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

Dietary nutrient availability and gene expression, together, influence tissue metabolic activity. Here, we explore whether altering dietary nutrient composi-tion 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 tumors 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 produc-tion of glycerol and succinate irrespective of specific tissue gene expression pat-terns. Conversely, differences in fatty acid utilization pathways between tumor and non-tumor liver are amplified with WD by both dietary carbohydrates and lipids together. Our data suggest that combined dietary component modifica-tions may be required to normalize the distinctive metabolic patterns that underlie selective targeting of tumor metabolism.