No abstract

Metabolic alterations can serve as targets for diagnosis and therapy of cancer. Due to the highly complex regulation of cellular metabolism, definite identification of metabolic pathway alterations remains challenging and requires sophisticated experimentation. Here, we applied a comprehensive kinetic model of the central carbon metabolism (CCM) to characterize metabolic reprogramming in murine liver cancer. We show that relative differences of protein abundances of metabolic enzymes obtained by mass spectrometry can be used to scale maximal enzyme capacities. Model simulations predicted tumor-specific alterations of various components of the CCM, a selected number of which were subsequently verified by in vitro and in vivo experiments. Furthermore, we demonstrate the ability of the kinetic model to identify metabolic pathways whose inhibition results in selective tumor cell killing. Our systems biology approach establishes that combining cellular experimentation with computer simulations of physiology-based metabolic models enables a comprehensive understanding of deregulated energetics in cancer.

Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common type of chronic liver disease in developed nations. Here, we present a generic model of free fatty acid (FFA)-induced NAFLD that constitutes the liver as ensemble of small liver units (LUs) differing in their vulnerability to toxic FFAs and capacities to metabolize FFAs and repair FFA-induced cell damage. The model describes NAFLD as cascading liver failure where failure of few LUs increases the risk for other LUs to fail as well. Model simulations provided the following insights: (1) Persistently high plasma levels of FFAs are sufficient to drive the liver through different stages of NAFLD; (2) Presence of NAFLD amplifies the deleterious impact of additional tissuedamaging hits; (3) Coexistence of non-steatotic and highly steatotic regions is indicative for the later occurrence of severe NAFLD stages.