(489o) Cybernetic Modeling of the Metabolic Homeostasis of the Liver

Metabolic homeostasis is maintained by complicated regulatory programs in many biological systems. Mathematical description of such a complex system often causes over-parameterization and predicts the metabolic dynamics only under limited conditions. On the other hand, the incorporation of sophisticated regulatory inputs and inferring the impact of regulation in metabolic networks can be systematically condensed in cybernetic modeling [Young, J. D. and D. Ramkrishna, Biotech. Progress, 23, 83-99, 2007]. Thus, a cybernetic model was applied for the metabolic homeostasis by the liver, which maintains a constant supply of oxidizable substrates, such as glucose, triglyceride, ketone bodies and fatty acid in the blood stream. The liver model is comprised of the major biochemical reactions for metabolic homeostasis including glycogen formation/hydrolysis and lipid synthesis/degradation. The objective function was designed to maximize the rate of glucose metabolism in the model and stoichiometric parameters were obtained from the elementary mode analysis of the liver metabolic network. The model fits well with the profiles of blood glucose, fatty acid and triglyceride during glucose tolerance test. It also showed a robust glucose homeostasis under randomized supply of either high-carbohydrate or high-fat diet over a long period of time. An extended model including other organs such as adipose tissue and muscle is under development to simulate the metabolic dynamics caused by environmental perturbations, for example, drug, disease or exercise.