The biophysical basis of enterocyte homeostasis

We present an approach to analysing cell homeostasis using a bond graph modelling approach that ensures that the conservation laws of physics (conservation of mass, charge, and energy, respectively) are satisfied for the interdependent biochemical, electrical, mechanical, and thermal energy storage mechanisms operating within the cell. We apply the bond graph approach to several cell membrane transport mechanisms and then consider how physics constrains intracellular electrolyte homeostasis for enterocytes (the epithelial absorptive cells of the gut). The model includes the electrogenic sodium-potassium ATPase pump (NKA), the glucose transporter (GLUT2), and an inwardly rectifying potassium channel, all in the basolateral membrane, and the electrogenic sodium-driven glucose transporter (SGLT1) in the apical membrane. Glycolysis converts the imported glucose to ATP to drive NKA. For specified levels of sodium, potassium, and glucose in the blood, the model demonstrates how enterocytes absorb sodium and glucose from the gut and transfer glucose to the blood while maintaining the membrane potential and homeostasis of intracellular sodium and potassium. The Gibbs free energy available from the ATP hydrolysis ensures that the cell operates as a sodium battery with a high external to internal ratio of sodium concentration in order to provide the energy for many other cellular transport processes. We show that the 3:2 stoichiometry of Na+/K+ exchange in NKA, coupled with 2:1 Na+/glucose cotransport in SGLT1, a 1:2:2 ratio between glucose consumption and ATP and water production in glycolysis, and K+ and glucose efflux through Kir and GLUT2, respectively, provides a balanced system that maintains homeostasis of intracellular Na+, K+, glucose, ATP and water, and homeostasis of the membrane potential, under varying levels of transport of glucose from the gut to the blood. We also show how the flux expressions for SLC transporters, ATPase pumps and ion channels can all be expressed in a consistent and thermodynamically valid way.