CASyM winter school of Systems Medicine took place between March 29th and April 1st 2017 in Ljubljana, Slovenia and is entitled »The 3rd SysBioMed hands-on tutorial: Systems Medicine Approaches in Personalized Medicine«
1Centre for Functional Genomics and Bio-chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Slovenia,2Faculty of Computer and Information Science, University of Ljubljana, Slovenia
Introduction:SteatoNet (1) is a mathematical model describing complex interaction of the liver with peripheral tissues. It is composed of almost 200 reactions and includes metabolic, gene regulatory and signal transduction pathways (2). SteatoNet can easily be adapted to liver-associated pathologies such as non-alcoholic fatty liver disease. Moreover, it can be used to perform dynamical simulations even in the case of sparse experimental data.
Problem and Aim: Liver is one of the most sexually dimorphic organs. Wide spectrum of liver diseases is gender-specific. Sex-based differences were discovered also in mouce livers with hepatocyte deletion of Cyp51. This indicates that the influence of disrupted hepatic cholesterol synthesis on the whole body homeostasis differs between females and males (3). However, the disruption in cholesterol synthesis hepatocyte deletion of Cyp51 could not be reproduced in silico with the uniform SteatoNet model which is based on literature data that include mainly experiments on male mice. The aim of this work is to adapt the SteatoNet model to enable in silico analyses of liver metabolism interacting with other organs in both sexes.
Results: Androgen and estrogen receptor responses and their link with growth hormone release are the imperative aspects of sexual adaptation of SteatoNet. These inclusions are the main components of LiverSex computational model, which enables a detailed insights into the role of the female and male sex in developing the complex liver pathologies. The extensive sex-dependent changes in liver metabolism due to Cyp51 knock-out can be reproduced in silico by the LiverSex model.
Conclusion:LiverSex represents the adaptation of SteatoNet mathematical model. It can be used to predict the metabolic effects of sex hormone levels in the blood and their networking with liver and peripheral tissues. To our knowledge LiverSex represents the first gender-based multi-tissue and multi-level liver metabolic model.
References: 1. Naik, A., Rozman, D. & Belic, A. SteatoNet: the first integrated human metabolic model with multi-layered regulation to investigate liver-associated pathologies. PLoS Comput Biol, 2014. 10(12): p. e1003993. 2. Cvitanović, T., Reichert, M. C., Moškon, M., Mraz, M., Lammert, F., & Rozman, D. Large-scale computational models of liver metabolism: How far from the clinics?. Hepatology, 2017. DOI: 10.1002/hep.29268 3. Lorbek, G., et al., Lessons from hepatocyte-specific cyp51 knockout mice: impaired cholesterol synthesis leads to oval cell-driven liver injury. Sci Rep, 2015. 5: p. 8777.
2006 - University of Ljubljana, Faculty of Medicine, Center for Functional Genomics and Bio-chips.