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37 Publications visible to you, out of a total of 37
The TGF-beta1 target WISP1 is highly expressed in liver cirrhosis and cirrhotic HCC microenvironment and involved in pro- and anti-tumorigenic effects.

Abstract (Expand)

INTRODUCTION: WNT1-inducible signalling pathway protein 1 (WISP1) promotes progression of several tumor entities often correlating with worse prognosis. Here its expression regulation and role in the … progression of chronic liver diseases (CLD) was investigated. METHODS: WISP1 expression was analyzed in human HCC datasets, in biopsies and serum samples and an HCC patient tissue microarray (TMA) including correlation to clinicopathological parameters. Spatial distribution of WISP1 expression was determined using RNAscope analysis. Regulation of WISP1 expression was investigated in cytokine-stimulated primary mouse hepatocytes (PMH) by array analysis and qRT-PCR. Outcome of WISP1 stimulation was analyzed by IncuCyte S3-live cell imaging, qRT-PCR, and immunoblotting in murine AML12 cells. RESULTS: In a TMA, high WISP1 expression was positively correlated with early HCC stages and male sex. Highest WISP1 expression levels were detected in patients with cirrhosis as compared to healthy individuals, patients with early fibrosis, and non-cirrhotic HCC in liver biopsies, expression datasets and serum samples. WISP1 transcripts were predominantly detected in hepatocytes of cirrhotic rather than tumorous liver tissue. High WISP1 expression was associated with better survival. In PMH, AML12 and HepaRG, WISP1 was identified as a specific TGF-beta1 target gene. Accordingly, expression levels of both cytokines positively correlated in human HCC patient samples. WISP1-stimulation induced the expression of Bcl-xL, PCNA and p21 in AML12 cells. CONCLUSIONS: WISP1 expression is induced by TGF-beta1 in hepatocytes and is associated with cirrhotic liver disease. We propose a crucial role of WISP1 in balancing pro- and anti-tumorigenic effects during premalignant stages of CLD.

Authors: A. Dropmann, S. Alex, K. Schorn, C. Tong, T. Caccamo, P. Godoy, I. Ilkavets, R. Liebe, D. Gonzalez, J. G. Hengstler, A. Piiper, L. Quagliata, M. S. Matter, O. Waidmann, F. Finkelmeier, T. Feng, T. S. Weiss, N. Rahbari, E. Birgin, E. Rasbach, S. Roessler, K. Breuhahn, M. Toth, M. P. Ebert, S. Dooley, S. Hammad, N. M. Meindl-Beinker

Date Published: 5th Nov 2024

Publication Type: Journal

A liver digital twin for in silico testing of cellular and inter-cellular mechanisms in regeneration after drug-induced damage.

Abstract (Expand)

This communication presents a mathematical mechanism-based model of the regenerating liver after drug-induced pericentral lobule damage resolving tissue microarchitecture. The consequence of alternative … hypotheses about the interplay of different cell types on regeneration was simulated. Regeneration dynamics has been quantified by the size of the damage-induced dead cell area, the hepatocyte density and the spatial-temporal profile of the different cell types. We use deviations of observed trajectories from the simulated system to identify branching points, at which the systems behavior cannot be explained by the underlying set of hypotheses anymore. Our procedure reflects a successful strategy for generating a fully digital liver twin that, among others, permits to test perturbations from the molecular up to the tissue scale. The model simulations are complementing current knowledge on liver regeneration by identifying gaps in mechanistic relationships and guiding the system toward the most informative (lacking) parameters that can be experimentally addressed.

Authors: J. Zhao, A. Ghallab, R. Hassan, S. Dooley, J. G. Hengstler, D. Drasdo

Date Published: 16th Feb 2024

Publication Type: Journal

Basal MET phosphorylation is an indicator of hepatocyte dysregulation in liver disease

Abstract (Expand)

Abstract Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, metabolic dysfunction-associated steatotic liver disease (MASLD) …otic liver disease (MASLD) is gaining importance as the disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in MASLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary hepatocytes from a preclinical model fed with a Western diet (WD) an increased basal MET phosphorylation and a strong downregulation of the PI3K-AKT pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.

Authors: Sebastian Burbano De Lara, Svenja Kemmer, Ina Biermayer, Svenja Feiler, Artyom Vlasov, Lorenza A D’Alessandro, Barbara Helm, Christina Mölders, Yannik Dieter, Ahmed Ghallab, Jan G Hengstler, Christiane Körner, Madlen Matz-Soja, Christina Götz, Georg Damm, Katrin Hoffmann, Daniel Seehofer, Thomas Berg, Marcel Schilling, Jens Timmer, Ursula Klingmüller

Date Published: 12th Jan 2024

Publication Type: Journal

Basal MET Phosphorylation is an Indicator of Hepatocyte Dysregulation in Liver Disease (preprint)

Abstract (Expand)

Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, Non-alcoholic fatty liver disease (NAFLD) is gaining importance as the … disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in NAFLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary hepatocytes from a preclinical model fed with a Western diet (WD) a strong downregulation of the PI3K-AKT pathway and an upregulation of the MAPK pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.

Authors: Sebastian Burbano De Lara, Svenja Kemmer, Ina Biermayer, Svenja Feiler, Artyom Vlasov, Lorenza D'Alessandro, Barbara Helm, Yannik Dieter, Ahmed Ghallab, Jan Hengstler, Professor Dr. med. Katrin Hoffmann, Marcel Schilling, Jens Timmer, Ursula Klingmüller

Date Published: 4th Jul 2023

Publication Type: Journal

Tolerance of repeated toxic injuries of murine livers is associated with steatosis and inflammation

Abstract (Expand)

Abstract The human liver has a remarkable capacity to regenerate and thus compensate over decades for fibrosis caused by toxic chemicals, drugs, alcohol, or malnutrition. To date, no protective mechanisms …rition. To date, no protective mechanisms have been identified that help the liver tolerate these repeated injuries. In this study, we revealed dysregulation of lipid metabolism and mild inflammation as protective mechanisms by studying longitudinal multi-omic measurements of liver fibrosis induced by repeated CCl 4 injections in mice ( n  = 45). Based on comprehensive proteomics, transcriptomics, blood- and tissue-level profiling, we uncovered three phases of early disease development—initiation, progression, and tolerance. Using novel multi-omic network analysis, we identified multi-level mechanisms that are significantly dysregulated in the injury-tolerant response. Public data analysis shows that these profiles are altered in human liver diseases, including fibrosis and early cirrhosis stages. Our findings mark the beginning of the tolerance phase as the critical switching point in liver response to repetitive toxic doses. After fostering extracellular matrix accumulation as an acute response, we observe a deposition of tiny lipid droplets in hepatocytes only in the Tolerant phase. Our comprehensive study shows that lipid metabolism and mild inflammation may serve as biomarkers and are putative functional requirements to resist further disease progression.

Authors: Seddik Hammad, Christoph Ogris, Amnah Othman, Pia Erdoesi, Wolfgang Schmidt-Heck, Ina Biermayer, Barbara Helm, Yan Gao, Weronika Piorońska, Christian H. Holland, Lorenza A. D’Alessandro, Carolina de la Torre, Carsten Sticht, Sherin Al Aoua, Fabian J. Theis, Heike Bantel, Matthias P. Ebert, Ursula Klingmüller, Jan G. Hengstler, Steven Dooley, Nikola S. Mueller

Date Published: 1st Jul 2023

Publication Type: Journal

Sublethal necroptosis signaling promotes inflammation and liver cancer

Abstract

Not specified

Authors: Mihael Vucur, Ahmed Ghallab, Anne T. Schneider, Arlind Adili, Mingbo Cheng, Mirco Castoldi, Michael T. Singer, Veronika Büttner, Leonie S. Keysberg, Lena Küsgens, Marlene Kohlhepp, Boris Görg, Suchira Gallage, Jose Efren Barragan Avila, Kristian Unger, Claus Kordes, Anne-Laure Leblond, Wiebke Albrecht, Sven H. Loosen, Carolin Lohr, Markus S. Jördens, Anne Babler, Sikander Hayat, David Schumacher, Maria T. Koenen, Olivier Govaere, Mark V. Boekschoten, Simone Jörs, Carlos Villacorta-Martin, Vincenzo Mazzaferro, Josep M. Llovet, Ralf Weiskirchen, Jakob N. Kather, Patrick Starlinger, Michael Trauner, Mark Luedde, Lara R. Heij, Ulf P. Neumann, Verena Keitel, Johannes G. Bode, Rebekka K. Schneider, Frank Tacke, Bodo Levkau, Twan Lammers, Georg Fluegen, Theodore Alexandrov, Amy L. Collins, Glyn Nelson, Fiona Oakley, Derek A. Mann, Christoph Roderburg, Thomas Longerich, Achim Weber, Augusto Villanueva, Andre L. Samson, James M. Murphy, Rafael Kramann, Fabian Geisler, Ivan G. Costa, Jan G. Hengstler, Mathias Heikenwalder, Tom Luedde

Date Published: 1st Jul 2023

Publication Type: Journal

Digital twin demonstrates significance of biomechanical growth control in liver regeneration after partial hepatectomy

Abstract

Not specified

Authors: Stefan Hoehme, Seddik Hammad, Jan Boettger, Brigitte Begher-Tibbe, Petru Bucur, Eric Vibert, Rolf Gebhardt, Jan G. Hengstler, Dirk Drasdo

Date Published: 2023

Publication Type: Journal

Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression

Abstract (Expand)

Mouse models of non-alcoholic fatty liver disease (NAFLD) are required to define therapeutic targets, but detailed time-resolved studies to establish a sequence of events are lacking. Here, we fed male …e, we fed male C57Bl/6N mice a Western or standard diet over 48 weeks. Multiscale time-resolved characterization was performed using RNA-seq, histopathology, immunohistochemistry, intravital imaging, and blood chemistry; the results were compared to human disease. Acetaminophen toxicity and ammonia metabolism were additionally analyzed as functional readouts. We identified a sequence of eight key events: formation of lipid droplets; inflammatory foci; lipogranulomas; zonal reorganization; cell death and replacement proliferation; ductular reaction; fibrogenesis; and hepatocellular cancer. Functional changes included resistance to acetaminophen and altered nitrogen metabolism. The transcriptomic landscape was characterized by two large clusters of monotonously increasing or decreasing genes, and a smaller number of ‘rest-and-jump genes’ that initially remained unaltered but became differentially expressed only at week 12 or later. Approximately 30% of the genes altered in human NAFLD are also altered in the present mouse model and an increasing overlap with genes altered in human HCC occurred at weeks 30–48. In conclusion, the observed sequence of events recapitulates many features of human disease and offers a basis for the identification of therapeutic targets.

Authors: Ahmed Ghallab, Maiju Myllys, Adrian Friebel, Julia Duda, Karolina Edlund, Emina Halilbasic, Mihael Vucur, Zaynab Hobloss, Lisa Brackhagen, Brigitte Begher-Tibbe, Reham Hassan, Michael Burke, Erhan Genc, Lynn Johann Frohwein, Ute Hofmann, Christian H. Holland, Daniela González, Magdalena Keller, Abdel-latif Seddek, Tahany Abbas, Elsayed S. I. Mohammed, Andreas Teufel, Timo Itzel, Sarah Metzler, Rosemarie Marchan, Cristina Cadenas, Carsten Watzl, Michael A. Nitsche, Franziska Kappenberg, Tom Luedde, Thomas Longerich, Jörg Rahnenführer, Stefan Hoehme, Michael Trauner, Jan G. Hengstler

Date Published: 1st Oct 2021

Publication Type: Journal

Transcriptomic Cross‐Species Analysis of Chronic Liver Disease Reveals Consistent Regulation Between Humans and Mice

Abstract

Not specified

Authors: Christian H. Holland, Ricardo O. Ramirez Flores, Maiju Myllys, Reham Hassan, Karolina Edlund, Ute Hofmann, Rosemarie Marchan, Cristina Cadenas, Jörg Reinders, Stefan Hoehme, Abdel‐latif Seddek, Steven Dooley, Verena Keitel, Patricio Godoy, Brigitte Begher‐Tibbe, Christian Trautwein, Christian Rupp, Sebastian Mueller, Thomas Longerich, Jan G. Hengstler, Julio Saez‐Rodriguez, Ahmed Ghallab

Date Published: 28th Aug 2021

Publication Type: Journal

On the mechanisms of biliary flux

Abstract

Not specified

Authors: Nachiket Vartak, Dirk Drasdo, Fabian Geisler, Tohru Itoh, Ronald P.J. Oude Elferink, Stan F.J. van de Graaf, John Chiang, Verena Keitel, Michael Trauner, Peter Jansen, Jan G Hengstler

Date Published: 23rd Jun 2021

Publication Type: Journal

Hepatocyte-specific NRF2 activation controls fibrogenesis and carcinogenesis in steatohepatitis.

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

Hepatocyte-specific NRF2 activation controls fibrogenesis and carcinogenesis in steatohepatitis

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

Intravital dynamic and correlative imaging reveals diffusion‐dominated canalicular and flow‐augmented ductular bile flux

Abstract (Expand)

Small‐molecule flux in tissue‐microdomains is essential for organ function, but knowledge of this process is scant due to the lack of suitable methods. We developed two independent techniques that allow … the quantification of advection (flow) and diffusion in individual bile canaliculi and in interlobular bile ducts of intact livers in living mice, namely Fluorescence Loss After Photoactivation (FLAP) and Intravital Arbitrary Region Image Correlation Spectroscopy (IVARICS). The results challenge the prevailing ‘mechano‐osmotic’ theory of canalicular bile flow. After active transport across hepatocyte membranes bile acids are transported in the canaliculi primarily by diffusion. Only in the interlobular ducts, diffusion is augmented by regulatable advection. Photoactivation of fluorescein bis‐(5‐carboxymethoxy‐2‐nitrobenzyl)‐ether (CMNB‐caged fluorescein) in entire lobules demonstrated the establishment of diffusive gradients in the bile canalicular network and the sink function of interlobular ducts. In contrast to the bile canalicular network, vectorial transport was detected and quantified in the mesh of interlobular bile ducts. In conclusion, the liver consists of a diffusion dominated canalicular domain, where hepatocytes secrete small molecules and generate a concentration gradient and a flow‐augmented ductular domain, where regulated water influx creates unidirectional advection that augments the diffusive flux.

Authors: Nachiket Vartak, Georgia Guenther, Florian Joly, Amruta Damle‐Vartak, Gudrun Wibbelt, Jörns Fickel, Simone Jörs, Brigitte Begher‐Tibbe, Adrian Friebel, Kasimir Wansing, Ahmed Ghallab, Marie Rosselin, Noemie Boissier, Irene Vignon‐Clementel, Christian Hedberg, Fabian Geisler, Heribert Hofer, Peter Jansen, Stefan Hoehme, Dirk Drasdo, Jan G. Hengstler

Date Published: 19th Jun 2020

Publication Type: Journal

Model predicts fundamental role of biomechanical control of cell cycle progression during liver regeneration after partial hepatectomy

Abstract

Not specified

Authors: Stefan Hoehme, Rolf Gebhardt, JG Hengstler, D. Drasdo

Date Published: 18th May 2020

Publication Type: Misc

Influence of Liver Fibrosis on Lobular Zonation

Abstract (Expand)

Little is known about how liver fibrosis influences lobular zonation. To address this question, we used three mouse models of liver fibrosis, repeated CCl4 administration for 2, 6 and 12 months to … induce pericentral damage, as well as bile duct ligation (21 days) and mdr2−/− mice to study periportal fibrosis. Analyses were performed by RNA-sequencing, immunostaining of zonated proteins and image analysis. RNA-sequencing demonstrated a significant enrichment of pericentral genes among genes downregulated by CCl4; vice versa, periportal genes were enriched among the upregulated genes. Immunostaining showed an almost complete loss of pericentral proteins, such as cytochrome P450 enzymes and glutamine synthetase, while periportal proteins, such as arginase 1 and CPS1 became expressed also in pericentral hepatocytes. This pattern of fibrosis-associated ‘periportalization’ was consistently observed in all three mouse models and led to complete resistance to hepatotoxic doses of acetaminophen (200 mg/kg). Characterization of the expression response identified the inflammatory pathways TGFβ, NFκB, TNFα, and transcription factors NFKb1, Stat1, Hif1a, Trp53, and Atf1 among those activated, while estrogen-associated pathways, Hnf4a and Hnf1a, were decreased. In conclusion, liver fibrosis leads to strong alterations of lobular zonation, where the pericentral region adopts periportal features. Beside adverse consequences, periportalization supports adaptation to repeated doses of hepatotoxic compounds.

Authors: Ahmed Ghallab, Maiju Myllys, Christian Holland, Ayham Zaza, Walaa Murad, Reham Hassan, Yasser A Ahmed, Tahany Abbas, Eman Abdelrahim, Kai Markus Schneider, Madlen Matz-Soja, Joerg Reinders, Rolf Gebhardt, Theresa Hildegard Wirtz, Maximilian Hatting, Dirk Drasdo, Julio Saez-Rodriguez, Christian Trautwein, Jan Hengstler

Date Published: 1st Dec 2019

Publication Type: Not specified

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