Christian Trautwein

About Christian Trautwein:
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SEEK ID: https://seek.lisym.org/people/104

Location:  Germany

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LiSyM-Krebs

LiSyM-Krebs ist ein nationales Forschungsnetz zur Früherkennung und Prävention von Leberkrebs, das unter Verwendung des systemmedizinischen Forschungsansatzes die komplexen, dynamischen Prozesse der Krankheitsprogression analysiert, um ausgehend von den Erkenntnissen aus dem Forschungsnetz LiSyM die Entstehung von Leberkrebs besser zu verstehen, vorherzusagen und im besten Fall sogar zu verhindern.

Projects: LiSyM-Krebs Partnering, LiSyM-Krebs

Web page: Not specified

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 ...

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, Project Management PTJ, LiSyM network, LiSyM Scientific Leadership Team (LiSyM-LT)

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

LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

In one in five people with NAFLD, the functioning liver cells, the hepatocytes, are replaced by connective tissue. Eventually this fibrosis becomes irreversible. In this state the liver is like a ‘scar that never heals’. Through it, the liver loses many of its vital functions. LiSyM-Pillar II wants to know more about which factors promote fibrosis and the conditions under which fibrosis becomes irreversible How can fibrosis be diagnosed as early as possible? Researchers in the pillar are also ...

Programme: LiSyM: Liver Systems Medicine

Public web page: http://www.lisym.org/our-work/pillar-research

Start date: 1st Jan 2016

LiSyM network

This comprises the whole LiSyM network

Programme: LiSyM: Liver Systems Medicine

Public web page: http://www.lisym.org

Start date: 1st Jan 2016

LiSyM-Krebs Partnering

This generic project is intended to be a forum for all LiSyM partner and external stakeholders interested in participating in the BMBF initiative LiSyM-Krebs.

Programme: LiSyM-Krebs

Public web page: https://www.ptj.de/projektfoerderung/gesundheitsforschung/lisym-krebs

LiSyM Scientific Leadership Team (LiSyM-LT)

Day-to-day science within the LiSyM is overseen and directed by the the LiSyM Scientific Leadership Team. This coordination team comprises the pillar coordinators and additional LiSyM members, and ensures smooth interaction between multi-skilled groups, often working in different institutions and across significant distances within Germany.

Programme: LiSyM: Liver Systems Medicine

Public web page: http://www.lisym.org/who-we-are

Unexpected Pro-Fibrotic Effect of MIF in Non-Alcoholic Steatohepatitis Is Linked to a Shift in NKT Cell Populations
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Abstract (Expand)

Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine with anti-fibrotic properties in toxic liver injury models and anti-steatotic functions in non-alcoholic fatty liver … disease (NAFLD) attributed to the CD74/AMPK signaling pathway. As NAFLD progression is associated with fibrosis, we studied MIF function during NAFLD-associated liver fibrogenesis in mice and men by molecular, histological and immunological methods in vitro and in vivo. After NASH diet feeding, hepatic Mif expression was strongly induced, an effect which was absent in Mif∆hep mice. In contrast to hepatotoxic fibrosis models, NASH diet-induced fibrogenesis was significantly abrogated in Mif−/− and Mif∆hep mice associated with a reduced accumulation of the pro-fibrotic type-I NKT cell subpopulation. In vitro, MIF skewed the differentiation of NKT cells towards the type-I subtype. In line with the murine results, expression of fibrosis markers strongly correlated with MIF, its receptors, and markers of NKT type-I cells in NASH patients. We conclude that MIF expression is induced during chronic metabolic injury in mice and men with hepatocytes representing the major source. In NAFLD progression, MIF contributes to liver fibrogenesis skewing NKT cell polarization toward a pro-fibrotic phenotype highlighting the complex, context-dependent role of MIF during chronic liver injury.

Authors: D. Heinrichs, E. F. Brandt, P. Fischer, Janine Koehncke, Theresa H. Wirtz, N. Guldiken, S. Djudjaj, P. Boor, D.Kroy, R. Weiskirchen, Richard Bucala, H.E. Wasmuth, P. Strnad, Christian Trautwein, J. Bernhagen, M. L. Berres

Date Published: 28th Jan 2021

Publication Type: Journal

Hepatocyte-specific NRF2 activation controls fibrogenesis and carcinogenesis in steatohepatitis.
LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi)

Abstract (Expand)

BACKGROUND & AIMS: In chronic liver diseases, inflammation induces oxidative stress and thus may contribute to the progression of liver injury, fibrosis, and carcinogenesis. The KEAP1/NRF2 axis is … a major regulator of cellular redox balance. In the present study, we investigated whether the KEAP1/NRF2 system is involved in liver disease progression in humans and mice. METHODS: The clinical relevance of oxidative stress was investigated by liver RNA sequencing in a well-characterized cohort of patients with non-alcoholic fatty liver disease (n = 63) and correlated with histological and clinical parameters. For functional analysis, hepatocyte-specific Nemo knockout (NEMO(Deltahepa)) mice were crossed with hepatocyte-specific Keap1 knockout (KEAP1(Deltahepa)) mice. RESULTS: Immunohistochemical analysis of human liver sections showed increased oxidative stress and high NRF2 expression in patients with chronic liver disease. RNA sequencing of liver samples in a human pediatric NAFLD cohort revealed a significant increase of NRF2 activation correlating with the grade of inflammation, but not with the grade of steatosis, which could be confirmed in a second adult NASH cohort. In mice, microarray analysis revealed that Keap1 deletion induces NRF2 target genes involved in glutathione metabolism and xenobiotic stress (e.g., Nqo1). Furthermore, deficiency of one of the most important antioxidants, glutathione (GSH), in NEMO(Deltahepa) livers was rescued after deleting Keap1. As a consequence, NEMO(Deltahepa)/KEAP1(Deltahepa) livers showed reduced apoptosis compared to NEMO(Deltahepa) livers as well as a dramatic downregulation of genes involved in cell cycle regulation and DNA replication. Consequently, NEMO(Deltahepa)/KEAP1(Deltahepa) compared to NEMO(Deltahepa) livers displayed decreased fibrogenesis, lower tumor incidence, reduced tumor number, and decreased tumor size. CONCLUSIONS: NRF2 activation in patients with non-alcoholic steatohepatitis correlates with the grade of inflammation, but not steatosis. Functional analysis in mice demonstrated that NRF2 activation in chronic liver disease is protective by ameliorating fibrogenesis, initiation and progression of hepatocellular carcinogenesis. LAY SUMMARY: The KEAP1 (Kelch-like ECH-associated protein-1)/NRF2 (erythroid 2-related factor 2) axis has a major role in regulating cellular redox balance. Herein, we show that NRF2 activity correlates with the grade of inflammation in patients with non-alcoholic steatohepatitis. Functional studies in mice actually show that NRF2 activation, resulting from KEAP1 deletion, protects against fibrosis and cancer.

Authors: A. Mohs, T. Otto, K. M. Schneider, M. Peltzer, M. Boekschoten, C. H. Holland, C. A. Hudert, L. Kalveram, S. Wiegand, J. Saez-Rodriguez, T. Longerich, J. G. Hengstler, C. Trautwein

Date Published: 22nd Dec 2020

Publication Type: Journal

Balance between macrophage migration inhibitory factor and sCD74 predicts outcome in patients with acute decompensation of cirrhosis
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Abstract

Not specified

Authors: Theresa H. Wirtz, Philipp A. Reuken, Christian Jansen, Petra Fischer, Irina Bergmann, Christina Backhaus, Christoph Emontzpohl, Johanna Reißing, Elisa F. Brandt, M. Teresa Koenen, Kai M. Schneider, Robert Schierwagen, Maximilian J. Brol, Johannes Chang, Henning W. Zimmermann, Nilay Köse-Vogel, Thomas Eggermann, Ingo Kurth, Christian Stoppe, Richard Bucala, Jürgen Bernhagen, Michael Praktiknjo, Andreas Stallmach, Christian Trautwein, Jonel Trebicka, Tony Bruns, Marie-Luise Berres

Date Published: 1st Dec 2020

Publication Type: Journal

Hepatocyte-specific NRF2 activation controls fibrogenesis and carcinogenesis in steatohepatitis
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Abstract (Expand)

Background & Aims Inflammation in chronic liver diseases induces oxidative stress and thus may contribute to progression of liver injury, fibrosis, and carcinogenesis. The KEAP1/NRF2 axis is a major … regulator of cellular redox balance. In the present study, we investigated whether the KEAP1/NRF2 system is involved in liver disease progression in human and mice. Methods The clinical relevance of oxidative stress was investigated in a well-characterized cohort of NAFLD patients (n=63) by liver RNA sequencing and correlated with histological and clinical parameters. For functional analysis hepatocyte-specific NEMO knock-out (NEMO Δhepa) mice were crossed with hepatocyte-specific KEAP1 knock-out (KEAP1 Δhepa) mice. Results Immunohistochemical analysis of human liver sections showed increased oxidative stress and high NRF2 expression in patients with chronic liver disease. RNA sequencing of liver samples in a human pediatric NAFLD cohort revealed a significant increase of NRF2 activation correlating with the grade of inflammation, but not with the grade of steatosis, which could be confirmed in a second adult NASH cohort. In mice, microarray analysis revealed that KEAP1 deletion induces NRF2 target genes involved in glutathione metabolism and xenobiotic stress (e.g., Nqo1). Furthermore, deficiency of one of the most important antioxidants, glutathione (GSH), in NEMO Δhepa livers was rescued after deleting KEAP1. As a consequence, NEMO Δhepa/KEAP1 Δhepa livers showed reduced apoptosis compared to NEMO Δhepa livers as well as a dramatic downregulation of genes involved in cell cycle regulation and DNA replication. Consequently, NEMO Δhepa/KEAP1 Δhepa compared to NEMO Δhepa livers displayed decreased fibrogenesis, lower tumor incidence, reduced tumor number, and decreased tumor size. Conclusions NRF2 activation in NASH patients correlates with the grade of inflammation, but not steatosis. Functional analysis in mice demonstrated that NRF2 activation in chronic liver disease is protective by ameliorating fibrogenesis, initiation and progression of hepatocellular carcinogenesis.

Authors: Antje Mohs, Tobias Otto, Kai Markus Schneider, Mona Peltzer, Mark Boekschoten, Christian H. Holland, Christian A. Hudert, Laura Kalveram, Susanna Wiegand, Julio Saez-Rodriguez, Thomas Longerich, Jan G. Hengstler, Christian Trautwein

Date Published: 1st Oct 2020

Publication Type: Journal

Lipid-encapsulated siRNA for hepatocyte-directed treatment of advanced liver disease
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM network

Abstract (Expand)

Lipid-based RNA nanocarriers have been recently accepted as a novel therapeutic option in humans, thus increasing the therapeutic options for patients. Tailored nanomedicines will enable to treat chronic … liver disease (CLD) and end-stage liver cancer, disorders with high mortality and few treatment options. Here, we investigated the curative potential of gene therapy of a key molecule in CLD, the c-Jun N-terminal kinase-2 (Jnk2). Delivery to hepatocytes was achieved using a lipid-based clinically employable siRNA formulation that includes a cationic aminolipid to knockdown Jnk2 (named siJnk2). After assessing the therapeutic potential of siJnk2 treatment, non-invasive imaging demonstrated reduced apoptotic cell death and improved hepatocarcinogenesis was evidenced by improved liver parenchyma as well as ameliorated markers of hepatic damage, reduced fibrogenesis in 1-year-old mice. Strikingly, chronic siJnk2 treatment reduced premalignant nodules, indicative of tumor initiation. Furthermore, siJnk2 treatment led to a significant activation of the immune cell compartment. In conclusion, Jnk2 knockdown in hepatocytes ameliorated hepatitis, fibrogenesis, and initiation of hepatocellular carcinoma (HCC), and hence might be a suitable therapeutic option, to define novel molecular targets for precision medicine in CLD.

Authors: Marius Maximilian Woitok, Miguel Eugenio Zoubek, Dennis Doleschel, Matthias Bartneck, Mohamed Ramadan Mohamed, Fabian Kießling, Wiltrud Lederle, Christian Trautwein, Francisco Javier Cubero

Date Published: 1st May 2020

Publication Type: Journal

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