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Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease

Maldonado, E. M., Fisher, C. P., Mazzatti, D. J., Barber, A. L., Tindall, M. J., Plant, N. J., Kierzek, A. M. and Moore, J. B. (2018) Multi-scale, whole-system models of liver metabolic adaptation to fat and sugar in non-alcoholic fatty liver disease. NPJ Systems Biology and Applications, 4. 33. ISSN 2056-7189

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To link to this item DOI: 10.1038/s41540-018-0070-3

Abstract/Summary

Non-alcoholic fatty liver disease (NAFLD) is a serious public health issue associated with high fat, high sugar diets. However, the molecular mechanisms mediating NAFLD pathogenesis are only partially understood. Here we adopt an iterative multi-scale, systems biology approach coupled to in vitro experimentation to investigate the roles of sugar and fat metabolism in NAFLD pathogenesis. The use of fructose as a sweetening agent is controversial; to explore this, we developed a predictive model of human monosaccharide transport, signalling and metabolism. The resulting quantitative model comprising a kinetic model describing monosaccharide transport and insulin signalling integrated with a hepatocyte-specific genome-scale metabolic network (GSMN). Differential kinetics for the utilisation of glucose and fructose were predicted, but the resultant triacylglycerol production was predicted to be similar for monosaccharides; these predictions were verified by in vitro data. The role of physiological adaptation to lipid overload was explored through the comprehensive reconstruction of the peroxisome proliferator activated receptor alpha (PPARα) regulome integrated with a hepatocyte-specific GSMN. The resulting qualitative model reproduced metabolic responses to increased fatty acid levels and mimicked lipid loading in vitro. The model predicted that activation of PPARα by lipids produces a biphasic response, which initially exacerbates steatosis. Our data support the evidence that it is the quantity of sugar rather than the type that is critical in driving the steatotic response. Furthermore, we predict PPARα-mediated adaptations to hepatic lipid overload, shedding light on potential challenges for the use of PPARα agonists to treat NAFLD.

Item Type:Article
Refereed:Yes
Divisions:Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR)
Faculty of Science > School of Mathematical, Physical and Computational Sciences > Department of Mathematics and Statistics
ID Code:78806
Publisher:Nature

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