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87 Publications visible to you, out of a total of 87
Hepatic Hedgehog Signaling Participates in the Crosstalk between Liver and Adipose Tissue in Mice by Regulating FGF21.

Abstract (Expand)

The Hedgehog signaling pathway regulates many processes during embryogenesis and the homeostasis of adult organs. Recent data suggest that central metabolic processes and signaling cascades in the liver … are controlled by the Hedgehog pathway and that changes in hepatic Hedgehog activity also affect peripheral tissues, such as the reproductive organs in females. Here, we show that hepatocyte-specific deletion of the Hedgehog pathway is associated with the dramatic expansion of adipose tissue in mice, the overall phenotype of which does not correspond to the classical outcome of insulin resistance-associated diabetes type 2 obesity. Rather, we show that alterations in the Hedgehog signaling pathway in the liver lead to a metabolic phenotype that is resembling metabolically healthy obesity. Mechanistically, we identified an indirect influence on the hepatic secretion of the fibroblast growth factor 21, which is regulated by a series of signaling cascades that are directly transcriptionally linked to the activity of the Hedgehog transcription factor GLI1. The results of this study impressively show that the metabolic balance of the entire organism is maintained via the activity of morphogenic signaling pathways, such as the Hedgehog cascade. Obviously, several pathways are orchestrated to facilitate liver metabolic status to peripheral organs, such as adipose tissue.

Authors: F. Ott, C. Korner, K. Werner, M. Gericke, I. Liebscher, D. Lobsien, S. Radrezza, A. Shevchenko, U. Hofmann, J. Kratzsch, R. Gebhardt, T. Berg, M. Matz-Soja

Date Published: 18th May 2022

Publication Type: Journal

FOXA2 prevents hyperbilirubinaemia in acute liver failure by maintaining apical MRP2 expression

Abstract (Expand)

Objective Multidrug resistance protein 2 (MRP2) is a bottleneck in bilirubin excretion. Its loss is sufficient to induce hyperbilirubinaemia, a prevailing characteristic of acute liver failure (ALF) … characteristic of acute liver failure (ALF) that is closely associated with clinical outcome. This study scrutinises the transcriptional regulation of MRP2 under different pathophysiological conditions. Design Hepatic MRP2, farnesoid X receptor (FXR) and Forkhead box A2 (FOXA2) expression and clinicopathologic associations were examined by immunohistochemistry in 14 patients with cirrhosis and 22 patients with ALF. MRP2 regulatory mechanisms were investigated in primary hepatocytes, Fxr −/− mice and lipopolysaccharide (LPS)-treated mice. Results Physiologically, homeostatic MRP2 transcription is mediated by the nuclear receptor FXR/retinoid X receptor complex. Fxr −/− mice lack apical MRP2 expression and rapidly progress into hyperbilirubinaemia. In patients with ALF, hepatic FXR expression is undetectable, however, patients without infection maintain apical MRP2 expression and do not suffer from hyperbilirubinaemia. These patients express FOXA2 in hepatocytes. FOXA2 upregulates MRP2 transcription through binding to its promoter. Physiologically, nuclear FOXA2 translocation is inhibited by insulin. In ALF, high levels of glucagon and tumour necrosis factor α induce FOXA2 expression and nuclear translocation in hepatocytes. Impressively, ALF patients with sepsis express low levels of FOXA2, lose MRP2 expression and develop severe hyperbilirubinaemia. In this case, LPS inhibits FXR expression, induces FOXA2 nuclear exclusion and thus abrogates the compensatory MRP2 upregulation. In both Fxr −/− and LPS-treated mice, ectopic FOXA2 expression restored apical MRP2 expression and normalised serum bilirubin levels. Conclusion FOXA2 replaces FXR to maintain MRP2 expression in ALF without sepsis. Ectopic FOXA2 expression to maintain MRP2 represents a potential strategy to prevent hyperbilirubinaemia in septic ALF.

Authors: Sai Wang, Rilu Feng, Shan Shan Wang, Hui Liu, Chen Shao, Yujia Li, Frederik Link, Stefan Munker, Roman Liebe, Christoph Meyer, Elke Burgermeister, Matthias Ebert, Steven Dooley, Huiguo Ding, Honglei Weng

Date Published: 20th Apr 2022

Publication Type: Journal

Transforming growth factor β latency: A mechanism of cytokine storage and signalling regulation in liver homeostasis and disease

Abstract

Not specified

Authors: Yujia Li, Weiguo Fan, Frederik Link, Sai Wang, Steven Dooley

Date Published: 1st Feb 2022

Publication Type: Journal

Review series on Pathophysiology and Clinical Management of Alcoholic Liver Disease

Abstract

Not specified

Authors: Steven Dooley, Jonel Trebicka, Sebastian Mueller

Date Published: 18th Jan 2022

Publication Type: Journal

Inflammation in alcohol-associated liver disease progression

Abstract (Expand)

Abstract Chronic alcohol consumption induces stress and damage in alcohol metabolising hepatocytes, which leads to inflammatory and fibrogenic responses. Besides these direct effects, alcohol disrupts …ffects, alcohol disrupts intestinal barrier functions and induces gut microbial dysbiosis, causing translocation of bacteria or microbial products through the gut mucosa to the liver and, which induce inflammation indirectly. Inflammation is one of the key drivers of alcohol-associated liver disease progression from steatosis to severe alcoholic hepatitis. The current standard of care for the treatment of severe alcoholic hepatitis is prednisolone, aiming to reduce inflammation. Prednisolone, however improves only short-term but not long-term survival rates in those patients, and even increases the risk for bacterial infections. Thus, recent studies focus on the exploration of more specific inflammatory targets for the treatment of severe alcoholic hepatitis. These comprise, among others interference with inflammatory cytokines, modulation of macrophage phenotypes or targeting of immune cell communication, as summarized in the present overview. Although several approaches give promising results in preclinical studies, data robustness and ability to transfer experimental results to human disease is still not sufficient for effective clinical translation.

Authors: Sophie Lotersztajn, Antonio Riva, Sai Wang, Steven Dooley, Shilpa Chokshi, Bin Gao

Date Published: 18th Jan 2022

Publication Type: Journal

Liver specific, systemic and genetic contributors to alcohol-related liver disease progression

Abstract (Expand)

Abstract Alcohol-related liver disease (ALD) impacts millions of patients worldwide each year and the numbers are increasing. Disease stages range from steatosis via steatohepatitis and fibrosis to …epatitis and fibrosis to cirrhosis, severe alcohol-associated hepatitis and liver cancer. ALD is usually diagnosed at an advanced stage of progression with no effective therapies. A major research goal is to improve diagnosis, prognosis and also treatments for early ALD. This however needs prioritization of this disease for financial investment in basic and clinical research to more deeply investigate mechanisms and identify biomarkers and therapeutic targets for early detection and intervention. Topics of interest are communication of the liver with other organs of the body, especially the gut microbiome, the individual genetic constitution, systemic and liver innate inflammation, including bacterial infections, as well as fate and number of hepatic stellate cells and the composition of the extracellular matrix in the liver. Additionally, mechanical forces and damaging stresses towards the sophisticated vessel system of the liver, including the especially equipped sinusoidal endothelium and the biliary tract, work together to mediate hepatocytic import and export of nutritional and toxic substances, adapting to chronic liver disease by morphological and functional changes. All the aforementioned parameters contribute to the outcome of alcohol use disorder and the risk to develop advanced disease stages including cirrhosis, severe alcoholic hepatitis and liver cancer. In the present collection, we summarize current knowledge on these alcohol-related liver disease parameters, excluding the aspect of inflammation, which is presented in the accompanying review article by Lotersztajn and colleagues.

Authors: Bernd Schnabl, Gavin E. Arteel, Felix Stickel, Jan Hengstler, Nachiket Vartak, Ahmed Ghallab, Steven Dooley, Yujia Li, Robert F. Schwabe

Date Published: 18th Jan 2022

Publication Type: Journal

MSPypeline: a python package for streamlined data analysis of mass spectrometry-based proteomics

Abstract (Expand)

Abstract Summary Mass spectrometry-based proteomics is increasingly employed in biology and medicine. To generate reliable information from large datasets and ensure comparability of results, it is …rge datasets and ensure comparability of results, it is crucial to implement and standardize the quality control of the raw data, the data processing steps and the statistical analyses. MSPypeline provides a platform for importing MaxQuant output tables, generating quality control reports, data preprocessing including normalization and performing exploratory analyses by statistical inference plots. These standardized steps assess data quality, provide customizable figures and enable the identification of differentially expressed proteins to reach biologically relevant conclusions. Availability and implementation The source code is available under the MIT license at https://github.com/siheming/mspypeline with documentation at https://mspypeline.readthedocs.io. Benchmark mass spectrometry data are available on ProteomeXchange (PXD025792). Supplementary information Supplementary data are available at Bioinformatics Advances online.

Authors: Simon Heming, Pauline Hansen, Artyom Vlasov, Florian Schwörer, Stephen Schaumann, Paulina Frolovaitė, Wolf-Dieter Lehmann, Jens Timmer, Marcel Schilling, Barbara Helm, Ursula Klingmüller

Date Published: 2022

Publication Type: Journal

Anisotropic expansion of hepatocyte lumina enforced by apical bulkheads

Abstract

Not specified

Authors: Lenka Belicova, Urska Repnik, Julien Delpierre, Elzbieta Gralinska, Sarah Seifert, José Ignacio Valenzuela, Hernán Andrés Morales-Navarrete, Christian Franke, Helin Räägel, Evgeniya Shcherbinina, Tatiana Prikazchikova, Victor Koteliansky, Martin Vingron, Yannis L. Kalaidzidis, Timofei Zatsepin, Marino Zerial

Date Published: 4th Oct 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

Cell atlas of the regenerating human liver after portal vein embolization

Abstract (Expand)

The liver has the remarkable capacity to regenerate. In the clinic, this capacity can be induced by portal vein embolization (PVE), which redirects portal blood flow resulting in liver hypertrophy in …pertrophy in locations with increased blood supply, and atrophy of embolized segments. Here we apply single-cell and single-nucleus transcriptomics on healthy, hypertrophied, and atrophied patient-derived liver samples to explore cell states in the liver during regeneration. We first establish an atlas of cell subtypes from the healthy human liver using fresh and frozen tissues, and then compare post-PVE samples with their reference counterparts. We find that PVE alters portal-central zonation of hepatocytes and endothelial cells. Embolization upregulates expression programs associated with development, cellular adhesion and inflammation across cell types. Analysis of interlineage crosstalk revealed key roles for immune cells in modulating regenerating tissue responses. Altogether, our data provides a rich resource for understanding homeostatic mechanisms arising during human liver regeneration and degeneration.

Authors: Agnieska Brazovskaja, Tomás Gomes, Christiane Körner, Zhisong He, Theresa Schaffer, Julian Connor Eckel, René Hänsel, Malgorzata Santel, Timm Denecke, Michael Dannemann, Mario Brosch, Jochen Hampe, Daniel Seehofer, Georg Damm, J. Gray Camp, Barbara Treutlein

Date Published: 3rd Jun 2021

Publication Type: Journal

Facilitating Study and Item Level Browsing for Clinical and Epidemiological COVID-19 Studies.

Abstract (Expand)

COVID-19 poses a major challenge to individuals and societies around the world. Yet, it is difficult to obtain a good overview of studies across different medical fields of research such as clinical … trials, epidemiology, and public health. Here, we describe a consensus metadata model to facilitate structured searches of COVID-19 studies and resources along with its implementation in three linked complementary web-based platforms. A relational database serves as central study metadata hub that secures compatibilities with common trials registries (e.g. ICTRP and standards like HL7 FHIR, CDISC ODM, and DataCite). The Central Search Hub was developed as a single-page application, the other two components with additional frontends are based on the SEEK platform and MICA, respectively. These platforms have different features concerning cohort browsing, item browsing, and access to documents and other study resources to meet divergent user needs. By this we want to promote transparent and harmonized COVID-19 research.

Authors: C. O. Schmidt, J. Darms, A. Shutsko, M. Lobe, R. Nagrani, B. Seifert, B. Lindstadt, M. Golebiewski, S. Koleva, T. Bender, C. R. Bauer, U. Sax, X. Hu, M. Lieser, V. Junker, S. Klopfenstein, A. Zeleke, D. Waltemath, I. Pigeot, J. Fluck

Date Published: 27th May 2021

Publication Type: Journal

Isolated bacterial infection without decompensation has no impact on survival of compensated patients with cirrhosis.

Abstract (Expand)

BACKGROUND & AIMS: Bacterial infections (BI) affect the natural course of cirrhosis and were suggested to be a landmark event marking the transition to the decompensated stage. Our specific aim was … to evaluate the impact of BI on the natural history of compensated cirrhosis. METHODS: We analyzed 858 patients with cirrhosis, evaluated for the INCA trial (EudraCT 2013-001626-26) in 2 academic medical centers between February 2014 and May 2019. Only patients with previously compensated disease were included. They were divided into 4 groups: compensated without BI, compensated with BI, 1st decompensation without BI, and 1st decompensation with BI. RESULTS: About 425 patients (median 61 [53-69] years) were included in the final prospective analysis. At baseline, 257 patients were compensated (12 [4.7%] with BI), whereas 168 patients presented with their 1st decompensation (42 [25.0%] with BI). In patients who remained compensated MELD scores were similar in those with and without BI. Patients with their first decompensation and BI had higher MELD scores than those without BI. Amongst patients who remained compensated, BI had no influence on transplant-free survival, whereas patients with their 1st decompensation and concurrent BI had significantly reduced transplant-free survival as compared with those without BI. The development of BI or decompensation during follow-up had a greater impact on survival than each of these complications at baseline. CONCLUSIONS: In compensated patients with cirrhosis, the 1st decompensation associated to BI has worse survival than decompensation without BI. By contrast, BI without decompensation does not negatively impact survival of patients with compensated cirrhosis.

Authors: M. C. Reichert, C. Schneider, R. Greinert, M. Casper, F. Grunhage, A. Wienke, A. Zipprich, F. Lammert, C. Ripoll

Date Published: 1st Mar 2021

Publication Type: Journal

PEtab—Interoperable specification of parameter estimation problems in systems biology

Abstract

Not specified

Authors: Leonard Schmiester, Yannik Schälte, Frank T. Bergmann, Tacio Camba, Erika Dudkin, Janine Egert, Fabian Fröhlich, Lara Fuhrmann, Adrian L. Hauber, Svenja Kemmer, Polina Lakrisenko, Carolin Loos, Simon Merkt, Wolfgang Müller, Dilan Pathirana, Elba Raimúndez, Lukas Refisch, Marcus Rosenblatt, Paul L. Stapor, Philipp Städter, Dantong Wang, Franz-Georg Wieland, Julio R. Banga, Jens Timmer, Alejandro F. Villaverde, Sven Sahle, Clemens Kreutz, Jan Hasenauer, Daniel Weindl

Date Published: 26th Jan 2021

Publication Type: Journal

Robustness and applicability of transcription factor and pathway analysis tools on single-cell RNA-seq data

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

Chronic Disruption of the Late Cholesterol Synthesis Leads to Female-Prevalent Liver Cancer.

Abstract (Expand)

While the role of cholesterol in liver carcinogenesis remains controversial, hepatocellular carcinoma generally prevails in males. Herein, we uncover pathways of female-prevalent progression to … hepatocellular carcinoma due to chronic repression of cholesterogenic lanosterol 14alpha-demethylase (CYP51) in hepatocytes. Tumors develop in knock-out mice after year one, with 2:1 prevalence in females. Metabolic and transcription factor networks were deduced from the liver transcriptome data, combined by sterol metabolite and blood parameter analyses, and interpreted with relevance to humans. Female knock-outs show increased plasma cholesterol and HDL, dampened lipid-related transcription factors FXR, LXRalpha:RXRalpha, and importantly, crosstalk between reduced LXRalpha and activated TGF-beta signalling, indicating a higher susceptibility to HCC in aging females. PI3K/Akt signalling and ECM-receptor interaction are common pathways that are disturbed by sex-specific altered genes. Additionally, transcription factors (SOX9)2 and PPARalpha were recognized as important for female hepatocarcinogenesis, while overexpressed Cd36, a target of nuclear receptor RORC, is a new male-related regulator of ECM-receptor signalling in hepatocarcinogenesis. In conclusion, we uncover the sex-dependent metabolic reprogramming of cholesterol-related pathways that predispose for hepatocarcinogenesis in aging females. This is important in light of increased incidence of liver cancers in post-menopausal women.

Authors: K. B. Cokan, Z. Urlep, G. Lorbek, M. Matz-Soja, C. Skubic, M. Perse, J. Jeruc, P. Juvan, T. Rezen, D. Rozman

Date Published: 9th Nov 2020

Publication Type: Journal

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