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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

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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

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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

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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

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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

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 applicable to live animals. We developed a methodology … based on dynamic and correlative imaging for quantitative intravital flux analysis. Application to the liver, challenged the prevailing ‘mechano-osmotic’ theory of canalicular bile flow. After active transport across hepatocyte membranes bile salts are transported in the canaliculi primarily by diffusion. Only in the interlobular ducts, diffusion is augmented by regulatable advection. We corroborate these observations with in silico simulations and pan-species comparisons of lobule size. This study demonstrates a flux mechanism, where the energy invested in transmembrane transport entropically dissipates in a sub-micron scale vessel network.

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: 26th Sep 2019

Publication Type: Journal

Aged Abcb4-/- mice upon acute sublethal chemical insult recapitulate features of acute-on-chronic liver failure in patients

Abstract

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Authors: S Hammad, JG Hengstler, S Dooley

Date Published: 2019

Publication Type: Not specified

Jagged-1 upregulation in stressed hepatocytes is crucial for liver regeneration

Abstract

Not specified

Authors: B Dewidar, S Hammad, MP Ebert, JG Hengstler, S Dooley

Date Published: 2019

Publication Type: Not specified

Cellular and nuclear hepatocyte ploidy represent a repository in regenerating livers

Abstract

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Authors: S Hammad, U Dahmen, A Othman, I Recklinghausen, JG Hengstler, U Klingmüller, S Dooley

Date Published: 2019

Publication Type: Not specified

CYP2E1 recovery is associated with a pericentral fibrosis pattern after repeated CCl4 insults

Abstract

Not specified

Authors: S Hammad, J Zhao, Y Yin, A Zaza, D Drasdo, JG Hengstler, S Dooley

Date Published: 2019

Publication Type: Not specified

Pipe-3D: A Pipeline Based on Immunofluorescence, 3D Confocal Imaging, Reconstructions, and Morphometry for Biliary Network Analysis in Cholestasis

Abstract

Not specified

Authors: Amruta Damle-Vartak, Brigitte Begher-Tibbe, Georgia Gunther, Fabian Geisler, Nachiket Vartak, Jan G. Hengstler

Date Published: 2019

Publication Type: Book

Bile micro-infarcts in cholestasis are initiated by rupture of the apical hepatocyte membrane and cause shunting of bile to sinusoidal blood

Abstract

Not specified

Authors: Ahmed Ghallab, Ute Hofmann, Selahaddin Sezgin, Nachiket Vartak, Reham Hassan, Ayham Zaza, Patricio Godoy, Kai Markus Schneider, Georgia Guenther, Yasser A Ahmed, Aya A Abbas, Verena Keitel, Lars Kuepfer, Steven Dooley, Frank Lammert, Christian Trautwein, Michael Spiteller, Dirk Drasdo, Alan F Hofmann, Peter L M Jansen, Jan G Hengstler, Raymond Reif

Date Published: 13th Aug 2018

Publication Type: Not specified

Spatio-temporal visualization of the distribution of acetaminophen as well as its metabolites and adducts in mouse livers by MALDI MSI

Abstract (Expand)

Acetaminophen (APAP) is one of the most intensively studied compounds that causes hepatotoxicity in the pericentral region of the liver lobules. However, spatio-temporal information on the distribution … of APAP, its metabolites and GSH adducts in the liver tissue is not yet available. Here, we addressed the question, whether APAP-GSH adducts and GSH depletion show a zonated pattern and whether the distribution of APAP and its glucuronide as well as sulfate conjugates in liver lobules are zonated. For this purpose, a matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) technique was established, where the MSI images were superimposed onto CYP2E1 immunostained tissue. A time-dependent analysis (5, 15, 30, 60, 120, 240, 480 min) after intraperitoneal administration of 300 mg/kg APAP and a dose-dependent analysis (56 up to 500 mg APAP/kg) at 30 min were performed. The results demonstrate that the MALDI MSI technique allows the assignment of compounds and their metabolites to specific lobular zones. APAP-GSH adducts and GSH depletion occurred predominantly in the CYP2E1-positive zone of the liver, although GSH also decreased in the periportal region. In contrast, the parent compound, APAP sulfate and APAP glucuronide did not show a zonated pattern and tissue concentrations showed a similar time course as the corresponding analyses were performed with blood from the portal and liver veins. In conclusion, the present study is in agreement with the concept that pericentral CYPs form NAPQI that in the same cell binds to and depletes GSH but a lower level of GSH adducts is also observed in the periportal region. The results also provide further evidence of the recently published concept of 'aggravated loss of clearance capacity' according to which also liver tissue that survives intoxication may transiently show decreased metabolic capacity.

Authors: Selahaddin Sezgin, Reham Hassan, Sebastian Zühlke, Lars Kuepfer, Jan G. Hengstler, Michael Spiteller, Ahmed Ghallab

Date Published: 23rd Jul 2018

Publication Type: Not specified

Confounding influence of tamoxifen in mouse models of Cre recombinase-induced gene activity or modulation

Abstract (Expand)

Tamoxifen (TAM) is commonly used for cell type specific Cre recombinase-induced gene inactivation and in cell fate tracing studies. Inducing a gene knockout by TAM and using non-TAM exposed mice as … controls lead to a situation where differences are interpreted as consequences of the gene knockout but in reality result from TAM-induced changes in hepatic metabolism. The degree to which TAM may compromise the interpretation of animal experiments with inducible gene expression still has to be elucidated. Here, we report that TAM strongly attenuates CCl4-induced hepatotoxicity in male C57Bl/6N mice, even after a 10 days TAM exposure-free period. TAM decreased (p < 0.0001) the necrosis index and the level of aspartate- and alanine transaminases in CCl4-treated compared to vehicle-exposed mice. TAM pretreatment also led to the downregulation of CYP2E1 (p = 0.0045) in mouse liver tissue, and lowered its activity in CYP2E1 expressing HepG2 cell line. Furthermore, TAM increased the level of the antioxidant ascorbate, catalase, SOD2, and methionine, as well as phase II metabolizing enzymes GSTM1 and UGT1A1 in CCl4-treated livers. Finally, we found that TAM increased the presence of resident macrophages and recruitment of immune cells in necrotic areas of the livers as indicated by F4/80 and CD45 staining. In conclusion, we reveal that TAM increases liver resistance to CCl4-induced toxicity. This finding is of high relevance for studies using the tamoxifen-inducible expression system particularly if this system is used in combination with hepatotoxic compounds such as CCl4.

Authors: Seddik Hammad, Amnah Othman, Christoph Meyer, Ahmad Telfah, Joerg Lambert, Bedair Dewidar, Julia Werle, Zeribe Chike Nwosu, Abdo Mahli, Christof Dormann, Yan Gao, Kerry Gould, Mei Han, Xiaodong Yuan, Mikheil Gogiashvili, Roland Hergenröder, Claus Hellerbrand, Maria Thomas, Matthias Philip Ebert, Salah Amasheh, Jan G. Hengstler, Steven Dooley

Date Published: 4th Jul 2018

Publication Type: Not specified

Genetic determinants of steatosis and fibrosis progression in pediatric non-alcoholic fatty liver disease.

Abstract (Expand)

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents today. In comparison to adult disease, pediatric NAFLD may show a … periportal localization, which is associated with advanced fibrosis. This study aimed to assess the role of genetic risk variants for histologic disease pattern and severity in childhood NAFLD. METHODS: We studied 14 single nucleotide polymorphisms (SNP) in a cohort of 70 adolescents with biopsy-proven NAFLD. Genotype was compared to an adult control cohort (n=200) and analyzed in relation to histologic disease severity and liver tissue proteomics. RESULTS: Three of the 14 SNPs were significantly associated with pediatric NAFLD after FDR adjustment, rs738409 (PNPLA3, P=2.80x10(-06) ), rs1044498 (ENPP1, P=0.0091) and rs780094 (GCKR, P=0.0281). The severity of steatosis was critically associated with rs738409 (OR=3.25; 95% CI: 1.72-6.52, FDR adjusted P=0.0070). The strongest variants associated with severity of fibrosis were rs1260326, rs780094 (both GCKR) and rs659366 (UCP2). PNPLA3 was associated with a portal pattern of steatosis, inflammation and fibrosis. Proteome profiling revealed decreasing levels of GCKR protein with increasing carriage of the rs1260326/rs780094 minor alleles and down-regulation of the retinol pathway in rs738409 G/G carriers. Computational metabolic modelling highlighted functional relevance of PNPLA3, GCKR and UCP2 for NAFLD development. CONCLUSIONS: This study provides evidence for the role of PNPLA3 as a determinant of portal NAFLD localization and severity of portal fibrosis in children and adolescents, the risk variant being associated with an impaired hepatic retinol metabolism. This article is protected by copyright. All rights reserved.

Authors: C. A. Hudert, S. Selinski, B. Rudolph, H. Blaker, C. Loddenkemper, R. Thielhorn, N. Berndt, K. Golka, C. Cadenas, J. Reinders, S. Henning, P. Bufler, P. L. M. Jansen, H. G. Holzhutter, D. Meierhofer, J. G. Hengstler, S. Wiegand

Date Published: 18th Jan 2018

Publication Type: Not specified

Model prediction and validation of an order mechanism controlling the spatio-temporal phenotype of early hepatocellular carcinoma

Abstract

Not specified

Authors: Stefan Hoehme, Francois Bertaux, William Weens, Bettina Grasl-Kraupp, Jan G. Hengstler, Dirk Drasdo

Date Published: 28th Dec 2017

Publication Type: Not specified

Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage

Abstract (Expand)

Diseases and toxins may lead to death of active liver tissue, resulting in a loss of total clearance capacity at the whole-body level. However, it remains difficult to study, whether the loss of … metabolizing tissue is sufficient to explain loss of metabolic capacity of the liver or whether the surviving tissue undergoes an adaptive response to compensate the loss. To understand the cellular impact of toxic liver damage in an in vivo situation, we here used physiologically-based pharmacokinetic modelling to investigate pharmacokinetics of a specifically designed drug cocktail at three different sampling sites of the body in healthy mice and mice treated with carbon tetrachloride (CCl4). Liver zonation was explicitly quantified in the models through immunostaining of cytochrome P450s enzymes. Comparative analyses between the simulated decrease in clearance capacity and the experimentally measured loss in tissue volume indicated that CCl4-induced impairment of metabolic functions goes beyond the mere loss of metabolically active tissue. The here established integrative modelling strategy hence provides mechanistic insights into functional consequences of toxic liver damage in an in vivo situation, which would not have been accessible by conventional methods.

Authors: Arne Schenk, Ahmed Ghallab, Ute Hofmann, Reham Hassan, Michael Schwarz, Andreas Schuppert, Lars Ole Schwen, Albert Braeuning, Donato Teutonico, Jan G. Hengstler, Lars Kuepfer

Date Published: 1st Dec 2017

Publication Type: Not specified

Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage

Abstract

Not specified

Authors: Arne Schenk, Ahmed Ghallab, Ute Hofmann, Reham Hassan, Michael Schwarz, Andreas Schuppert, Lars Ole Schwen, Albert Braeuning, Donato Teutonico, Jan G. Hengstler, Lars Kuepfer

Date Published: 1st Dec 2017

Publication Type: Not specified

Adverse outcome pathways: opportunities, limitations and open questions.

Abstract (Expand)

Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory … purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field.

Authors: M. Leist, A. Ghallab, R. Graepel, R. Marchan, R. Hassan, S. H. Bennekou, A. Limonciel, M. Vinken, S. Schildknecht, T. Waldmann, E. Danen, B. van Ravenzwaay, H. Kamp, I. Gardner, P. Godoy, F. Y. Bois, A. Braeuning, R. Reif, F. Oesch, D. Drasdo, S. Hohme, M. Schwarz, T. Hartung, T. Braunbeck, J. Beltman, H. Vrieling, F. Sanz, A. Forsby, D. Gadaleta, C. Fisher, J. Kelm, D. Fluri, G. Ecker, B. Zdrazil, A. Terron, P. Jennings, B. van der Burg, S. Dooley, A. H. Meijer, E. Willighagen, M. Martens, C. Evelo, E. Mombelli, O. Taboureau, A. Mantovani, B. Hardy, B. Koch, S. Escher, C. van Thriel, C. Cadenas, D. Kroese, B. van de Water, J. G. Hengstler

Date Published: 19th Oct 2017

Publication Type: Not specified

A frequent misinterpretation in current research on liver fibrosis: the vessel in the center of CCl4-induced pseudolobules is a portal vein.

Abstract (Expand)

Carbon tetrachloride-induced liver injury is a thoroughly studied model for regeneration and fibrosis in rodents. Nevertheless, its pattern of liver fibrosis is frequently misinterpreted as portal type. … To clarify this, we show that collagen type IV+ "streets" and alpha-SMA+ cells accumulate pericentrally and extend to neighbouring central areas of the liver lobule, forming a 'pseudolobule'. Blood vessels in the center of such pseudolobules are portal veins as indicated by the presence of bile duct cells (CK19+) and the absence of pericentral hepatocytes (glutamine synthetase+). It is critical to correctly describe this pattern of fibrosis, particulary for metabolic zonation studies.

Authors: S. Hammad, A. Braeuning, C. Meyer, F. E. Z. A. Mohamed, J. G. Hengstler, S. Dooley

Date Published: 22nd Aug 2017

Publication Type: Not specified

Towards knowledge-driven cross-species extrapolation

Abstract

Not specified

Authors: Christoph Thiel, Ute Hofmann, Ahmed Ghallab, Rolf Gebhardt, Jan G. Hengstler, Lars Kuepfer

Date Published: 1st Apr 2017

Publication Type: Not specified

In vivo imaging of systemic transport and elimination of xenobiotics and endogenous molecules in mice

Abstract (Expand)

We describe a two-photon microscopy-based method to evaluate the in vivo systemic transport of compounds. This method comprises imaging of the intact liver, kidney and intestine, the main organs …gans responsible for uptake and elimination of xenobiotics and endogenous molecules. The image quality of the acquired movies was sufficient to distinguish subcellular structures like organelles and vesicles. Quantification of the movement of fluorescent dextran and fluorescent cholic acid derivatives in different organs and their sub-compartments over time revealed significant dynamic differences. Calculated half-lives were similar in the capillaries of all investigated organs but differed in the specific sub-compartments, such as parenchymal cells and bile canaliculi of the liver, glomeruli, proximal and distal tubules of the kidney and lymph vessels (lacteals) of the small intestine. Moreover, tools to image immune cells, which can influence transport processes in inflamed tissues, are described. This powerful approach provides new possibilities for the analysis of compound transport in multiple organs and can support physiologically based pharmacokinetic modeling, in order to obtain more precise predictions at the whole body scale.

Authors: Raymond Reif, Ahmed Ghallab, Lynette Beattie, Georgia Günther, Lars Kuepfer, Paul M. Kaye, Jan G. Hengstler

Date Published: 1st Mar 2017

Publication Type: Not specified

The ascending pathophysiology of cholestatic liver disease.

Abstract (Expand)

In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending … course of the disease process. The first and early lesions are in "downstream" bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)-mediated toxic injury of the "upstream" liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom-poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50%-60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more "tailored" use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium-dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis-suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti-inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor-ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and cholangitis, not for cholestasis in end-stage disease. These are arguments to consider a step-wise pathophysiology for these diseases, with therapy adjusted to disease stage. An obstacle in such an approach is that disease stage-defining biomarkers are still lacking. This review is meant to serve as a call to prioritize the development of biomarkers that help to obtain a better stratification of these diseases. (Hepatology 2017;65:722-738).

Authors: P. L. Jansen, A. Ghallab, N. Vartak, R. Reif, F. G. Schaap, J. Hampe, J. G. Hengstler

Date Published: 17th Feb 2017

Publication Type: Not specified

The ascending pathophysiology of cholestatic liver disease

Abstract (Expand)

In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending … course of the disease process. The first and early lesions are in "downstream" bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)-mediated toxic injury of the "upstream" liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom-poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50%-60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more "tailored" use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium-dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis-suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti-inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor-ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and cholangitis, not for cholestasis in end-stage disease. These are arguments to consider a step-wise pathophysiology for these diseases, with therapy adjusted to disease stage. An obstacle in such an approach is that disease stage-defining biomarkers are still lacking. This review is meant to serve as a call to prioritize the development of biomarkers that help to obtain a better stratification of these diseases. (Hepatology 2017;65:722-738).

Authors: Peter L.M. Jansen, Ahmed Ghallab, Nachiket Vartak, Raymond Reif, Frank G. Schaap, Jochen Hampe, Jan G. Hengstler

Date Published: 1st Feb 2017

Publication Type: Not specified

Creation of Three-Dimensional Liver Tissue Models from Experimental Images for Systems Medicine.

Abstract (Expand)

In this chapter, we illustrate how three-dimensional liver tissue models can be created from experimental image modalities by utilizing a well-established processing chain of experiments, microscopic … imaging, image processing, image analysis and model construction. We describe how key features of liver tissue architecture are quantified and translated into model parameterizations, and show how a systematic iteration of experiments and model simulations often leads to a better understanding of biological phenomena in systems biology and systems medicine.

Authors: S. Hoehme, A. Friebel, S. Hammad, D. Drasdo, J. G. Hengstler

Date Published: 11th Nov 2016

Publication Type: Not specified

Model-guided identification of a therapeutic strategy to reduce hyperammonemia in liver diseases

Abstract (Expand)

BACKGROUND & AIMS: Recently, spatial-temporal/metabolic mathematical models have been established that allow the simulation of metabolic processes in tissues. We applied these models to decipher …er ammonia detoxification mechanisms in the liver. METHODS: An integrated metabolic-spatial-temporal model was used to generate hypotheses of ammonia metabolism. Predicted mechanisms were validated using time-resolved analyses of nitrogen metabolism, activity analyses, immunostaining and gene expression after induction of liver damage in mice. Moreover, blood from the portal vein, liver vein and mixed venous blood was analyzed in a time dependent manner. RESULTS: Modeling revealed an underestimation of ammonia consumption after liver damage when only the currently established mechanisms of ammonia detoxification were simulated. By iterative cycles of modeling and experiments, the reductive amidation of alpha-ketoglutarate (α-KG) via glutamate dehydrogenase (GDH) was identified as the lacking component. GDH is released from damaged hepatocytes into the blood where it consumes ammonia to generate glutamate, thereby providing systemic protection against hyperammonemia. This mechanism was exploited therapeutically in a mouse model of hyperammonemia by injecting GDH together with optimized doses of cofactors. Intravenous injection of GDH (720 U/kg), α-KG (280 mg/kg) and NADPH (180 mg/kg) reduced the elevated blood ammonia concentrations (>200 μM) to levels close to normal within only 15 min. CONCLUSION: If successfully translated to patients the GDH-based therapy might provide a less aggressive therapeutic alternative for patients with severe hyperammonemia.

Authors: Ahmed Ghallab, Géraldine Cellière, Sebastian G. Henkel, Dominik Driesch, Stefan Hoehme, Ute Hofmann, Sebastian Zellmer, Patricio Godoy, Agapios Sachinidis, Meinolf Blaszkewicz, Raymond Reif, Rosemarie Marchan, Lars Kuepfer, Dieter Häussinger, Dirk Drasdo, Rolf Gebhardt, Jan G. Hengstler

Date Published: 1st Apr 2016

Publication Type: Not specified

Cholestasis-induced adaptive remodeling of interlobular bile ducts.

Abstract (Expand)

UNLABELLED: Cholestasis is a common complication in liver diseases that triggers a proliferative response of the biliary tree. Bile duct ligation (BDL) is a frequently used model of cholestasis in … rodents. To determine which changes occur in the three-dimensional (3D) architecture of the interlobular bile duct during cholestasis, we used 3D confocal imaging, surface reconstructions, and automated image quantification covering a period up to 28 days after BDL. We show a highly reproducible sequence of interlobular duct remodeling, where cholangiocyte proliferation initially causes corrugation of the luminal duct surface, leading to an approximately five-fold increase in surface area. This is analogous to the function of villi in the intestine or sulci in the brain, where an expansion of area is achieved within a restricted volume. The increase in surface area is further enhanced by duct branching, branch elongation, and loop formation through self-joining, whereby an initially relatively sparse mesh surrounding the portal vein becomes five-fold denser through elongation, corrugation, and ramification. The number of connections between the bile duct and the lobular bile canalicular network by the canals of Hering decreases proportionally to the increase in bile duct length, suggesting that no novel connections are established. The diameter of the interlobular bile duct remains constant after BDL, a response that is qualitatively distinct from that of large bile ducts, which tend to enlarge their diameters. Therefore, volume enhancement is only due to net elongation of the ducts. Because curvature and tortuosity of the bile duct are unaltered, this enlargement of the biliary tree is caused by branching and not by convolution. CONCLUSION: BDL causes adaptive remodeling that aims at optimizing the intraluminal surface area by way of corrugation and branching.

Authors: N. Vartak, A. Damle-Vartak, B. Richter, O. Dirsch, U. Dahmen, S. Hammad, J. G. Hengstler

Date Published: 27th Nov 2015

Publication Type: Not specified

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