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336 Publications visible to you, out of a total of 336
Acute liver injury induces expression of FGF23 in hepatocytes via orphan nuclear receptor ERRγ signaling

Abstract

Not specified

Authors: Yoon Seok Jung, Yong-Hoon Kim, Kamalakannan Radhakrishnan, Jung-Ran Noh, Jung Hyeon Choi, Hyo-Jin Kim, Jae-Ho Jeong, Steven Dooley, Chul-Ho Lee, Hueng-Sik Choi

Date Published: 1st May 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

Capsaicin receptor TRPV1 maintains quiescence of hepatic stellate cells in the liver via recruitment of SARM1

Abstract

Not specified

Authors: Le Tao, Guangyue Yang, Tiantian Sun, Jie Tao, Chan Zhu, Huimin Yu, Yalan Cheng, Zongguo Yang, Mingyi Xu, Yuefeng Jiang, Wei Zhang, Zhiyi Wang, Wenting Ma, Liu Wu, Dongying Xue, Dongxue Wang, Wentao Yang, Yongjuan Zhao, Shane Horsefield, Bostjan Kobe, Zhe Zhang, Zongxiang Tang, Qigen Li, Qiwei Zhai, Steven Dooley, Ekihiro Seki, Ping Liu, Jianrong Xu, Hongzhuan Chen, Cheng Liu

Date Published: 2023

Publication Type: Journal

Hepatocytes reprogram liver macrophages involving control of TGF-β activation, influencing liver regeneration and injury

Abstract (Expand)

Background: Macrophages play an important role in maintaining liver homeostasis and regeneration. However, it is not clear to what extent the different macrophage populations of the liver differ in … terms of their activation state and which other liver cell populations may play a role in regulating the same. Methods: Reverse transcription PCR, flow cytometry, transcriptome, proteome, secretome, single cell analysis, and immunohistochemical methods were used to study changes in gene expression as well as the activation state of macrophages in vitro and in vivo under homeostatic conditions and after partial hepatectomy. Results: We show that F4/80+/CD11bhi/CD14hi macrophages of the liver are recruited in a C-C motif chemokine receptor (CCR2)–dependent manner and exhibit an activation state that differs substantially from that of the other liver macrophage populations, which can be distinguished on the basis of CD11b and CD14 expressions. Thereby, primary hepatocytes are capable of creating an environment in vitro that elicits the same specific activation state in bone marrow–derived macrophages as observed in F4/80+/CD11bhi/CD14hi liver macrophages in vivo. Subsequent analyses, including studies in mice with a myeloid cell–specific deletion of the TGF-β type II receptor, suggest that the availability of activated TGF-β and its downregulation by a hepatocyte-conditioned milieu are critical. Reduction of TGF-βRII-mediated signal transduction in myeloid cells leads to upregulation of IL-6, IL-10, and SIGLEC1 expression, a hallmark of the activation state of F4/80+/CD11bhi/CD14hi macrophages, and enhances liver regeneration. Conclusions: The availability of activated TGF-β determines the activation state of specific macrophage populations in the liver, and the observed rapid transient activation of TGF-β may represent an important regulatory mechanism in the early phase of liver regeneration in this context.

Authors: Stephanie D. Wolf, Christian Ehlting, Sophia Müller-Dott, Gereon Poschmann, Patrick Petzsch, Tobias Lautwein, Sai Wang, Barbara Helm, Marcel Schilling, Julio Saez-Rodriguez, Mihael Vucur, Kai Stühler, Karl Köhrer, Frank Tacke, Steven Dooley, Ursula Klingmüller, Tom Luedde, Johannes G. Bode

Date Published: 2023

Publication Type: Journal

Retinoic acid generates a beneficial microenvironment for liver progenitor cell activation in acute liver failure

Abstract

Not specified

Authors: Sai Wang, Frederik Link, Rilu Feng, Stefan Munker, Yujia Li, Roman Liebe, Matthias P. Ebert, Steven Dooley, Huiguo Ding, Shanshan Wang, Honglei Weng

Date Published: 2023

Publication Type: Journal

Monitoring TGF-β1 effects on liver cells in vivo

Abstract

Not specified

Authors: Alaa Hammad, Seddik Hammad, Kerry Gould, Matthias P. Ebert, Steven Dooley, Anne Dropmann

Date Published: 2023

Publication Type: Journal

Repeated toxic injuries of murine liver are tolerated through minute steatosis and mild inflammation

Abstract

Not specified

Authors: Seddik Hammad, Christoph Ogris, Amnah Othman, Pia Erdoesi, Wolfgang Schmidt-Heck, Ina Biermayer, Barbara Helm, Yan Gao, Weronika Piorońska, Lorenza D'Alessandro, Fabian J. Theis, Matthias P. Ebert, Ursula Klingmüller, Jan Hengstler, Nikola S. Mueller, Steven Dooley

Date Published: 2023

Publication Type: Journal

A hierarchical regulatory network ensures stable albumin transcription under various pathophysiological conditions

Abstract

Not specified

Authors: Rilu Feng, Kejia Kan, Carsten Sticht, Yujia Li, Shanshan Wang, Hui Liu, Chen Shao, Stefan Munker, Hanno Niess, Sai Wang, Christoph Meyer, Roman Liebe, Matthias P. Ebert, Steven Dooley, Huiguo Ding, Honglei Weng

Date Published: 1st Dec 2022

Publication Type: Journal

Guided interactive image segmentation using machine learning and color-based image set clustering.

Abstract (Expand)

MOTIVATION: Over the last decades, image processing and analysis have become one of the key technologies in systems biology and medicine. The quantification of anatomical structures and dynamic processes … in living systems is essential for understanding the complex underlying mechanisms and allows, i.e. the construction of spatio-temporal models that illuminate the interplay between architecture and function. Recently, deep learning significantly improved the performance of traditional image analysis in cases where imaging techniques provide large amounts of data. However, if only a few images are available or qualified annotations are expensive to produce, the applicability of deep learning is still limited. RESULTS: We present a novel approach that combines machine learning-based interactive image segmentation using supervoxels with a clustering method for the automated identification of similarly colored images in large image sets which enables a guided reuse of interactively trained classifiers. Our approach solves the problem of deteriorated segmentation and quantification accuracy when reusing trained classifiers which is due to significant color variability prevalent and often unavoidable in biological and medical images. This increase in efficiency improves the suitability of interactive segmentation for larger image sets, enabling efficient quantification or the rapid generation of training data for deep learning with minimal effort. The presented methods are applicable for almost any image type and represent a useful tool for image analysis tasks in general. AVAILABILITY AND IMPLEMENTATION: The presented methods are implemented in our image processing software TiQuant which is freely available at tiquant.hoehme.com. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Authors: A. Friebel, T. Johann, D. Drasdo, S. Hoehme

Date Published: 30th Sep 2022

Publication Type: Journal

Erythropoietin-driven dynamic proteome adaptations during erythropoiesis prevent iron overload in the developing embryo.

Abstract (Expand)

Erythropoietin (Epo) ensures survival and proliferation of colony-forming unit erythroid (CFU-E) progenitor cells and their differentiation to hemoglobin-containing mature erythrocytes. A lack of … Epo-induced responses causes embryonic lethality, but mechanisms regulating the dynamic communication of cellular alterations to the organismal level remain unresolved. By time-resolved transcriptomics and proteomics, we show that Epo induces in CFU-E cells a gradual transition from proliferation signature proteins to proteins indicative for differentiation, including heme-synthesis enzymes. In the absence of the Epo receptor (EpoR) in embryos, we observe a lack of hemoglobin in CFU-E cells and massive iron overload of the fetal liver pointing to a miscommunication between liver and placenta. A reduction of iron-sulfur cluster-containing proteins involved in oxidative phosphorylation in these embryos leads to a metabolic shift toward glycolysis. This link connecting erythropoiesis with the regulation of iron homeostasis and metabolic reprogramming suggests that balancing these interactions is crucial for protection from iron intoxication and for survival.

Authors: S. Chakraborty, G. Andrieux, P. Kastl, L. Adlung, S. Altamura, M. E. Boehm, L. E. Schwarzmuller, Y. Abdullah, M. C. Wagner, B. Helm, H. J. Grone, W. D. Lehmann, M. Boerries, H. Busch, M. U. Muckenthaler, M. Schilling, U. Klingmuller

Date Published: 20th Sep 2022

Publication Type: Journal

Serum Glial Cell Line-Derived Neurotrophic Factor (sGDNF) Is a Novel Biomarker in Predicting Cirrhosis in Patients with Chronic Hepatitis B

Abstract (Expand)

Objectives. We assessed the potential of glial cell line-derived neurotrophic factor (GDNF) as a useful biomarker to predict cirrhosis in chronic hepatitis B (CHB) patients. Methods. A total of 735 …nts. Methods. A total of 735 patients from two medical centers (385 CHB patients and 350 healthy controls) were included to determine the association of serum and tissue GDNF levels with biopsy-proven cirrhosis. The diagnostic accuracy of serum GDNF (sGDNF) was estimated and compared with other indices of cirrhosis. Results. We showed significantly higher levels of sGDNF in CHB patients with fibrosis (28.4 pg/ml vs. 11.6 pg/ml in patients without) and patients with cirrhosis (33.8 pg/ml vs. 23.5 pg/ml in patients without). The areas under receiver operating curve (AUROCs) of sGDNF were 0.83 (95% confidence interval (CI): 0.80–0.87) for predicting liver fibrosis and 0.84 (95% CI: 0.79–0.89) for cirrhosis. Findings from the serum protein level and hepatic mRNA expression were consistent. Using the best cutoff to predict cirrhosis, we categorized the patients into sGDNF-high and sGDNF-low groups. The sGDNF-high group had significantly larger Masson’s trichrome and reticulin staining-positive area, higher Scheuer score, and METAVIR fibrosis stage (all p < 0.001 ) but not steatosis. On multivariable regression, sGDNF was independently associated with cirrhosis with an odds ratio of 6.98 (95% CI: 1.10–17.94). Finally, we demonstrated that sGDNF outperformed AST to platelet ratio index, FIB-4, fibroscore, forn index, and fibrometer in differentiating F4 vs. F3. Conclusion. Using serum, tissue mRNA, and biopsy data, our study revealed a significant potential of sGDNF as a novel noninvasive biomarker for cirrhosis in CHB patients.

Authors: Guangyue Yang, Liping Zhuang, Tiantian Sun, Yee Hui Yeo, Le Tao, Wei Zhang, Wenting Ma, Liu Wu, Zongguo Yang, Yanqin Yang, Dongying Xue, Jie Zhang, Rilu Feng, Ebert Matthias P., Steven Dooley, Ekihiro Seki, Ping Liu, Cheng Liu

Date Published: 9th Jul 2022

Publication Type: Journal

Deciphering signal transduction networks in the liver by mechanistic mathematical modelling

Abstract (Expand)

In health and disease, liver cells are continuously exposed to cytokines and growth factors. While individual signal transduction pathways induced by these factors were studied in great detail, the … cellular responses induced by repeated or combined stimulations are complex and less understood. Growth factor receptors on the cell surface of hepatocytes were shown to be regulated by receptor interactions, receptor trafficking and feedback regulation. Here, we exemplify how mechanistic mathematical modelling based on quantitative data can be employed to disentangle these interactions at the molecular level. Crucial is the analysis at a mechanistic level based on quantitative longitudinal data within a mathematical framework. In such multi-layered information, step-wise mathematical modelling using submodules is of advantage, which is fostered by sharing of standardized experimental data and mathematical models. Integration of signal transduction with metabolic regulation in the liver and mechanistic links to translational approaches promise to provide predictive tools for biology and personalized medicine.

Authors: Lorenza A. D’Alessandro, Ursula Klingmüller, Marcel Schilling

Date Published: 30th Jun 2022

Publication Type: Journal

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

Follistatin‐controlled activin‐HNF4α‐coagulation factor axis in liver progenitor cells determines outcome of acute liver failure

Abstract

Not specified

Authors: Tao Lin, Shanshan Wang, Stefan Munker, Kyounghwa Jung, Ricardo U. Macías‐Rodríguez, Astrid Ruiz‐Margáin, Robert Schierwagen, Hui Liu, Chen Shao, Chunlei Fan, Rilu Feng, Xiaodong Yuan, Sai Wang, Franziska Wandrer, Christoph Meyer, Ralf Wimmer, Roman Liebe, Jens Kroll, Long Zhang, Tobias Schiergens, Peter ten Dijke, Andreas Teufel, Alexander Marx, Peter R. Mertens, Hua Wang, Matthias P.A. Ebert, Heike Bantel, Enrico De Toni, Jonel Trebicka, Steven Dooley, Donghun Shin, Huiguo Ding, Hong‐Lei Weng

Date Published: 1st Feb 2022

Publication Type: Journal

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