Parameter adaptations during phenotype transitions in progressive diseases

The study of phenotype transitions is important to understand progressive diseases, e.g., diabetes mellitus, metabolic syndrome, and cardiovascular diseases. A challenge remains to explain phenotype transitions in terms of adaptations in molecular components and interactions in underlying biological systems.

Here, mathematical modeling is used to describe the different phenotypes by integrating experimental data on metabolic pools and fluxes. Subsequently, trajectories of parameter adaptations are identified that are essential for the phenotypical changes. These changes in parameters reflect progressive adaptations at the transcriptome and proteome level, which occur at larger timescales. The approach was employed to study the metabolic processes underlying liver X receptor induced hepatic steatosis. Model analysis predicts which molecular processes adapt in time after pharmacological activation of the liver X receptor. Our results show that hepatic triglyceride fluxes are increased and triglycerides are especially stored in cytosolic fractions, rather than in endoplasmic reticulum fractions. Furthermore, the model reveals several possible scenarios for adaptations in cholesterol metabolism. According to the analysis, the additional quantification of one cholesterol flux is sufficient to exclude many of these hypotheses.

We propose a generic computational approach to analyze biological systems evolving through various phenotypes and to predict which molecular processes are responsible for the transition. For the case of liver X receptor induced hepatic steatosis the novel approach yields information about the redistribution of fluxes and pools of triglycerides and cholesterols that was not directly apparent from the experimental data. Model analysis provides guidance which specific molecular processes to study in more detail to obtain further understanding of the underlying biological system.