Computational Modelling of Fructose Metabolism and Lipid Deposition in Non-Alcoholic Fatty Liver Disease

Introduction: Non-alcoholic fatty liver disease (NAFLD) is the commonest chronic liver condition that is globally affecting 20-30 % of the general population. It covers a spectrum of conditions resulting from excess lipid accumulation in the liver without alcohol abuse. Among all the risk factors, fructose has been identified as a problematic component by recent clinical and experimental studies. Methodology: A systems biology approach has been applied to explore the metabolic mechanisms whereby fructose consumption can induce dyslipidaemia associated with NAFLD and to explore whether the pathological conditions can be reversed during the early stages of disease. Both ex vivo experiments and computational modelling are employed in an iterative process. Results: A computational model of the hepatic fructose metabolism has been established, containing approximately 120 parameters, 25 variables and 25 first order differential equations. Model predictions and experimental results presented a clear deposition of lipid profiles within the liver cells as a direct consequence of high-fructose feeding. Furthermore, the model was also used to identify the potential regulatory targets for novel therapeutic interventions. Synergistic application of PK, KHK and PPARα in silico has been predicted as the most effective treatment to reduce the production of both fatty acids and triglycerides under both moderate and severe insulin resistance conditions. Conclusion: Fructose over-consumption has a significant influence on the development of NAFLD. The results suggest that the constructed model is robust and it has sufficient detail to present the kinetic relationship between fructose and fatty liver under both healthy and insulin-resistant conditions. Regulatory point identification provides a guidance for further experimental conduction. Keywords: Fructose metabolism, Lipid, NAFLD, Computational modelling, Systems biology