Matthias König

HepatoNet1: a comprehensive metabolic reconstruction of the human hepatocyte for the analysis of liver physiology

We present HepatoNet1, the first reconstruction of a comprehensive metabolic network of the human hepatocyte that is shown to accomplish a large canon of known metabolic liver functions. The network comprises 777 metabolites in six intracellular and two extracellular compartments and 2539 reactions, including 1466 transport reactions. It is based on the manual evaluation of >1500 original scientific research publications to warrant a high‐quality evidence‐based model. The final network is the result of an iterative process of data compilation and rigorous computational testing of network functionality by means of constraint‐based modeling techniques. Taking the hepatic detoxification of ammonia as an example, we show how the availability of nutrients and oxygen may modulate the interplay of various metabolic pathways to allow an efficient response of the liver to perturbations of the homeostasis of blood compounds.

Quantifying the Contribution of the Liver to Glucose Homeostasis: A Detailed Kinetic Model of Human Hepatic Glucose Metabolism

Despite the crucial role of the liver in glucose homeostasis, a detailed mathematical model of human hepatic glucose metabolism is lacking so far. Here we present a detailed kinetic model of glycolysis, gluconeogenesis and glycogen metabolism in human hepatocytes integrated with the hormonal control of these pathways by insulin, glucagon and epinephrine. Model simulations are in good agreement with experimental data on (i) the quantitative contributions of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization under varying physiological states. (ii) the time courses of postprandial glycogen storage as well as glycogen depletion in overnight fasting and short term fasting (iii) the switch from net hepatic glucose production under hypoglycemia to net hepatic glucose utilization under hyperglycemia essential for glucose homeostasis (iv) hormone perturbations of hepatic glucose metabolism. Response analysis reveals an extra high capacity of the liver to counteract changes of plasma glucose level below 5 mM (hypoglycemia) and above 7.5 mM (hyperglycemia). Our model may serve as an important module of a whole-body model of human glucose metabolism and as a valuable tool for understanding the role of the liver in glucose homeostasis under normal conditions and in diseases like diabetes or glycogen storage diseases.

Enzymatic features of the glucose metabolism in tumor cells

Many tumor types exhibit an impaired Pasteur effect, i.e. despite the presence of oxygen, glucose is consumed at an extraordinarily high rate compared with the tissue from which they originate – the so‐called ‘Warburg effect’. Glucose has to serve as the source for a diverse array of cellular functions, including energy production, synthesis of nucleotides and lipids, membrane synthesis and generation of redox equivalents for antioxidative defense. Tumor cells acquire specific enzyme‐regulatory mechanisms to direct the main flux of glucose carbons to those pathways most urgently required under challenging external conditions such as varying substrate availability, presence of anti‐cancer drugs or different phases of the cell cycle. In this review we summarize the currently available information on tumor‐specific expression, activity and kinetic properties of enzymes involved in the main pathways of glucose metabolism with due regard to the explanation of the regulatory basis and physiological significance of the Warburg effect. We conclude that, besides the expression level of the metabolic enzymes involved in the glucose metabolism of tumor cells, the unique tumor‐specific pattern of isozymes and accompanying changes in the metabolic regulation below the translation level enable tumor cells to drain selfishly the blood glucose pool that non‐transformed cells use as sparingly as possible.

libRoadRunner: a high performance SBML simulation and analysis library

MOTIVATION This article presents libRoadRunner, an extensible, high-performance, cross-platform, open-source software library for the simulation and analysis of models expressed using Systems Biology Markup Language (SBML). SBML is the most widely used standard for representing dynamic networks, especially biochemical networks. libRoadRunner is fast enough to support large-scale problems such as tissue models, studies that require large numbers of repeated runs and interactive simulations. RESULTS libRoadRunner is a self-contained library, able to run both as a component inside other tools via its C++ and C bindings, and interactively through its Python interface. Its Python Application Programming Interface (API) is similar to the APIs of MATLAB ( WWWMATHWORKSCOM: ) and SciPy ( HTTP//WWWSCIPYORG/: ), making it fast and easy to learn. libRoadRunner uses a custom Just-In-Time (JIT) compiler built on the widely used LLVM JIT compiler framework. It compiles SBML-specified models directly into native machine code for a variety of processors, making it appropriate for solving extremely large models or repeated runs. libRoadRunner is flexible, supporting the bulk of the SBML specification (except for delay and non-linear algebraic equations) including several SBML extensions (composition and distributions). It offers multiple deterministic and stochastic integrators, as well as tools for steady-state analysis, stability analysis and structural analysis of the stoichiometric matrix. AVAILABILITY AND IMPLEMENTATION libRoadRunner binary distributions are available for Mac OS X, Linux and Windows. The library is licensed under Apache License Version 2.0. libRoadRunner is also available for ARM-based computers such as the Raspberry Pi. http://www.libroadrunner.org provides online documentation, full build instructions, binaries and a git source repository. CONTACTS hsauro@u.washington.edu or somogyie@indiana.edu SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

Modeling function-perfusion behavior in liver lobules including tissue, blood, glucose, lactate and glycogen by use of a coupled two-scale PDE-ODE approach.

This study focuses on a two-scale, continuum multicomponent model for the description of blood perfusion and cell metabolism in the liver. The model accounts for a spatial and time depending hydro-diffusion–advection–reaction description. We consider a solid-phase (tissue) containing glycogen and a fluid-phase (blood) containing glucose as well as lactate. The five-component model is enhanced by a two-scale approach including a macroscale (sinusoidal level) and a microscale (cell level). The perfusion on the macroscale within the lobules is described by a homogenized multiphasic approach based on the theory of porous media (mixture theory combined with the concept of volume fraction). On macro level, we recall the basic mixture model, the governing equations as well as the constitutive framework including the solid (tissue) stress, blood pressure and solutes chemical potential. In view of the transport phenomena, we discuss the blood flow including transverse isotropic permeability, as well as the transport of solute concentrations including diffusion and advection. The continuum multicomponent model on the macroscale finally leads to a coupled system of partial differential equations (PDE). In contrast, the hepatic metabolism on the microscale (cell level) was modeled via a coupled system of ordinary differential equations (ODE). Again, we recall the constitutive relations for cell metabolism level. A finite element implementation of this framework is used to provide an illustrative example, describing the spatial and time-depending perfusion–metabolism processes in liver lobules that integrates perfusion and metabolism of the liver.

Toward Community Standards and Software for Whole-Cell Modeling

Objective: Whole-cell (WC) modeling is a promising tool for biological research, bioengineering, and medicine. However, substantial work remains to create accurate comprehensive models of complex cells. Methods: We organized the 2015 Whole-Cell Modeling Summer School to teach WC modeling and evaluate the need for new WC modeling standards and software by recoding a recently published WC model in the Systems Biology Markup Language. Results: Our analysis revealed several challenges to representing WC models using the current standards. Conclusion: We, therefore, propose several new WC modeling standards, software, and databases. Significance: We anticipate that these new standards and software will enable more comprehensive models.

CySBML: a Cytoscape plugin for SBML

SUMMARY CySBML is a plugin designed to work with Systems Biology Markup Language (SBML) in Cytoscape having the following features: SBML import, support of the SBML layout and qualitative model packages, navigation in network layouts based on SBML structure, access to MIRIAM and SBO-based annotations and SBML validation. CySBML includes an importer for BioModels to load SBML from standard repositories. AVAILABILITY AND IMPLEMENTATION Freely available for non-commercial purposes through the Cytoscape plugin manager or for download at http://sourceforge.net/projects/cysbml/. CONTACT cysbml-team@lists.sourceforge.net SUPPLEMENTARY INFORMATION Tutorial, usage guide, installation instructions and additional figures are available for download at http://www.charite.de/sysbio/people/koenig/software/cysbml/.

Kinetic Modeling of Human Hepatic Glucose Metabolism in Type 2 Diabetes Mellitus Predicts Higher Risk of Hypoglycemic Events in Rigorous Insulin Therapy

Background: Hepatic glucose metabolism is altered in type 2 diabetes mellitus (T2DM). Results: Detailed kinetic modeling of hepatic glucose metabolism including its hormonal regulation predicts the hepatic T2DM phenotype and hypoglycemia in insulin treatment. Conclusion: Rigorous insulin therapy increases the risk of hypoglycemic events due to reduced hepatic counter-regulatory capacity. Significance: Modeling allows to assess the efficiency and risk of hormone-substitution therapies in T2DM. A major problem in the insulin therapy of patients with diabetes type 2 (T2DM) is the increased occurrence of hypoglycemic events which, if left untreated, may cause confusion or fainting and in severe cases seizures, coma, and even death. To elucidate the potential contribution of the liver to hypoglycemia in T2DM we applied a detailed kinetic model of human hepatic glucose metabolism to simulate changes in glycolysis, gluconeogenesis, and glycogen metabolism induced by deviations of the hormones insulin, glucagon, and epinephrine from their normal plasma profiles. Our simulations reveal in line with experimental and clinical data from a multitude of studies in T2DM, (i) significant changes in the relative contribution of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization; (ii) decreased postprandial glycogen storage as well as increased glycogen depletion in overnight fasting and short term fasting; and (iii) a shift of the set point defining the switch between hepatic glucose production and hepatic glucose utilization to elevated plasma glucose levels, respectively, in T2DM relative to normal, healthy subjects. Intriguingly, our model simulations predict a restricted gluconeogenic response of the liver under impaired hormonal signals observed in T2DM, resulting in an increased risk of hypoglycemia. The inability of hepatic glucose metabolism to effectively counterbalance a decline of the blood glucose level becomes even more pronounced in case of tightly controlled insulin treatment. Given this Janus face mode of action of insulin, our model simulations underline the great potential that normalization of the plasma glucagon profile may have for the treatment of T2DM.

Simulation Experiment Description Markup Language (SED-ML) Level 1 Version 2.

The number, size and complexity of computational models of biological systems are growing at an ever increasing pace. It is imperative to build on existing studies by reusing and adapting existing models and parts thereof. The description of the structure of models is not sufficient to enable the reproduction of simulation results. One also needs to describe the procedures the models are subjected to, as recommended by the Minimum Information About a Simulation Experiment (MIASE) guidelines. This document presents Level 1 Version 2 of the Simulation Experiment Description Markup Language (SED-ML), a computer-readable format for encoding simulation and analysis experiments to apply to computational models. SED-ML files are encoded in the Extensible Markup Language (XML) and can be used in conjunction with any XML-based model encoding format, such as CellML or SBML. A SED-ML file includes details of which models to use, how to modify them prior to executing a simulation, which simulation and analysis procedures to apply, which results to extract and how to present them. Level 1 Version 2 extends the format by allowing the encoding of repeated and chained procedures.

FLUXVIZ — CYTOSCAPE PLUG-IN FOR VISUALIZATION OF FLUX DISTRIBUTIONS IN NETWORKS

MOTIVATION Methods like FBA and kinetic modeling are widely used to calculate fluxes in metabolic networks. For the analysis and understanding of simulation results and experimentally measured fluxes visualization software within the network context is indispensable. RESULTS We present Flux Viz, an open-source Cytoscape plug-in for the visualization of flux distributions in molecular interaction networks. FluxViz supports (i) import of networks in a variety of formats (SBML, GML, XGMML, SIF, BioPAX, PSI-MI) (ii) import of flux distributions as CSV, Cytoscape attributes or VAL files (iii) limitation of views to flux carrying reactions (flux subnetwork) or network attributes like localization (iv) export of generated views (SVG, EPS, PDF, BMP, PNG). Though FluxViz was primarily developed as tool for the visualization of fluxes in metabolic networks and the analysis of simulation results from FASIMU, a flexible software for batch flux-balance computation in large metabolic networks, it is not limited to biochemical reaction networks and FBA but can be applied to the visualization of arbitrary fluxes in arbitrary graphs. AVAILABILITY The platform-independent program is an open-source project, freely available at http://sourceforge.net/projects/fluxvizplugin/ under GNU public license, including manual, tutorial and examples.