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PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Overview

PoLiMeR is funded through the EU Marie Skłodowska-Curie Innovative Training Network (ITN), which drives scientific excellence and innovation. ITNs bring together universities, research institutes, industry and clinical partners from across the world to train researchers to doctorate level.

Metabolic diseases are a burden on the European population and health care system. It is increasingly recognised that individual differences with respect to history, lifestyle, and genetic make-up affect disease progression and treatment response. A Systems Medicine approach, based on computational models fed with individual patient data, has the potential to provide the basis for a personalised diagnosis and treatment strategy. The PoLiMeR consortium (Polymers in the Liver: Metabolism and Regulation) has identified the inherited, liver-related diseases of glycogen and lipid metabolism as the ideal starting point for innovative research training in personalised ‘Systems Medicine'.

Programme: This Project is not associated with a Programme

SEEK ID: https://fairdomhub.org/projects/130

Public web page: http://polimer-itn.eu/

Organisms: Homo sapiens, Mus musculus, Rattus norvegicus

FAIRDOM PALs: No PALs for this Project

Project created: 6th Dec 2018

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Kishore Alagere Krishnamurthy

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: University of Groningen

Barbara Bakker project_administrator

Projects: SilicoTryp, Multiscale modelling of state transitions in the host-microbiome-brain network, MESI-STRAT, PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: University of Groningen

https://orcid.org/0000-0001-6274-3633
Flavio Bonanini

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: Mimetas

Terry G.J. Derks

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: University of Leiden

Oliver Ebenhöh

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: University of Duesseldorf

Gaia Fancellu

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: John Innes Centre

Eugenio Ferrario

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: University of Bergen

Robert Field

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: John Innes Centre

Ronan Fleming

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: University of Leiden

Chilperic Armel Foko Kuate

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: University of Duesseldorf

Stephan Goetz

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: Iceni Diagnostics Ltd

Thomas Hankemeier

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: University of Leiden

Amy HARMS

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: University of Leiden

Emmalie Jager

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: University Medical Centre Groningen

Ligia Akemi Kiyuna

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: University Medical Centre Groningen

https://orcid.org/0000-0002-9872-2102
Olga Krebs adminproject_administratorasset_housekeeperasset_gatekeeperprogramme_administrator

Projects: SysMO DB, FAIRDOM, ICYSB 2015 - International Practical Course in Systems Biology, ZucAt, SysMO-LAB, Kinetics on the move - Workshop 2016, Example use cases, FAIRDOM user meeting, ErasysApp Funders, EraCoBiotech 2 nd call proposal preparation, Service to URV Tarragona, Spain with respect to their Safety Assessment of Endocrine Disrupting Chemicals model (Active NOW), FAIRDOM & LiSyM & de.NBI Data Structuring Training, MESI-STRAT, INCOME, Multiscale modelling of state transitions in the host-microbiome-brain network, BESTER, TRALAMINOL, Sustainable co-production, INDIE - Biotechnological production of sustainable indole, Extremophiles metabolsim, PoLiMeR - Polymers in the Liver: Metabolism and Regulation, GB-XMap: Assessing the risk of gut-brain cross-diseases Investigating the gut-brain-axis, NAD COMPARTMENTATION, HOTSOLUTE, Stress granules, FAIRDOM Community Workers, GMDS Project Group "FAIRe Dateninfrastrukturen für die Biomedizinische Informatik", Mechanism based modeling viral disease ( COVID-19 ) dynamics in human population, COVID-19 Disease Map, AquaHealth (ERA-BlueBio), LiSyM Core Infrastructure and Management (LiSyM-PD), Early Metabolic Injury (LiSyM-EMI - Pillar I), Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF - Pillar III), Chronic Liver Disease Progression (LiSyM-DP - Pillar II), Liver Function Diagnostics (LiSyM-LiFuDi - Pillar IV), The Hedgehog Signalling Pathway (LiSyM-JGMMS), Multi-Scale Models for Personalized Liver Function Tests (LiSyM-MM-PLF), Model Guided Pharmacotherapy In Chronic Liver Disease (LiSyM-MGP), Molecular Steatosis - Imaging & Modeling (LiSyM-MSIM)

Institutions: Heidelberg Institute for Theoretical Studies (HITS gGmbH), FAIRDOM User meeting, Norwegian University of Science and Technology

https://orcid.org/0000-0003-3540-0402
Dorota Kurek

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: Mimetas

Adil Mardinoglu

Projects: IMOMESIC, HUMET Startup, PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: Chalmers University of Technology

PoLiMeR_user Martines_data

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: Heidelberg Institute for Theoretical Studies (HITS gGmbH)

Ghadeer Mobasher

Projects: PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Institutions: Heidelberg Institute for Theoretical Studies (HITS gGmbH)

https://orcid.org/0000-0003-4026-6965
Chalmers University of Technology

Country:  Sweden

City: Gothenburg

Web page: http://www.chalmers.se/en/

Heidelberg Institute for Theoretical Studies (HITS gGmbH)

Country:  Germany

City: Heidelberg

Web page: http://www.h-its.org/

Heinrich Heine University of Düsseldorf

Country:  Germany

City: Düsseldorf

Web page: http://www.biologie.hhu.de/institute-und-abteilungen/pflanzengenetik/leitung-institut.html

Iceni Diagnostics Ltd

Country:  United Kingdom

City: Norwich

Web page: http://www.icenidiagnostics.com/company/

John Innes Centre

Country:  United Kingdom

City: Norwich

Web page: https://www.jic.ac.uk/

Mimetas

Country:  Netherlands

City: Leiden

Web page: https://mimetas.com/

National University of Ireland

Country:  Ireland

City: Galway

Web page: http://www.nuigalway.ie/

University Medical Centre Groningen

Country:  Netherlands

City: Not specified

Web page: Not specified

University of Bergen

Country:  Norway

City: Not specified

Web page: Not specified

University of Duesseldorf

Country:  Germany

City: Not specified

Web page: Not specified

University of Freiburg

Country:  Germany

City: Freiburg

Web page: http://www.uni-freiburg.de/

University of Groningen

Country:  Netherlands

City: Groningen

Web page: http://www.rug.nl/corporate/index

University of Innsbruck

Country:  Austria

City: Innsbruck

Web page: https://www.uibk.ac.at/

University of Leiden

Country:  Netherlands

City: Not specified

Web page: Not specified

University of Luxembourg

Country:  Luxembourg

City: Not specified

Web page: http://wwwen.uni.lu/

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Transcriptome analysis in medium-chain acyl-CoA dehydrogenase knockout mice
PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Transcriptome analysis suggests a compensatory role of the cofactors coenzyme A and NAD+ in medium-chain acyl-CoA dehydrogenase knockout mice. Expression profiling by high throughput sequencing

Submitter: PoLiMeR_user Martines_data

Assay type: Transcriptomics

Technology type: Rna-seq

Snapshots: No snapshots

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Transcriptome analysis in medium-chain acyl-CoA dehydrogenase knockout mice
PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Transcriptome analysis suggests a compensatory role of the cofactors coenzyme A and NAD+ in medium-chain acyl-CoA dehydrogenase knockout mice. During fasting, mitochondrial fatty-acid β-oxidation (mFAO) is essential for the generation of glucose by the liver. Children with a loss-of-function deficiency in the mFAO enzyme medium-chain acyl-Coenzyme A dehydrogenase (MCAD) are at serious risk of life-threatening low blood glucose levels during fasting in combination with intercurrent disease. However,
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Creators: PoLiMeR_user Martines_data, Terry G.J. Derks, Barbara Bakker, Martines AMF

Submitter: PoLiMeR_user Martines_data

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Transcriptome analysis suggests a compensatory role of the cofactors coenzyme A and NAD+ in medium-chain acyl-CoA dehydrogenase knockout mice
PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Abstract (Expand)

Abstract During fasting, mitochondrial fatty-acid β-oxidation (mFAO) is essential for the generation of glucose by the liver. Children with a loss-of-function deficiency in the mFAO enzyme medium-chain … acyl-Coenzyme A dehydrogenase (MCAD) are at serious risk of life-threatening low blood glucose levels during fasting in combination with intercurrent disease. However, a subset of these children remains asymptomatic throughout life. In MCAD-deficient (MCAD-KO) mice, glucose levels are similar to those of wild-type (WT) mice, even during fasting. We investigated if metabolic adaptations in the liver may underlie the robustness of this KO mouse. WT and KO mice were given a high- or low-fat diet and subsequently fasted. We analyzed histology, mitochondrial function, targeted mitochondrial proteomics, and transcriptome in liver tissue. Loss of MCAD led to a decreased capacity to oxidize octanoyl-CoA. This was not compensated for by altered protein levels of the short- and long-chain isoenzymes SCAD and LCAD. In the transcriptome, we identified subtle adaptations in the expression of genes encoding enzymes catalyzing CoA- and NAD(P)(H)-involving reactions and of genes involved in detoxification mechanisms. We discuss how these processes may contribute to robustness in MCAD-KO mice and potentially also in asymptomatic human subjects with a complete loss of MCAD activity.

Authors: Anne-Claire M. F. Martines, Albert Gerding, Sarah Stolle, Marcel A. Vieira-Lara, Justina C. Wolters, Angelika Jurdzinski, Laura Bongiovanni, Alain de Bruin, Pieter van der Vlies, Gerben van der Vries, Vincent W. Bloks, Terry G. J. Derks, Dirk-Jan Reijngoud, Barbara M. Bakker

Date Published: 1st Dec 2019

Publication Type: Journal

Hepatocytes contribute to residual glucose production in a mouse model for glycogen storage disease type Ia.
PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Abstract (Expand)

It is a long-standing enigma how glycogen storage disease (GSD) type I patients retain a limited capacity for endogenous glucose production despite the loss of glucose-6-phosphatase activity. Insight … into the source of residual endogenous glucose production is of clinical importance given the risk of sudden death in these patients, but so far contradictory mechanisms have been proposed. We investigated glucose-6-phosphatase-independent endogenous glucose production in hepatocytes isolated from a liver-specific GSD Ia mouse model (L-G6pc(-/-) mice) and performed real-time analysis of hepatic glucose fluxes and glycogen metabolism in L-G6pc(-/-) mice using state-of-the-art stable isotope methodologies. Here we show that G6pc-deficient hepatocytes are capable of producing glucose. In vivo analysis of hepatic glucose metabolism revealed that the hepatic glucokinase flux was decreased by 95% in L-G6pc(-/-) mice. It also showed increased glycogen phosphorylase flux in L-G6pc(-/-) mice, which is coupled to the release of free glucose through glycogen debranching. Although the ex vivo activities of debranching enzyme and lysosomal acid maltase, two major hepatic alpha-glucosidases, were unaltered in L-G6pc(-/-) mice, pharmacological inhibition of alpha-glucosidase activity almost completely abolished residual glucose production by G6pc-deficient hepatocytes. CONCLUSION: Our data indicate that hepatocytes contribute to residual glucose production in GSD Ia. We show that alpha-glucosidase activity, i.e. glycogen debranching and/or lysosomal glycogen breakdown, contributes to residual glucose production by GSD Ia hepatocytes. A strong reduction in hepatic GCK flux in L-G6pc-/- mice furthermore limits the phosphorylation of free glucose synthesized by G6pc-deficient hepatocytes, allowing the release of glucose into the circulation. The almost complete abrogation of GCK flux in G6pc-deficient liver also explains the contradictory reports on residual glucose production in GSD Ia patients. (Hepatology 2017;66:2042-2054).

Authors: B. S. Hijmans, A. Boss, T. H. van Dijk, M. Soty, H. Wolters, E. Mutel, A. K. Groen, T. G. J. Derks, G. Mithieux, A. Heerschap, D. J. Reijngoud, F. Rajas, M. H. Oosterveer

Date Published: 21st Jul 2017

Publication Type: Journal

Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders.
PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Abstract (Expand)

BACKGROUND: Defects in genes involved in mitochondrial fatty-acid oxidation (mFAO) reduce the ability of patients to cope with metabolic challenges. mFAO enzymes accept multiple substrates of different … chain length, leading to molecular competition among the substrates. Here, we combined computational modeling with quantitative mouse and patient data to investigate whether substrate competition affects pathway robustness in mFAO disorders. RESULTS: First, we used comprehensive biochemical analyses of wild-type mice and mice deficient for medium-chain acyl-CoA dehydrogenase (MCAD) to parameterize a detailed computational model of mFAO. Model simulations predicted that MCAD deficiency would have no effect on the pathway flux at low concentrations of the mFAO substrate palmitoyl-CoA. However, high concentrations of palmitoyl-CoA would induce a decline in flux and an accumulation of intermediate metabolites. We proved computationally that the predicted overload behavior was due to substrate competition in the pathway. Second, to study the clinical relevance of this mechanism, we used patients' metabolite profiles and generated a humanized version of the computational model. While molecular competition did not affect the plasma metabolite profiles during MCAD deficiency, it was a key factor in explaining the characteristic acylcarnitine profiles of multiple acyl-CoA dehydrogenase deficient patients. The patient-specific computational models allowed us to predict the severity of the disease phenotype, providing a proof of principle for the systems medicine approach. CONCLUSION: We conclude that substrate competition is at the basis of the physiology seen in patients with mFAO disorders, a finding that may explain why these patients run a risk of a life-threatening metabolic catastrophe.

Authors: K. van Eunen, C. M. Volker-Touw, A. Gerding, A. Bleeker, J. C. Wolters, W. J. van Rijt, A. M. Martines, K. E. Niezen-Koning, R. M. Heiner, H. Permentier, A. K. Groen, D. J. Reijngoud, T. G. Derks, B. M. Bakker

Date Published: 7th Dec 2016

Publication Type: Journal

A systems study reveals concurrent activation of AMPK and mTOR by amino acids.
PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Abstract (Expand)

Amino acids (aa) are not only building blocks for proteins, but also signalling molecules, with the mammalian target of rapamycin complex 1 (mTORC1) acting as a key mediator. However, little is known … about whether aa, independently of mTORC1, activate other kinases of the mTOR signalling network. To delineate aa-stimulated mTOR network dynamics, we here combine a computational-experimental approach with text mining-enhanced quantitative proteomics. We report that AMP-activated protein kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR complex 2 (mTORC2) are acutely activated by aa-readdition in an mTORC1-independent manner. AMPK activation by aa is mediated by Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKKbeta). In response, AMPK impinges on the autophagy regulators Unc-51-like kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an mTORC1 antagonist that is activated by starvation. We find that aa acutely activate AMPK concurrently with mTOR. We show that AMPK under aa sufficiency acts to sustain autophagy. This may be required to maintain protein homoeostasis and deliver metabolite intermediates for biosynthetic processes.

Authors: P. Dalle Pezze, S. Ruf, A. G. Sonntag, M. Langelaar-Makkinje, P. Hall, A. M. Heberle, P. Razquin Navas, K. van Eunen, R. C. Tolle, J. J. Schwarz, H. Wiese, B. Warscheid, J. Deitersen, B. Stork, E. Fassler, S. Schauble, U. Hahn, P. Horvatovich, D. P. Shanley, K. Thedieck

Date Published: 21st Nov 2016

Publication Type: Journal

Translational Targeted Proteomics Profiling of Mitochondrial Energy Metabolic Pathways in Mouse and Human Samples.
PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Abstract (Expand)

Absolute measurements of protein abundance are important in the understanding of biological processes and the precise computational modeling of biological pathways. We developed targeted LC-MS/MS assays … in the selected reaction monitoring (SRM) mode to quantify over 50 mitochondrial proteins in a single run. The targeted proteins cover the tricarboxylic acid cycle, fatty acid beta-oxidation, oxidative phosphorylation, and the detoxification of reactive oxygen species. Assays used isotopically labeled concatemers as internal standards designed to target murine mitochondrial proteins and their human orthologues. Most assays were also suitable to quantify the corresponding protein orthologues in rats. After exclusion of peptides that did not pass the selection criteria, we arrived at SRM assays for 55 mouse, 52 human, and 51 rat proteins. These assays were optimized in isolated mitochondrial fractions from mouse and rat liver and cultured human fibroblasts and in total liver extracts from mouse, rat, and human. The developed proteomics approach is suitable for the quantification of proteins in the mitochondrial energy metabolic pathways in mice, rats, and humans as a basis for translational research. Initial data show that the assays have great potential for elucidating the adaptive response of human patients to mutations in mitochondrial proteins in a clinical setting.

Authors: J. C. Wolters, J. Ciapaite, K. van Eunen, K. E. Niezen-Koning, A. Matton, R. J. Porte, P. Horvatovich, B. M. Bakker, R. Bischoff, H. P. Permentier

Date Published: 2nd Sep 2016

Publication Type: Journal

Parallel DNA Polymerase Chain Reaction (PD-PCR)
FAIRDOM, PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Abstract (Expand)

This protocol describe an approach in which the first primer binds in a parallel complementary orientation to the single-stranded DNA, leading to synthesis in a parallel direction. Further reactions … happened in a conventional way leading to the synthesis of PCR product having polarity opposite to the template used. Here in FAIRDOM we use this SOP as an example/template

Authors: vikash bhardwaj, Vikash bhardwaj, Kulbhushan Sharma

Date Published: 5th May 2016

Publication Type: Journal

Know when your numbers are significant
PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Abstract (Expand)

Experimental biologists, their reviewers and their publishers must grasp basic statistics, urges David L. Vaux, or sloppy science will continue to grow. "And, once in the lab, people generally …y just do what everyone else does, without always understanding why." (D. Vaux)

Author: David L. Vaux

Date Published: 1st Dec 2012

Publication Type: Journal

Disturbed hepatic carbohydrate management during high metabolic demand in medium-chain acyl-CoA dehydrogenase (MCAD)-deficient mice.
PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Abstract (Expand)

UNLABELLED: Medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) catalyzes crucial steps in mitochondrial fatty acid oxidation, a process that is of key relevance for maintenance of energy homeostasis, … especially during high metabolic demand. To gain insight into the metabolic consequences of MCAD deficiency under these conditions, we compared hepatic carbohydrate metabolism in vivo in wild-type and MCAD(-/-) mice during fasting and during a lipopolysaccharide (LPS)-induced acute phase response (APR). MCAD(-/-) mice did not become more hypoglycemic on fasting or during the APR than wild-type mice did. Nevertheless, microarray analyses revealed increased hepatic peroxisome proliferator-activated receptor gamma coactivator-1alpha (Pgc-1alpha) and decreased peroxisome proliferator-activated receptor alpha (Ppar alpha) and pyruvate dehydrogenase kinase 4 (Pdk4) expression in MCAD(-/-) mice in both conditions, suggesting altered control of hepatic glucose metabolism. Quantitative flux measurements revealed that the de novo synthesis of glucose-6-phosphate (G6P) was not affected on fasting in MCAD(-/-) mice. During the APR, however, this flux was significantly decreased (-20%) in MCAD(-/-) mice compared with wild-type mice. Remarkably, newly formed G6P was preferentially directed toward glycogen in MCAD(-/-) mice under both conditions. Together with diminished de novo synthesis of G6P, this led to a decreased hepatic glucose output during the APR in MCAD(-/-) mice; de novo synthesis of G6P and hepatic glucose output were maintained in wild-type mice under both conditions. APR-associated hypoglycemia, which was observed in wild-type mice as well as MCAD(-/-) mice, was mainly due to enhanced peripheral glucose uptake. CONCLUSION: Our data demonstrate that MCAD deficiency in mice leads to specific changes in hepatic carbohydrate management on exposure to metabolic stress. This deficiency, however, does not lead to reduced de novo synthesis of G6P during fasting alone, which may be due to the existence of compensatory mechanisms or limited rate control of MCAD in murine mitochondrial fatty acid oxidation.

Authors: H. Herrema, T. G. Derks, T. H. van Dijk, V. W. Bloks, A. Gerding, R. Havinga, U. J. Tietge, M. Muller, G. P. Smit, F. Kuipers, D. J. Reijngoud

Date Published: 7th May 2008

Publication Type: Not specified

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Chilperic Presentation November 2019 Meeting
PoLiMeR - Polymers in the Liver: Metabolism and Regulation
No description specified

Creator: Chilperic Armel Foko Kuate

Submitter: Chilperic Armel Foko Kuate

Chilperic Poster
PoLiMeR - Polymers in the Liver: Metabolism and Regulation

A computational model of lipids synthesis.

Creator: Chilperic Armel Foko Kuate

Submitter: Chilperic Armel Foko Kuate

Python presentation by Adelaide Raguin, Friday May 31st
PoLiMeR - Polymers in the Liver: Metabolism and Regulation

Slides for the Python Workshop

Creator: Oliver Ebenhöh

Submitter: Oliver Ebenhöh

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