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

Overview

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 developing anti-fibrotic drugs, but these are not yet available.

SEEK ID: https://seek.lisym.org/projects/4

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

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

FAIRDOM PALs: Janine Koehncke, Annika Schneider, Daniel Lill, Seddik Hammad, Matthias Reichert

Project start date: 1st Jan 2016

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Claire Barbieux

Projects: 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

Institutions: Deutsches Krebsforschungszentrum

Johannes Bausch : inactive since 2018-05-16

Projects: LiSyM Core Infrastructure and Management (LiSyM-PD), LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI), LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM network, LiSyM Scientific Leadership Team (LiSyM-LT)

Institutions: University of Freiburg - Institute of Physics, LiSyM programme directorate

https://orcid.org/0000-0002-1003-1682
Marie-Luise Berres

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

Institutions: RWTH Aachen University Hospital - Department of Internal Medicine III

Johannes Bode

Projects: 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, LiSyM-Krebs Partnering

Institutions: Universitätsklinikum Düsseldorf - Klinik für Gastroenterologie, Hepatologie und Infektiologie

Lorenza D'Alessandro

Projects: LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM network, LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Institutions: Deutsches Krebsforschungszentrum

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

Pillar II dooley

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CCl4 Treatment in mice
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
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Person responsible: Seddik Hammad

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Metabolic CCl4
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Submitter: Seddik Hammad

Assay type: Proteomics

Technology type: FACS

Snapshots: No snapshots

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Robustness and applicability of transcription factor and pathway analysis tools on single-cell RNA-seq data
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

GitHub repository containing the analysis code

Creator: Christian Holland

Submitter: Christian Holland

External Link
Transfer of regulatory knowledge from human to mouse for functional genomics analysis
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

GitHub repository that contains all analyses scripts to reproduce the results reported in "Transfer of regulatory knowledge from human to mouse for functional genomics analysis"

Creator: Christian Holland

Submitter: Christian Holland

Movies for quantification
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
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Creator: Seddik Hammad

Submitter: Seddik Hammad

TextBookData
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
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Creators: None

Submitter: Seddik Hammad

F4-80
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
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Creators: None

Submitter: Seddik Hammad

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SOP RNA Isolation from healthy and fatty liver
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF)
No description specified

Creator: Sonja Kleeschulte

Submitter: Sonja Kleeschulte

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SOP FACS analysis of Macrophage population in healthy and fatty liver
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF)

Non-parenchymal liver cells are isolated and staining for FACS analysis

Creator: Sonja Kleeschulte

Submitter: Sonja Kleeschulte

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SOP Immunhistochemistry Mac2 staining
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF)

Macrophage staining in paraffin-embedded tissue

Creator: Sonja Kleeschulte

Submitter: Sonja Kleeschulte

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Robustness and applicability of transcription factor and pathway analysis tools on single-cell RNA-seq data
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM network

Abstract (Expand)

Background Many functional analysis tools have been developed to extract functional and mechanistic insight from bulk transcriptome data. With the advent of single-cell RNA sequencing (scRNA-seq), it … is in principle possible to do such an analysis for single cells. However, scRNA-seq data has characteristics such as drop-out events and low library sizes. It is thus not clear if functional TF and pathway analysis tools established for bulk sequencing can be applied to scRNA-seq in a meaningful way. Results To address this question, we perform benchmark studies on simulated and real scRNA-seq data. We include the bulk-RNA tools PROGENy, GO enrichment, and DoRothEA that estimate pathway and transcription factor (TF) activities, respectively, and compare them against the tools SCENIC/AUCell and metaVIPER, designed for scRNA-seq. For the in silico study, we simulate single cells from TF/pathway perturbation bulk RNA-seq experiments. We complement the simulated data with real scRNA-seq data upon CRISPR-mediated knock-out. Our benchmarks on simulated and real data reveal comparable performance to the original bulk data. Additionally, we show that the TF and pathway activities preserve cell type-specific variability by analyzing a mixture sample sequenced with 13 scRNA-seq protocols. We also provide the benchmark data for further use by the community. Conclusions Our analyses suggest that bulk-based functional analysis tools that use manually curated footprint gene sets can be applied to scRNA-seq data, partially outperforming dedicated single-cell tools. Furthermore, we find that the performance of functional analysis tools is more sensitive to the gene sets than to the statistic used.

Authors: Christian H. Holland, Jovan Tanevski, Javier Perales-Patón, Jan Gleixner, Manu P. Kumar, Elisabetta Mereu, Brian A. Joughin, Oliver Stegle, Douglas A. Lauffenburger, Holger Heyn, Bence Szalai, Julio Saez-Rodriguez

Date Published: 1st Dec 2020

Publication Type: Journal

Orphan Nuclear Receptor ERRγ Is a Novel Transcriptional Regulator of IL-6 Mediated Hepatic BMP6 Gene Expression in Mice
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Abstract

Not specified

Authors: Kamalakannan Radhakrishnan, Yong-Hoon Kim, Yoon Seok Jung, Jina Kim, Don-Kyu Kim, Sung Jin Cho, In-Kyu Lee, Steven Dooley, Chul-Ho Lee, Hueng-Sik Choi

Date Published: 1st Oct 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

Expression of TLR-2 in hepatocellular carcinoma is associated with tumour proliferation, angiogenesis and Caspase-3 expression.
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM network

Abstract (Expand)

AIMS: Unlike other Toll-like receptors (TLRs), the role of toll like receptor 2 (TLR-2) in the pathogenesis of chronic liver disease and hepatocellular carcinoma (HCC) is not well studied. We, therefore, … set out to investigate the expression of TLR-2 in different chronic liver disease states along with other markers of cell death, cellular proliferation and tissue vascularisation METHODS AND RESULTS: Immunohistochemistry was performed on liver tissue microarrays comprising hepatitis, cirrhosis and HCC patient samples using antibodies against TLR-2, Ki-67, Caspase-3 and VEGF. This was done in order to characterise receptor expression and translocation, apoptosis, cell proliferation and vascularisation. Cytoplasmic TLR-2 expression was found to be weak in 5/8 normal liver cases, 10/19 hepatitis cases and 8/21 cirrhosis patients. Moderate to strong TLR-2 expression was observed in some cases of hepatitis and cirrhosis. Both, nuclear and cytoplasmic TLR-2 expression was present in HCC with weak intensity in 11/41 cases, and moderate to strong staining in 19/41 cases. Eleven HCC cases were TLR-2 negative. Surprisingly, both cytoplasmic and nuclear TLR-2 expression in HCC were found to significantly correlate with proliferative index (r = 0.24 and 0.37), Caspase-3 expression (r = 0.27 and 0.38) and vascularisation (r = 0.56 and 0.23). Further, nuclear TLR-2 localisation was predominant in HCC, whereas cytoplasmic expression was more prevalent in hepatitis and cirrhosis. Functionally, treatment of HUH7 HCC cells with a TLR-2 agonist induced the expression of cellular proliferation and vascularisation markers CD34 and VEGF. CONCLUSIONS: Our results demonstrate a positive correlation between the expression of TLR-2 and other markers of proliferation and vascularisation in HCC which suggests a possible role for TLR-2 in HCC pathogenesis.

Authors: F. E. A. Mohamed, S. Hammad, T. V. Luong, B. Dewidar, R. Al-Jehani, N. Davies, S. Dooley, R. Jalan

Date Published: 25th Jul 2020

Publication Type: Journal

Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction.
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF)

Abstract (Expand)

Tightly interlinked feedback regulators control the dynamics of intracellular responses elicited by the activation of signal transduction pathways. Interferon alpha (IFNalpha) orchestrates antiviral … responses in hepatocytes, yet mechanisms that define pathway sensitization in response to prestimulation with different IFNalpha doses remained unresolved. We establish, based on quantitative measurements obtained for the hepatoma cell line Huh7.5, an ordinary differential equation model for IFNalpha signal transduction that comprises the feedback regulators STAT1, STAT2, IRF9, USP18, SOCS1, SOCS3, and IRF2. The model-based analysis shows that, mediated by the signaling proteins STAT2 and IRF9, prestimulation with a low IFNalpha dose hypersensitizes the pathway. In contrast, prestimulation with a high dose of IFNalpha leads to a dose-dependent desensitization, mediated by the negative regulators USP18 and SOCS1 that act at the receptor. The analysis of basal protein abundance in primary human hepatocytes reveals high heterogeneity in patient-specific amounts of STAT1, STAT2, IRF9, and USP18. The mathematical modeling approach shows that the basal amount of USP18 determines patient-specific pathway desensitization, while the abundance of STAT2 predicts the patient-specific IFNalpha signal response.

Authors: F. Kok, M. Rosenblatt, M. Teusel, T. Nizharadze, V. Goncalves Magalhaes, C. Dachert, T. Maiwald, A. Vlasov, M. Wasch, S. Tyufekchieva, K. Hoffmann, G. Damm, D. Seehofer, T. Boettler, M. Binder, J. Timmer, M. Schilling, U. Klingmuller

Date Published: 23rd Jul 2020

Publication Type: Journal

CYP2E1 recovery is associated with a pericentral fibrosis pattern after repeated CCl4 insults
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Creator: Seddik Hammad

Submitter: Seddik Hammad

Cellular and nuclear hepatocyte ploidy represent a repository in regenerating livers
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Creator: Seddik Hammad

Submitter: Seddik Hammad

Decreased ECM1 expression is consistent in HCC and correlates with overall survival
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Creator: Seddik Hammad

Submitter: Seddik Hammad

GPNMB as hepatocytic suppressor of steatosis and liver cancer
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Creator: Seddik Hammad

Submitter: Seddik Hammad

Robustness and applicability of functional genomic tools on scRNA-seq data
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM network
No description specified

Creator: Christian Holland

Submitter: Christian Holland

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