Filter and export

Publications

What is a Publication?
3 Publications matching the given criteria: (Clear all filters)
Project: LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)3
Published year: 20233
Extracellular Matrix Protein 1 Attenuates Hepatic Fibrosis by Inhibiting TSP-, ADAMTS-, and MMP-Mediated Latent TGF-β1 Activation

Abstract (Expand)

Abstract Objective Extracellular Matrix Protein 1 ( Ecm1 ) knockout results in latent transforming growth factor-β1 (LTGF-β1) activation and hepatic fibrosis with rapid mortality in mice. In chronic …ctor-β1 (LTGF-β1) activation and hepatic fibrosis with rapid mortality in mice. In chronic liver disease (CLD), ECM1 is gradually lost with increasing CLD severity. We investigated the underlying mechanism and its impact on CLD progression. Design RNAseq was performed to analyze gene expression in the liver. Functional assays were performed using hepatic stellate cells (HSCs), WT and Ecm1 -KO mice, and liver tissue. Computer modeling was used to verify experimental findings. Results RNAseq shows that expression of thrombospondins (TSPs), ADAMTS proteases, and matrix metalloproteinases (MMPs) increases along with TGF-β1 target, pro-fibrotic genes in liver tissue of Ecm1 -KO mice. In LX-2 or primary human HSCs, ECM1 prevented TSP-1-, ADAMTS1-, and MMP-2/9-mediated LTGF-β1 activation. I n vitro interaction assays demonstrated that ECM1 inhibited LTGF-β1 activation through interacting with TSP-1 and ADAMTS1 via their respective, intrinsic KRFK or KTFR amino acid sequences, while also blunting MMP-2/9 proteolytic activity. In mice, AAV8-mediated ECM1 overexpression attenuated KRFK-induced LTGF-β1 activation and fibrosis, while KTFR reversed Ecm1 -KO-induced liver injury. Furthermore, a correlation between decreasing ECM1 and increasing protease expression and LTGF-β1 activation was found in CLD patients. A computational model validated the impact of restoring ECM1 on reducing LTGF-β1 activation, HSC activation, and collagen deposition in the liver. Conclusion Our findings underscore the hepatoprotective effect of ECM1, which inhibits protease-mediated LTGF-β1 activation, suggesting that preventing its decrease or restoring ECM1 function in the liver could serve as a novel and safer than direct TGF-β1-directed therapies in CLD. One sentence summary ECM1 loss fails to prevent TSP/ADAMTS/MMP-mediated LTGF-β1 activation, leading to liver fibrosis progression.

Authors: Frederik Link, Yujia Li, Jieling Zhao, Stefan Munker, Weiguo Fan, Zeribe Nwosu, Ye Yao, Seddik Hammad, Roman Liebe, Hui Liu, Chen Shao, Bing Sun, Natalie J. Török, Huiguo Ding, Matthias P. A. Ebert, Hong-Lei Weng, Peter ten Dijke, Dirk Drasdo, Steven Dooley, Sai Wang

Date Published: 12th Dec 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

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

Powered by
 (v.1.16.1)
About FAIRDOM | About LiSyM | Funding and Programmes | Credits | Terms & Conditions | Imprint
Copyright © 2008 - 2024 The University of Manchester and HITS gGmbH