Nonalcoholic steatohepatitis (NASH) is a disease characterized by excessive accumulation of lipid in the liver. The occurrence of excess lipid accumulation in plasma or liver (as opposed to adipocytes) is the key driver of disease progression not only in NASH, but also in cardiovascular disease (CVD) and is estimated to affect 33 % of the population in the US.
Proper lipid storage is of utmost important to prevent both NASH and CVD, pointing to an urgent need to understand how lipids distribute and metabolize across organs in response to genetic variation, disease states, and pharmacological interventions.
One way to address this problem is by use of systems biology and systems pharmacology. Here, we apply the concepts of systems engineering, systems biology, and pharmacokinetics-pharmacodynamics (PKPD) to build a mathematical model to study the complex biological system of lipid metabolism.
Our research focuses on simulating the metabolic interplays within and between adipose, muscle and liver tissues in healthy populations as well as in untreated and treated patient populations. Through computer-based simulations of the model, we can test multiple hypotheses and evaluate drug interactions in the system, that would otherwise need to be evaluated by extensive and invasive experimental techniques in man.
By watching the biological system from a holistic point of view, as opposed to the behaviour of its individual constituents, we hope to promote an understanding of the fundamental metabolic interactions that drive disease pathology. We can use this knowledge to manipulate lipid fluxes between different tissues in disease states and thereby assess potential therapies and drug candidates for CVD and NASH.
A qualified organ-wide model of human metabolism is the basis of the present project and will have potential applications far beyond the work presented in this PhD project. For example, a qualified QSP model can be used to evaluate potential outcomes of concurrent drug therapies in silico.
This project is a collaboration between DTU Compute, Novo Nordisk A/S and Oxford University. The project is 100% funded by Novo Nordisk A/S.
Image: Multiple systems biology models of human metabolism have been developed depending on the research questions. The figure shows an example of a reaction network of whole-body model describing the fluxes between different tissues following from dietary intake of fat and glucose. Credit: Pratt, A.C., J.A. Wattis, and A.M. Salter, Mathematical modelling of hepatic lipid metabolism. Math Biosci, 2015. 262: p. 167-81.