Systematic diet composition swap in a mouse genome-scale metabolic model reveals determinants of obesogenic diet metabolism in liver cancer

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Abstract

Dietary nutrient availability and gene expression, together, influence tissue metabolic activity. Here, we explore whether altering dietary nutrient composition in the context of mouse liver cancer suffices to overcome chronic gene expression changes that arise from tumorigenesis and western-style diet (WD). We construct a mouse genome-scale metabolic model and estimate metabolic fluxes in liver tumours and non-tumoral tissue after computationally varying the composition of input diet. This approach, called Systematic Diet Composition Swap (SyDiCoS), revealed that, compared to a control diet, WD increases production of glycerol and succinate irrespective of specific tissue gene expression patterns. Conversely, differences in fatty acid utilisation pathways between tumour and non-tumour liver are amplified with WD by both dietary carbohydrates and lipids together. Our data suggest that combined dietary component modifications may be required to normalise the distinctive metabolic patterns that underlie selective targeting of tumour metabolism.