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Modellierung zellulärer Prozesse in der Leber

Kinetische Modellierung des Leberstoffwechsels

The epidemic increase of non-alcoholic fatty liver diseases (NAFLD) requires a deeper understanding of the regulatory circuits controlling the response of liver metabolism to nutritional challenges, medical drugs, and genetic enzyme variants. As in vivo studies of human liver metabolism are encumbered with serious ethical and technical issues, we developed a comprehensive biochemistry-based kinetic model of the central liver metabolism including the regulation of enzyme activities by their reactants, allosteric effectors, and hormone-dependent phosphorylation. The utility of the model for basic research and applications in medicine and pharmacology is illustrated by simulating diurnal variations of the metabolic state of the liver at various perturbations caused by nutritional challenges (alcohol), drugs (valproate), and inherited enzyme disorders (galactosemia). Using proteomics data to scale maximal enzyme activities, the model is used to highlight differences in the metabolic functions of normal hepatocytes and malignant liver cells (adenoma and hepatocellular carcinoma).

Projektfinanzierung: Systembiologie-Programme "Virtual Liver" (Nr. 0315741) und "LiSyM" (Nr. 31L0057 und 031L0058) sowie e:Bio (Module I) Projekt "HepatomaSys" (Nr.0316172A), alle durch das BMBF gefördert.

Publikation: Berndt N, Bulik S, Wallach I, Wünsch T, König M, Stockmann M, Meierhofer D, Holzhütter HG. HEPATOKIN1 is a biochemistry-based model of liver metabolism for applications in medicine and pharmacology. Nat Commun, 2018. 9(1): p. 2386.

Martin Stockmann (Charité, Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Workgroup for the Liver)
David Meierhofer (Max-Planck-Institut für molekulare Genetik, Mass Spectroscopy)
Ingolf Sack (Charité, Klinik für Radiologie)
Susanna Wiegand (Charité, Sozialpädiatrisches Zentrum)
Madlen Matz-Soja (Universität Leipzig, Institut für Biochemie, Arbeitsgruppe Matz-Soja)
Jochen Hampe (Universitätsklinikum Carl Gustav Carus Dresden, Gastroenterologie)
Jan Hengstler (IfADo – Leibniz Institut für Arbeitsforschung an der TU Dortmund, Systemtoxikologie)

Multiskalen-Modellierung des Lebergewebes

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 (‘metabolic zonation’) have been reported. Understanding how this variability may affect the regional metabolic capacity of the liver is important for interpretation of functional liver tests and planning of pharmacological and surgical interventions. Here, we treat the liver as an ensemble of a large number (more than a million) of sinusoidal tissue units (STUs), each composed of a single sinusoid surrounded by the space of Disse and a monolayer of hepatocytes. We develop spatio-temporal kinetic models of the STU and calculate the total metabolic output of the liver (arterio-venous glucose difference) by integration across the metabolic output of a sufficiently large number of representative STUs differing in their anatomical structure (thickness and length of the sinusoid, number and size of hepatocytes etc.). Application of the model to the hepatic glucose metabolism provided the following insights: (i) At portal glucose concentrations between 6 to 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 showing the metabolic activities in various liver regions in a time-resolved manner. The model suggests that variations of tissue parameters are equally important as variations of enzyme activities for the control of the arterio-venous glucose difference.

Projektfinanzierung: Systembiologie-Programme "Virtual Liver" (Nr. 0315741) und "LiSyM" (Nr. 31L0057 und 031L0058) sowie e:Bio (Module I) Projekt "HepatomaSys" (Nr.0316172A), alle durch das BMBF gefördert.

Publikation: Berndt N, Horger MS, Bulik S, Holzhütter HG. A multiscale modelling approach to assess the impact of metabolic zonation and microperfusion on the hepatic carbohydrate metabolism. PLoS Comput Biol, 2018. 14(2): p. e1006005.

Marius Horger (Universitätsklinikum Tübingen, Diagnostische and Interventionelle Radiologie)
Jochen Hampe (Universitätsklinikum Carl Gustav Carus Dresden, Gastroenterologie)

Regulationsebenen des zellulären Metabolismus: hierarchisch oder demokratisch?

Adaptation of cellular metabolism to varying external conditions is brought about by regulated changes in the activity of enzymes and transporters. Hormone-dependent reversible enzyme phosphorylation and concentration changes of reactants and allosteric effectors are the major types of rapid kinetic enzyme regulation, whereas on longer time scales changes in protein abundance may also become operative. We used a comprehensive mathematical model of the hepatic glucose metabolism of rat hepatocytes to decipher the relative importance of different regulatory modes and their mutual interdependencies in the hepatic control of plasma glucose homeostasis.

Model simulations reveal significant differences in the capability of liver metabolism to counteract variations of plasma glucose in different physiological settings (starvation, ad libitum nutrient supply, diabetes). Changes in enzyme abundances adjust the metabolic output to the anticipated physiological demand but may turn into a regulatory disadvantage if sudden unexpected changes of the external conditions occur. Allosteric and hormonal control of enzyme activities allow the liver to assume a broad range of metabolic states and may even fully reverse flux changes resulting from changes of enzyme abundances alone. Metabolic control analysis reveals that – depending on the (patho)physiological condition – control of the hepatic glucose metabolism is mainly exerted by specific enzymes, which are differently controlled by alterations in enzyme abundance, reversible phosphorylation, and allosteric effects.

In hepatic glucose metabolism, regulation of enzyme activities by changes of reactants, allosteric effects, and reversible phosphorylation is equally important as changes in protein abundance of key regulatory enzymes.

Projektfinanzierung: Systembiologie-Programme "Virtual Liver" (Nr. 0315741) und "LiSyM" (Nr. 31L0057 und 031L0058) sowie e:Bio (Module I) Projekt "HepatomaSys" (Nr.0316172A), alle durch das BMBF gefördert.

Publikation: Bulik S, Holzhütter HG, Berndt N. The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism - insights from mathematical modeling. BMC Biology, 2016. 14:15

Integration von Stoffwechsel und Signalwegen



Hepatischer Lipidmetabolismus

The liver responds to elevated plasma concentrations of free fatty acids (FFAs) with enhanced uptake and esterification of FFAs to triacylglycerol (TAG). This may result in massive hepatic TAG accumulation called fatty liver (steatosis hepatis), the first stage on the route towards more serious liver diseases, such as cirrhosis, fibrosis or hepatocellular carcinoma. In hepatocytes, the poor water-soluble TAG is packed in lipid droplets (LDs) serving as transient cellular deposit or lipoproteins transporting TAG and cholesterol esters to extra-hepatic tissues. The dynamics of these ‘organelles’ is controlled by a variety of regulatory surface proteins (RSPs). Knockdown or overexpression of RSPs may significantly affect the total number and size distribution of LDs. Intriguingly, a large cell-to-cell heterogeneity with respect to the number and size of LDs has been found in various cell types including hepatocytes. These findings suggest that the extent of cellular lipid accumulation is determined not only by the imbalance between lipid supply and utilization but also by variations in the expression of RSPs and metabolic enzymes. To better understand the relative regulatory impact of individual processes involved in the cellular TAG turnover, we developed a comprehensive kinetic model encompassing the pathways of the fatty acid and TAG metabolism and the main molecular processes governing the dynamics of LDs (Wallstab et al., The FEBS Journal, 2017). We are using the model to investigate LD size distributions in human hepatocytes under physiological and pathological conditions such as steatosis, fibrosis, cirrhosis or hepatocellular carcinoma.

Projektfinanzierung: DFG-Graduiertenkolleg "Computational Systems Biology" (GRK 1722) und das BMBF-geförderte Systembiologie-Programm "LiSyM" (Nr. 31L0057).

Publikation: Wallstab C, Eleftheriadou D, Schulz T, Damm G, Seehofer D, Borlak J, Holzhütter HG, Berndt N. A unifying mathematical model of lipid droplet metabolism reveals key molecular players in the development of hepatic steatosis. FEBS J, 2017. 284(19): p. 3245-3261.

Georg Damm and Daniel Seehofer (Universität Leipzig, Hepatobiliäre Chirurgie und viszerale Transplantation, Arbeitsgruppe Leberregeneration)
Jürgen Borlak (Medizinische Hochschule Hannover, Institut für Pharmako- und Toxikogenomikforschung)
Martin Stockmann (Charité, Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Workgroup for the Liver)
David Meierhofer (Max-Planck-Institut für molekulare Genetik, Mass Spectroscopy)
Nachiket Vartak (IfADo – Leibniz Institut für Arbeitsforschung an der TU Dortmund, Systemtoxikologie)

Membrandomänenentstehung und Lipidsekretion in die Galle

We developed a mathematical model of lateral diffusion of lipids and proteins in cellular membranes. The movement of lipids and proteins along the membrane surface is modeled as a movement on a triangular lattice, governed by nearest neighbor interactions. The lipids may switch between two alternative states of ordering energy resulting in different mobilities. Minimizing the ordering energies results in the formation of liquid ordered or liquid disordered phase domains. The model also includes proteins of two different species that have a high affinity for either one of the two phases. The lipid and protein mobilities were parameterized using experimental data from different model membranes. The influence of protein size and density on the formation of lipid domains can be studied.

Model simulations provided support for a budding mechanism of lipid transfer into the bile consisting in the bile salt dependent extraction of membrane patches from liquid disordered microdomains of the canalicular membrane. We applied the model to the canalicular membrane of hepatocytes to study how changes of the lipid composition and protein density may influence the size distribution of microdomains and efficiency of lipid extraction into the bile. Our simulations recapitulate the dependence of lipid secretion from the bile salt secretion measured in mouse models.

Projektfinanzierung: SFB 618 "Theoretische Biologie: Robustheit, Modularitaet und evolutionaeres Design lebender Systeme" (Nr. 5485271) und Graduiertenkolleg "Computational Systems Biology" (GRK 1722), beide von der DFG gefördert, sowie das BMBF-geförderte Systembiologie-Programm "LiSyM" (Nr. 31L0057 und 031L0058).

Eckstein J, Holzhütter HG*, Berndt N*. Correction: The importance of membrane microdomains for bile salt-dependent biliary lipid secretion. J Cell Sci, 2018. 131(6).
Eckstein J, Holzhütter HG*, Berndt N*. The importance of membrane microdomains for bile salt-dependent biliary lipid secretion. J Cell Sci, 2018. 131(5).
Eckstein J, Berndt N*, Holzhütter HG*. Computer simulations suggest a key role of membranous nanodomains in biliary lipid secretion. PLoS Comput Biol, 2015. 11(2): p. e1004033.

Kooperationspartner: Frank Lammert (Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes, Gastroenterologie und Endokrinologie

Nicht-invasive Leberfunktionsdiagnostiken



Metabolische Veränderungen in Leberpathologien



Leberstoffwechsel in Jugendlichen mit nichtalkoholischer Fettlebererkrankung (NAFLD)



Modellierung zellulärer Prozesse in neuronalen Zellen

Sauerstoffverbrauch in Hirnschnitten



Neuronaler Energiestoffwechsel



Neurodegenerative Erkrankungen



Einfluss von Anästhetika auf den zerebralen Energiestoffwechsel bei leichter und tiefer Narkose



Einfluss der Gefäßstruktur auf den neuronalen Energiestoffwechsel in verschiedenen Spezies



Die Neurovaskuläre Einheit: neurovaskuläre Kopplung in Patienten mit Schädel-Hirn-Trauma






Modellierung zellulärer Prozesse im Herzen

Integratives Modell des kardialen Stoffwechsels



Kardialer Stoffwechsel in Patienten mit Herzversagen



Kardialer Stoffwechsel in diabetischen Patienten



Metabolische Veränderungen im Herzen bei systemischer Inflammation während viraler Infektion