LiSyM Pillar I: Early Metabolic Injury

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SEEK ID: https://seek.lisym.org/investigations/15

Projects: LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI)

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Martin Golebiewski

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Martin Golebiewski

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Created: 12th Jul 2018 at 16:04

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Martin Golebiewski

Projects: LiSyM Core Infrastructure and Management (LiSyM-PD), LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI), LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi), Model Guided Pharmacotherapy In Chronic Liver Disease (LiSyM-MGP), Molecular Steatosis - Imaging & Modeling (LiSyM-MSIM), The Hedgehog Signalling Pathway (LiSyM-JGMMS), Multi-Scale Models for Personalized Liver Function Tests (LiSyM-MM-PLF), LiSyM PALs, LiSyM network, LiSyM-Krebs Partnering

Institutions: HITS gGmbH

https://orcid.org/0000-0002-8683-7084

Expertise: Data Management, Databases, Biochemistry, Bioinformatics, Systems Biology, Standards

Tools: kinetic modelling, Databases, Mathematical Modelling, Ontologies, Workflows

Data management and standardization expert for systems biology and systems medicine, responsible for the data management user requirements and user contacts within the German LiSyM network (Liver Systems Medicine: http://lisym.org/) and associated to the FAIRDOM team. Involved in different standardization initiatives and committees, i.e. COMBINE (http://co.mbine.org), ISO/TC 276 Biotechnology (https://www.iso.org/committee/4514241.html), European COST action CHARME (http://www.cost-charme.eu) and ...

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LiSyM: Liver Systems Medicine

Liver Systems Medicine : striving to develop non-invasive methods for diagnosing and treating NAFLD by combining mathematical modeling and biological research. LiSyM, is a multidisciplinary research network, in which molecular and cell biologists, clinical researchers, pharmacologists and experts in mathematical modeling examine the liver in its entirety. LiSyM research focuses on the metabolic liver disease non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis ...

Web page: https://www.lisym.org/

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LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI)

One of the tasks of the healthy liver is to store fat. Yet, at some stage, too much fat makes the liver sick. One critical time point occurs when a healthy fatty liver becomes inflamed and progresses to steatohepatitis, or NASH. LiSyM-Pillar I will identify what events lead to this transition. Does it occur in all parts of the liver? Which molecules indicate that it is taking place? Can the degeneration be stopped or undone - and if so, how?

Programme: LiSyM: Liver Systems Medicine

Public web page: http://www.lisym.org/our-work/pillar-research/zones-of-the-liver

Start date: 1st Jan 2016

Organisms: Mus musculus, Rattus rattus, Rattus norvegicus, Homo sapiens

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Loss of hepatic Mboat7 leads to liver fibrosis.

LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI), LiSyM network

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Veera Raghavan Thangapandi

Oskar Knittelfelder

Mario Brosch

Olga Vvedenskaya

Thomas Berg

Madlen Matz-Soja

Edda Klipp

Josch Pauling

Witigo von Schönfels

Sophie Nehring

Clemens Schafmayer

Jochen Hampe

Judith Wodke

Abstract (Expand)

OBJECTIVE: The rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty … liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD. DESIGN: Mice with hepatocyte-specific deletion of MBOAT7 (Mboat7(Deltahep)) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies. RESULTS: Allelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7(Deltahep) mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p<0.05), hydroxyproline content (p<0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p=0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7(Deltahep) mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered lysophosphatidylinositol and phosphatidylinositol subspecies in MBOAT7(Deltahep) livers and human rs641738TT carriers were similar. CONCLUSION: Mboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD.

Authors: V. R. Thangapandi, O. Knittelfelder, M. Brosch, E. Patsenker, O. Vvedenskaya, S. Buch, S. Hinz, A. Hendricks, M. Nati, A. Herrmann, D. R. Rekhade, T. Berg, M. Matz-Soja, K. Huse, E. Klipp, J. K. Pauling, J. A. Wodke, J. Miranda Ackerman, M. V. Bonin, E. Aigner, C. Datz, W. von Schonfels, S. Nehring, S. Zeissig, C. Rocken, A. Dahl, T. Chavakis, F. Stickel, A. Shevchenko, C. Schafmayer, J. Hampe, P. Subramanian

Date Published: 26th Jun 2020

Publication Type: Journal

PubMed ID: 32591434

Citation: Gut. 2020 Jun 26. pii: gutjnl-2020-320853. doi: 10.1136/gutjnl-2020-320853.

Created: 24th Jul 2020 at 11:10, Last updated: 8th Mar 2024 at 07:44

An environment for sustainable research software in Germany and beyond: current state, open challenges, and call for action

LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI)

All authors

Lutz Brusch

Abstract (Expand)

Research software has become a central asset in academic research. It optimizes existing and enables new research methods, implements and embeds research knowledge, and constitutes an essential research … product in itself. Research software must be sustainable in order to understand, replicate, reproduce, and build upon existing research or conduct new research effectively. In other words, software must be available, discoverable, usable, and adaptable to new needs, both now and in the future. Research software therefore requires an environment that supports sustainability. Hence, a change is needed in the way research software development and maintenance are currently motivated, incentivized, funded, structurally and infrastructurally supported, and legally treated. Failing to do so will threaten the quality and validity of research. In this paper, we identify challenges for research software sustainability in Germany and beyond, in terms of motivation, selection, research software engineering personnel, funding, infrastructure, and legal aspects. Besides researchers, we specifically address political and academic decision-makers to increase awareness of the importance and needs of sustainable research software practices. In particular, we recommend strategies and measures to create an environment for sustainable research software, with the ultimate goal to ensure that software-driven research is valid, reproducible and sustainable, and that software is recognized as a first class citizen in research.

Authors: Hartwig Anzt, Felix Bach, Stephan Druskat, Frank Löffler, Axel Loewe, Bernhard Y. Renard, Gunnar Seemann, Alexander Struck, Elke Achhammer, Piush Aggarwal, Franziska Appel, Michael Bader, Lutz Brusch, Christian Busse, Gerasimos Chourdakis, Piotr Wojciech Dabrowski, Peter Ebert, Bernd Flemisch, Sven Friedl, Bernadette Fritzsch, Maximilian D. Funk, Volker Gast, Florian Goth, Jean-Noël Grad, Sibylle Hermann, Florian Hohmann, Stephan Janosch, Dominik Kutra, Jan Linxweiler, Thilo Muth, Wolfgang Peters-Kottig, Fabian Rack, Fabian H.C. Raters, Stephan Rave, Guido Reina, Malte Reißig, Timo Ropinski, Joerg Schaarschmidt, Heidi Seibold, Jan P. Thiele, Benjamin Uekermann, Stefan Unger, Rudolf Weeber

Date Published: 2020

Publication Type: Not specified

DOI: 10.12688/f1000research.23224.1

Citation: F1000Res 9 : 295

Created: 29th Jun 2020 at 07:42, Last updated: 8th Mar 2024 at 07:44

Three-dimensional spatially resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression.

LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI), LiSyM network

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Fabian Segovia Miranda

Michael Kücken

Vincent Moser

Fabian Rost

Mario Brosch

Clemens Schafmayer

Lutz Brusch

Jochen Hampe

Marino Zerial

Abstract (Expand)

Early disease diagnosis is key to the effective treatment of diseases. Histopathological analysis of human biopsies is the gold standard to diagnose tissue alterations. However, this approach has low … resolution and overlooks 3D (three-dimensional) structural changes resulting from functional alterations. Here, we applied multiphoton imaging, 3D digital reconstructions and computational simulations to generate spatially resolved geometrical and functional models of human liver tissue at different stages of non-alcoholic fatty liver disease (NAFLD). We identified a set of morphometric cellular and tissue parameters correlated with disease progression, and discover profound topological defects in the 3D bile canalicular (BC) network. Personalized biliary fluid dynamic simulations predicted an increased pericentral biliary pressure and micro-cholestasis, consistent with elevated cholestatic biomarkers in patients' sera. Our spatially resolved models of human liver tissue can contribute to high-definition medicine by identifying quantitative multiparametric cellular and tissue signatures to define disease progression and provide new insights into NAFLD pathophysiology.

Authors: F. Segovia-Miranda, H. Morales-Navarrete, M. Kucken, V. Moser, S. Seifert, U. Repnik, F. Rost, M. Brosch, A. Hendricks, S. Hinz, C. Rocken, D. Lutjohann, Y. Kalaidzidis, C. Schafmayer, L. Brusch, J. Hampe, M. Zerial

Date Published: 2nd Dec 2019

Publication Type: Not specified

PubMed ID: 31792455

Citation: Nat Med. 2019 Dec 2. pii: 10.1038/s41591-019-0660-7. doi: 10.1038/s41591-019-0660-7.

Created: 4th Dec 2019 at 10:11, Last updated: 8th Mar 2024 at 07:44

Mutual Zonated Interactions of Wnt and Hh Signaling Are Orchestrating the Metabolism of the Adult Liver in Mice and Human

LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI)

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Erik Kolbe

Christiane Körner

Fritzi Ott

David Meierhofer

Stefan Höhme

Michael Kücken

Lutz Brusch

Witigo von Schönfels

Clemens Schafmayer

Mario Brosch

Ute Hofmann

Jochen Hampe

Madlen Matz-Soja

Georg Damm

Daniel Seehofer

Abstract (Expand)

The Hedgehog (Hh) and Wnt/β-Catenin (Wnt) cascades are morphogen pathways whose pronounced influence on adult liver metabolism has been identified in recent years. How both pathways communicate and … control liver metabolic functions are largely unknown. Detecting core components of Wnt and Hh signaling and mathematical modeling showed that both pathways in healthy liver act largely complementary to each other in the pericentral (Wnt) and the periportal zone (Hh) and communicate mainly by mutual repression. The Wnt/Hh module inversely controls the spatiotemporal operation of various liver metabolic pathways, as revealed by transcriptome, proteome, and metabolome analyses. Shifting the balance to Wnt (activation) or Hh (inhibition) causes pericentralization and periportalization of liver functions, respectively. Thus, homeostasis of the Wnt/Hh module is essential for maintaining proper liver metabolism and to avoid the development of certain metabolic diseases. With caution due to minor species-specific differences, these conclusions may hold for human liver as well.

Authors: Erik Kolbe, Susanne Aleithe, Christiane Rennert, Luise Spormann, Fritzi Ott, David Meierhofer, Robert Gajowski, Claus Stöpel, Stefan Hoehme, Michael Kücken, Lutz Brusch, Michael Seifert, Witigo von Schoenfels, Clemens Schafmayer, Mario Brosch, Ute Hofmann, Georg Damm, Daniel Seehofer, Jochen Hampe, Rolf Gebhardt, Madlen Matz-Soja

Date Published: 1st Dec 2019

Publication Type: Not specified

DOI: 10.1016/j.celrep.2019.11.104

Citation: Cell Reports 29(13) : 4553

Created: 22nd Jan 2020 at 09:56, Last updated: 8th Mar 2024 at 07:44

Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control

LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI)

(Show All)

All authors

Mario Brosch

Witigo von Schönfels

Sophie Nehring

Vincent Moser

Clemens Schafmayer

Jochen Hampe

Ann-Kristin Becker

Madlen Matz-Soja

Daniel Seehofer

Georg Damm

Veera Raghavan Thangapandi

Abstract (Expand)

A deeper epigenomic understanding of spatial organization of cells in human tissues is an important challenge. Here we report the first combined positional analysis of transcriptomes and methylomes … across three micro-dissected zones (pericentral, intermediate and periportal) of human liver. We identify pronounced anti-correlated transcriptional and methylation gradients including a core of 271 genes controlling zonated metabolic and morphogen networks and observe a prominent porto-central gradient of DNA methylation at binding sites of 46 transcription factors. The gradient includes an epigenetic and transcriptional Wnt signature supporting the concept of a pericentral hepatocyte regeneration pathway under steady-state conditions. While donors with non-alcoholic fatty liver disease show consistent gene expression differences corresponding to the severity of the disease across all zones, the relative zonated gene expression and DNA methylation patterns remain unchanged. Overall our data provide a wealth of new positional insights into zonal networks controlled by epigenetic and transcriptional gradients in human liver.

Authors: Mario Brosch, Kathrin Kattler, Alexander Herrmann, Witigo von Schönfels, Karl Nordström, Daniel Seehofer, Georg Damm, Thomas Becker, Sebastian Zeissig, Sophie Nehring, Fabian Reichel, Vincent Moser, Raghavan Veera Thangapandi, Felix Stickel, Gustavo Baretton, Christoph Röcken, Michael Muders, Madlen Matz-Soja, Michael Krawczak, Gilles Gasparoni, Hella Hartmann, Andreas Dahl, Clemens Schafmayer, Jörn Walter, Jochen Hampe

Date Published: 1st Dec 2018

Publication Type: Not specified

DOI: 10.1038/s41467-018-06611-5

Citation: Nat Commun 9(1) : 416

Created: 20th Dec 2018 at 12:30, Last updated: 8th Mar 2024 at 07:44