A multiscale modelling approach to assess the impact of metabolic zonation and microperfusion on the hepatic carbohydrate metabolism

The capacity of the liver to convert the metabolic input received from the incoming portal and arterial blood into the metabolic output of the outgoing venous blood has three major determinants: The intra-hepatic blood flow, the transport of metabolites between blood vessels (sinusoids) and hepatocytes and the metabolic capacity of hepatocytes. These determinants are not constant across the organ: Even in the normal organ, but much more pronounced in the fibrotic and cirrhotic liver, regional variability of the capillary blood pressure, tissue architecture and the expression level of metabolic enzymes (zonation) have been reported. Understanding how this variability may affect the regional metabolic capacity of the liver is important for the interpretation of functional liver tests and planning of pharmacological and surgical interventions. Here we present a mathematical model of the sinusoidal tissue unit (STU) that is composed of a single sinusoid surrounded by the space of Disse and a monolayer of hepatocytes. The total metabolic output of the liver (arterio-venous glucose difference) is obtained by integration across the metabolic output of a representative number of STUs. Application of the model to the hepatic glucose metabolism provided the following insights: (i) At portal glucose concentrations between 6–8 mM, an intra-sinusoidal glucose cycle may occur which is constituted by glucose producing periportal hepatocytes and glucose consuming pericentral hepatocytes, (ii) Regional variability of hepatic blood flow is higher than the corresponding regional variability of the metabolic output, (iii) a spatially resolved metabolic functiogram of the liver is constructed. Variations of tissue parameters are equally important as variations of enzyme activities for the control of the arterio-venous glucose difference.Author summary: Glucose homeostasis is one of the central liver functions. The liver extracts glucose from the blood when plasma glucose levels are high and produces glucose when plasma glucose levels are low. To fulfill this function the liver is organized in smallest functional units, the sinusoidal tissue units (STUs). These STUs consist of a single sinusoid surrounded by linear arranged hepatocytes. Liver zonation describes the spatial separation of metabolic pathways along the STUs. As blood flows through the sinusoid the plasma nutrient and hormone composition changes and in conjunction with the heterogeneous endowment of metabolic enzymes this leads to big differences in the metabolic performance of hepatocytes depending on their position within the sinusoid. This makes liver zonation and blood flow two central determinants for the functional output of the liver. In this work we present a tissue model of hepatic carbohydrate metabolism that combines liver zonation and microperfusion within the STU. We show that structural properties, enzymatic properties and regional bloodflow are equally important for the understanding of liver functionality. With our work we provide a true multi-scale model bridging the scale from the cellular to the tissue level.