Code for: "Kinetic analysis of cellular ATP dynamics provides quantitative insight into the contribution of oxygen to liver metabolic zonation."

Quantitative analysis of metabolic zonation is crucial for understanding liver function, but the difficulty of in vivo observation necessitates the use of advanced in vitro and in silico models. However, standard cell culture systems fail to reflect the physiological oxygen supply that drives zonation, and existing mathematical models often oversimplify oxygen contributions. Here we quantitatively describe oxygen contributions to liver metabolic zonation using an experimentally validated in silico ATP production model. We confirmed that our cell culture system using an oxygen-permeable material satisfied physiological oxygen consumption rates (OCR) in both venous and arterial regions under 5% and 10% oxygen atmospheres, respectively, whereas the OCR in a standard cell culture system only reached a third of the venous OCR, even in 20% oxygen. In our culture system, we found that the ATP production rates of mitochondria were 5 and 10 times larger than those of glycolysis in venous and arterial conditions, respectively. We further developed a kinetic model of ATP production by integrating hypoxia-inducible factor (HIF) dependency in a sigmoidal manner and validated it with experimental observations. The model predicted that the ATP consumption rates in the venous and arterial regions could be 0.6 mM/s and 1.0 mM/s, respectively, while ATP concentration was maintained at a physiological level (2.0 mM) in both regions. This supports the validity of enriching ATP-demanding metabolisms in the arterial region. Taken together, our newly developed mathematical and cell culture models quantitatively demonstrated that ATP availability, rather than concentration, underlies the distribution of hepatic functions.