The liver shows a close coexistence between endothelial cells and hepatocytes (HepG2). Endothelial cells' main purpose is to protect (HepG2) from blood vessel shear stress, acting as a barrier, but experimental evidence suggests that they could also play a role in regulating (HepG2) glucose metabolism. A well-known singular effect in hepatocyte-endothelial co-cultures is the reduction of glucose consumption respect to (HepG2) in single culture. (HepG2) were shown to reduce their glucose consumption supporting energy needs of endothelial cells. Monti have studied the effects of endothelin-1 (Et-1) on Glucokinase activity in adult rat (HepG2). They observed a reduction in hepatocytes Glucokinase catalytic rate, which is dependent on Et-1 concentration. We developed crosstalking of endothelial cells and hepatocyte metabolism (CREPE) that is a mathematical model of the endothelin-1 mediated crosstalk between HepG2 and endothelial cells (human umbilical vein endothelial cells) in a traditional static co-culture system. CREPE was validated against experimental data, showing good agreement with them. CREPE can be a starting point to develop predictive tools on complex and highly interconnected environments.