A Distributed Model of Carbohydrate Transport and Metabolism in the Liver during Rest and High-Intensity Exercise

Abstract

Abstract-A model of reaction and transport in the liver was developed that describes the metabolite concentration and reaction flux dynamics separately within the tissue and blood domains. The blood domain contains equations for convec tion, axial dispersion, and transport to the surrounding tissue; and the tissue domain consists of reactions represent ing key carbohydrate metabolic pathways. The model includes the metabolic heterogeneity of the liver by incorpo rating spatial variation of key enzymatic maximal activities. Simulation results of the overnight fasted, resting state agree closely with experimental values of overall glucose uptake and lactate output by the liver. The incorporation of zonation of glycolytic and gluconeogenic enzyme activities causes the expected increase in glycolysis and decrease in gluconeogenesis along the sinusoid length from periportal to perivenous regions, while fluxes are nearly constant along the sinusoid length in the absence of enzyme zonation. These results confirm that transport limitations are not sufficient to account for the observed tissue heterogeneity of metabolic fluxes. Model results indicate that changes in arterial substrate concentrations and hepatic blood flow rate, which occur in the high-intensity exercise state, are not sufficient to shift the liver metabolism enough to account for the 5-fold increase in hepatic glucose production measured during exercise. Changes in maximal activities, whether caused by exercise-induced changes in insulin, glucagon, or other hormones are shown to be needed to achieve the expected glucose output. This model provides a framework for evaluating the relative importance to hepatic function of various phenomenological changes that occur during exer cise. The model can also be used to assess the potential effect of metabolic heterogeneity on metabolism.

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

“…For example, Bartel and Holzhütter (1990) modeled the adenine nucleotide salvage metabolism of hepatocytes and simulated the impact of anoxia and subsequent re-oxygenation on variations in the total adenine nucleotide pool of the cell. Chalhoub et al (2007a, b) used kinetic models to study the interdependence of carbohydrate and lipid metabolism. Beard and Qian (2005) investigated the impairment of hepatic glucose production in von Gierke’s and Hers’ diseases.…”

Insulin resistance in the liver: Deficiency or excess of insulin?

“…However, in the acini area, the hepatocytes are exposed to a spatial biochemical gradient that influences metabolism and gene expression, so cell specialization does exist to some degree, depending on locale. [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] Parenchymal acini of the liver are divisible into 2 circulatory zones, based on proximity to afferent vessels. 36 Periportal hepatocytes are supplied by blood rich in oxygen and nutrients, whereas the blood reaching perivenous hepatocytes (at the periphery of acini) is oxygen-poor and nutrient-depleted.…”

Inbuilt Mechanisms for Overcoming Functional Problems Inherent in Hepatic Microlobular Structure

“…Fourthly, since there is a balance between the requirement for centrilobular ATP for biosynthetic, and other reactions, and the need to raise the centrilobular temperature for the reasons outlined above, the explanation for the additional, though less marked, colocation of UCP-2 and TRPv4 in the outer layer of peripheral cells is less obvious. It may be that the necessary rates of gluconeogenesis and ureogenesis, known to be maximal in the most peripheral zone in each lobule [11–13], are best achieved at the increased temperature provided by UCP-2 whilst high Q 10 proteins such as TRPv4 might have some additional function, not yet identified, in this site. However, because of the particularly high requirements of gluconeogenesis and ureogenesis for ATP, the amount of periportal uncoupling is likely to be limited.…”