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

Abstract

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.

Spatial sorting enables comprehensive characterization of liver zonation

“…Recent works have begun to develop in-silico multi-scale models for predicting the liver's response to stimulations by metabolites and xenobiotics [50][51][52] . These models consider multiple units representing hepatocytes at different zones that exchange materials and process them through individualized metabolic networks, thus modeling the polarized blood perfusion throughout the lobule.…”

Metabolic modelling of kidney diseases: Lessons learned from the liver

“…7,8 Notably, disease progression occurs often silently and without clear clinical symptoms. 15 This tissue model takes into account the heterogeneous enzymatic endowment of hepatocytes along the porto-central axis of the sinusoid (metabolic zonation) and reveals intra-organic metabolic cycles, where glucose produced by hepatocytes of the portal region is partially consumed by hepatocytes of the central region. 11,12 Starting point of any metabolic model is the knowledge of the network architecture given in terms of the so-called stoichiometric matrix assigning to each biochemical reaction the metabolites that are consumed and produced.…”

“…9 Metabolic models of the liver range from genome-wide network models 10 to small-scale metabolic models of single pathways. 15 To study the dynamic adaptation of the protein abundance of liver enzymes to pathological conditions, the model in Ref. Knowledge of network stoichiometry is already sufficient to highlight possible routes that a given metabolite can take in a series of subsequent biochemical reactions.…”

“…In order to include blood supply and the interstitial transport of nutrients as metabolic determinants, a multi-scale model of the so-called sinusoidal tissue unit was proposed, comprising a single liver capillary (sinusoid) which is surrounded by the space of Disse and a monolayer of hepatocytes. 15 This tissue model takes into account the heterogeneous enzymatic endowment of hepatocytes along the porto-central axis of the sinusoid (metabolic zonation) and reveals intra-organic metabolic cycles, where glucose produced by hepatocytes of the portal region is partially consumed by hepatocytes of the central region. 15 To study the dynamic adaptation of the protein abundance of liver enzymes to pathological conditions, the model in Ref.…”

“…15 This tissue model takes into account the heterogeneous enzymatic endowment of hepatocytes along the porto-central axis of the sinusoid (metabolic zonation) and reveals intra-organic metabolic cycles, where glucose produced by hepatocytes of the portal region is partially consumed by hepatocytes of the central region. 15 To study the dynamic adaptation of the protein abundance of liver enzymes to pathological conditions, the model in Ref. 16 extended the multi-scale tissue model by treating the protein abundances as dynamic variables whose synthesis and degradation rates depend on the metabolic state.…”