Transepithelial glucose transport and Na⁺/K⁺ homeostasis in enterocytes: an integrative model

Abstract

Thorsen K, Drengstig T, Ruoff P. Transepithelial glucose transport and Na ϩ /K ϩ homeostasis in enterocytes: an integrative model. Am J Physiol Cell Physiol 307: C320 -C337, 2014. First published June 4, 2014; doi:10.1152/ajpcell.00068.2013.-The uptake of glucose and the nutrient coupled transcellular sodium traffic across epithelial cells in the small intestine has been an ongoing topic in physiological research for over half a century. Driving the uptake of nutrients like glucose, enterocytes must have regulatory mechanisms that respond to the considerable changes in the inflow of sodium during absorption. The Na-K-ATPase membrane protein plays a major role in this regulation. We propose the hypothesis that the amount of active Na-K-ATPase in enterocytes is directly regulated by the concentration of intracellular Na ϩ and that this regulation together with a regulation of basolateral K permeability by intracellular ATP gives the enterocyte the ability to maintain ionic Na ϩ /K ϩ homeostasis. To explore these regulatory mechanisms, we present a mathematical model of the sodium coupled uptake of glucose in epithelial enterocytes. Our model integrates knowledge about individual transporter proteins including apical SGLT1, basolateral Na-K-ATPase, and GLUT2, together with diffusion and membrane potentials. The intracellular concentrations of glucose, sodium, potassium, and chloride are modeled by nonlinear differential equations, and molecular flows are calculated based on experimental kinetic data from the literature, including substrate saturation, product inhibition, and modulation by membrane potential. Simulation results of the model without the addition of regulatory mechanisms fit well with published short-term observations, including cell depolarization and increased concentration of intracellular glucose and sodium during increased concentration of luminal glucose/sodium. Adding regulatory mechanisms for regulation of Na-K-ATPase and K permeability to the model show that our hypothesis predicts observed long-term ionic homeostasis.enterocytes; epithelial transport; homeostasis; mathematical modeling; ionic regulation THE UPTAKE AND TRANSPORT OF glucose by the epithelial enterocytes in the small intestine are essential steps in all higher animals. Much of the glucose uptake in the small intestine is coupled to transport of sodium, and the different transporter proteins involved in the sodium coupled glucose uptake are well known (23,61,67,97). Although the electrochemical kinetics of the individual transporter proteins responsible for glucose and nutrient uptake are fairly elucidated (19,54,67,82,97), the combined function in which these transporters drive a net inflow of nutrients from the intestinal lumen to the serosal blood has not yet been modeled in detail.We have developed a mathematical model of an enterocyte that incorporates the available kinetic data from studies on individual transporter proteins. The model includes apical SGLT1 (the glucose sodium cotransporter), coupled apical flow of Na ϩ an...

A simple recipe for setting up the flux equations of cyclic and linear reaction schemes of ion transport with a high number of states: The arrow scheme

“…One example is the Na C /glucose cotransporter 36 with the following transmembrane movements: In the model of Figure 2A, the reaction S 1 -S 6 is the translocation of the unloaded "carrier." In cotransporters, the "movement of the carrier" means conformational change of the protein from "open to the outside" to "open to the inside."…”

Comparison of the Effects of Green and Black Tea Extracts on Na+/K+‐ATPase Activity in Intestine of Type 1 and Type 2 Diabetic Mice

“…Na + /K + ‐ATPase (EC 3.6.1.37) is an important membrane‐bound enzyme that is almost ubiquitous in animal cells. This enzyme exports three Na + ions and imports two K + ions across the plasma membrane using the energy released during the hydrolysis of one ATP molecule to ADP and inorganic phosphate (Pi) . Na + /K + ‐ATPase is an important enzyme for maintaining membrane potential, providing the basis for neuronal communication, and regulating cellular volume .…”

“…Reducing intestinal glucose absorption relies on the sodium gradient established by the Na + /K + ‐ATPase . Na + /K + ‐ATPase present in the basolateral membrane exports three Na + ions and imports two K + ions . Using the energy stored in the Na + electrochemical gradient, glucose is co‐transported with Na + through the brush border membrane of the enterocytes by Na + /glucose co‐transporter (SGLT1) .…”

“…This enzyme exports three Na + ions and imports two K + ions across the plasma membrane using the energy released during the hydrolysis of one ATP molecule to ADP and inorganic phosphate (Pi). [1] The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/mnfr.201801039 DOI: 10.1002/mnfr.201801039 Na + /K + -ATPase is an important enzyme for maintaining membrane potential, providing the basis for neuronal communication, and regulating cellular volume. [2] Moreover, the Na + gradient created by Na + /K + -ATPase is the driving force for a multitude of secondary active transporters [3] Due to the important regulatory role of Na + /K + -ATPase in cellular functions, various inhibitors of this pump have been discovered or developed for disease treatment.…”

Passivity-based analysis of biochemical networks displaying homeostasis

“…We have previously investigated a class of simple two-component biochemical networks displaying homeostasis. These networks have been used in modelling ionic homeostasis in enterocytes (Thorsen et al, 2014), the development of biochemical controllers with robust control to perturbations changing rapidly in time (Fjeld et al, 2017), and developing yeast cells with an increased tolerance to high copper concentrations (Thorsen et al, 2016a). The networks consist of a controlled compound x 1 and a controller compound x 2 , and through certain signalling reactions between these two compounds, the systems form negative feedback connections with integral action, giving robust control of x 1 .…”