A computational model of hepatic energy metabolism: Understanding the role of zonation in the development and treatment of non-alcoholic fatty liver disease (NAFLD).
Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition associated with increased risk of liver failure, diabetes and numerous further conditions. In NAFLD, lipid build-up and the resulting damage occurs most severely in hepatocytes at the pericentral end of the capillaries (sinusoids) which supply the cells with blood [1-3]. Due to the complexity of studying individual regions of the sinusoids, the causes of this zone specificity and its implications on treatment have largely been ignored in previous research. In this study, a computational model of liver glucose and lipid metabolism was developed which includes zone-dependent enzyme expression. This model was then used to study the development of NAFLD across the sinusoid. By simulating insulin resistance and high intake diets leading to the development of steatosis in the model, we propose a novel mechanism leading to pericentral steatosis in NAFLD patients. Sensitivity analysis on the rate parameters in the model was then used to highlight key inter-individual variations in hepatic metabolism with the largest effect on steatosis development. Secondly, the model, in combination with cell culture experiments, was used to assess potential drug targets for clearing steatosis across the sinusoid without disrupting other aspects of metabolism. Adverse effects were highlighted when targeting (stimulating or inhibiting through altering the rate constants) for most processes in the model, and these were largely validated in the hepatocyte-like cell culture line through the addition of small molecule inhibitors. However, inhibition of lipogenesis combined with stimulation of β-oxidation was predicted to clear steatosis, reduce hepatic FFA levels, reduce excess ETC flux and increase hepatic ATP concentrations across the sinusoid without causing adverse effects elsewhere in metabolism. Furthermore, in the cell culture model, inhibition of lipogenesis combined with stimulation of β-oxidation using acetyl-CoA carboxylase inhibitor TOFA, resulted in clearance of steatosis, improved cell viability, reduced oxidative stress and increased mitochondrial function
