated comprehensive Boolean model of the central intrinsic and extrinsic apoptosis pathways as well as pathways connected with them is described. In the future, the according mathematical models will be a valuable approach to understand the complex crosstalks and interactions within hepatocytes and between different cells in the liver. Thus, modeling of apoptosis in hepatocytes will proceed on different routes on the way to a functional representation of the whole liver.
This work was funded by the BMBF (German Federal Ministry of Education and Research) within the Virtual Liver Network (http://www.virtual-liver.de).
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