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84 Publications visible to you, out of a total of 84
ERRγ-inducible FGF23 promotes alcoholic liver injury through enhancing CYP2E1 mediated hepatic oxidative stress

Abstract

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Authors: Yoon Seok Jung, Kamalakannan Radhakrishnan, Seddik Hammad, Sebastian Müller, Johannes Müller, Jung-Ran Noh, Jina kim, In-Kyu Lee, Sung Jin Cho, Don-Kyu Kim, Yong-Hoon Kim, Chul-Ho Lee, Steven Dooley, Hueng-Sik Choi

Date Published: 1st Mar 2024

Publication Type: Journal

EGF/STAT1 signals to maintain ECM1 expression in hepatic homeostasis are disrupted by IFNγ/NRF2 in chronic liver disease

Abstract (Expand)

Objective In healthy livers, latent transforming growth factor-β (LTGF-β) is stored in the extracellular matrix and kept quiescent by extracellular matrix protein 1 (ECM1). Upon damage, ECM1 is …age, ECM1 is downregulated in hepatocytes, facilitating LTGF-β activation and hepatic fibrosis. This study investigates the underlying molecular mechanisms by which ECM1 expression in the liver is controlled under patho-physiological conditions. Design In silico promoter analysis was used to predict pathways that regulate Ecm1 transcription. Functional assays were performed in AML12 cells, mouse and human primary hepatocytes (MPHs, HPHs), and in liver tissue of mice and patients. Results In healthy liver, EGF/Egfr signaling maintains Ecm1 expression through phosphorylation of Stat1 at S727, which promotes its binding to the Ecm1 gene promoter to enhance gene transcription. During liver inflammation, accumulated IFNγ interferes with EGF signaling by downregulating Egfr expression and by disrupting EGF/Egfr/Stat1-mediated Ecm1 promoter binding. Mechanistically, IFNγ induces Stat1 phosphorylation at position Y701, which is competing with the ability of p-Stat1 S727 to bind to the Ecm1 gene promoter. Additionally, IFNγ induces Nrf2 nuclear translocation and repressive binding to the Ecm1 gene promoter, thus further reducing Ecm1 expression. Importantly, patients suffering from liver cirrhosis who lack nuclear NRF2 expression consistently maintain higher levels of ECM1, inferring a better prognosis. Conclusion ECM1 expression in healthy livers is controlled by EGF/EGFR/STAT1 signaling. Upon liver injury, ECM1 expression is repressed by accumulating IFNγ/NRF2, leading to increased LTGF-β activation and the onset of hepatic fibrosis.

Authors: Yujia Li, Frederik Link, Weiguo Fan, Zeribe C. Nwosu, Weronika Pioronska, Kerry Gould, Christoph Meyer, Ye Yao, Seddik Hammad, Rilu Feng, Hui Liu, Chen Shao, Bing Sun, Huiguo Ding, Roman Liebe, Matthias P. A. Ebert, Hong-Lei Weng, Peter ten Dijke, Steven Dooley, Sai Wang

Date Published: 19th Feb 2024

Publication Type: Journal

TGFβR1 inhibition drives hepatocellular carcinoma proliferation through induction of toll‐like‐receptor signalling

Abstract (Expand)

Abstract Transforming growth factor (TGF)‐β and toll‐like receptors (TLRs) have been shown to independently modulate the proliferation of hepatocellular carcinoma (HCC). Since a direct cross‐talk between … (HCC). Since a direct cross‐talk between these two signalling pathways in HCC has not been clearly described before, we aimed here to explore the possibility of such interaction. A human HCC tissue array ( n  = 20 vs. four control samples), human HCC samples ( n  = 10) and steatohepatitis‐driven murine HCC samples (control, NASH and HCC; n  = 6/group) were immunostained for TGFβR1, pSMAD2, TRAF6, IRAK1 and PCNA. The results were confirmed by immunoblotting. Effects of constant activation of the SMAD pathway by constitutive expression of ALK5 or knockdown of mediators of TLR signalling, IRAK1 and MyD88, on HCC proliferation, were investigated in the HCC cell line (HUH‐7) after treatment with TGFβ1 cytokine or TGFβR1 kinase inhibitor (LY2157299) using PCNA and MTS assay. TGFβR1 expression is decreased in human and murine HCC and associated with downregulated pSMAD2, but increased IRAK1, TRAF6 and PCNA staining. TGFβR1 kinase inhibition abolished the cytostatic effects of TGFβ1 and led to the induction of IRAK1, pIRAK1 and elevated mRNA levels of TLR‐9. Overexpression of ALK5 and knockdown of MyD88 or IRAK1 augmented the cytostatic effects of TGFβ1 on HUH‐7. In another epithelial HCC cell line, that is, HepG2, TGFβR1 kinase inhibitor similarly elevated cellular proliferation. There is a balance between the canonical SMAD‐driven tumour‐suppressing arm and the non‐canonical tumour‐promoting arm of TGFβ signalling. Disruption of this balance, by inhibition of the canonical pathway, induces HCC proliferation through TLR signalling.

Authors: Fatma El Zahraa Ammar Mohamed, Bedair Dewidar, Tao Lin, Matthias P. Ebert, Steven Dooley, Nadja M. Meindl‐Beinker, Seddik Hammad

Date Published: 8th Feb 2024

Publication Type: Journal

ECM1-Mediated Inhibition of Protease-Induced LTGF-β1 Activation in Chronic Liver Disease: Implications for Therapeutic Strategies

Abstract

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Authors: Frederik Link, Yujia Li, Jieling Zhao, Stefan Munker, Weiguo Fan, Zeribe Nwosu, Ye Yao, Seddik Hammad, Roman Liebe, Peter ten Dijke, Honglei Weng, Matthias Ebert, Drik Drasdo, Steven Dooley, Sai Wang

Date Published: 2024

Publication Type: Journal

Reciprocal Inhibitory Regulation of TGF-β1 Signaling and Cholesterol Metabolism in Hepatocytes

Abstract

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Authors: Sai Wang, Frederik Link, Mei Han, Roohi Chaudhary, Anastasia Asimakopoulos, Roman Liebe, Ye Yao, Seddik Hammad, Anne Dropmann, Marinela Krizanac, Matthias Ebert, Ralf Weiskirchen, Yoav I. Henis, Marcelo Ehrlich, Steven Dooley

Date Published: 2024

Publication Type: InProceedings

The Interplay of TGF-β1 and Cholesterol Orchestrating Hepatocyte Cell Fate, EMT, and Signals for HSC Activation

Abstract

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Authors: Sai Wang, Frederik Link, Mei Han, Roohi Chaudhary, Anastasia Asimakopoulos, Roman Liebe, Ye Yao, Seddik Hammad, Anne Dropmann, Marinela Krizanac, Claudia Rubie, Laura Kim Feiner, Matthias Glanemann, Matthias P.A. Ebert, Ralf Weiskirchen, Yoav I. Henis, Marcelo Ehrlich, Steven Dooley

Date Published: 2024

Publication Type: Journal

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

TGF-β1 inhibits cholesterol metabolism in hepatocytes to facilitate cell death, EMT and signals for HSC activation.

Abstract (Expand)

Objective: Transforming growth factor-β1 (TGF-β1) plays important roles in chronic liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), which involves various …lves various biological processes including dysfunctional cholesterol metabolism contributing to progression to metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). However, how TGF-β1 signaling and cholesterol metabolism affects each other in MASLD is yet unknown. Design: Changes in transcription of genes associated with cholesterol metabolism were assessed by RNA-Seq of AML12 cells and mouse primary hepatocytes (MPH) treated with TGF-β1. Functional assays were performed on AML12 cells (untreated, TGF-β1 treated, or subjected to cholesterol enrichment (CE) or depletion (CD)), and on mice injected with adeno-associated virus 8 (AAV8)-Control/TGF-β1. Results: TGF-β1 inhibited mRNA expression of several cholesterol metabolism regulatory genes, including rate-limiting enzymes of cholesterol biosynthesis in AML12 cells, MPHs, and AAV8-TGF- β1-treated mice. Total cholesterol levels in AML12 cells, as well as lipid droplet accumulation in AML12 cells and AAV-treated mice were also reduced. Smad2/3 phosphorylation following 2 h TGF-β1 treatment persisted after CE or CD and was mildly increased following CD, while TGF-β1-mediated AKT phosphorylation (30 min) was inhibited by CE. Furthermore, CE protected AML12 cells from several effects mediated by 72 h incubation with TGF-β1, including EMT, actin polymerization, and apoptosis. CD mimicked the outcome of long term TGF-β1 administration, an effect that was blocked by an inhibitor of the type I TGF-β receptor. Additionally, the supernatant of CE- or CD-treated AML12 cells inhibited or promoted, respectively, the activation of LX-2 hepatic stellate cells. Conclusion: TGF-β1 inhibits cholesterol metabolism while cholesterol attenuates TGF-β1 downstream effects in hepatocytes.

Authors: Sai Wang, Frederik Link, Mei Han, Roman Liebe, Ye Yao, Seddik Hammad, Anne Dropmann, Roohi Chaudhary, Anastasia Asimakopoulos, Marinela Krizanac, Ralf Weiskirchen, Yoav I Henis, Marcelo Ehrlich, Matthias Ebert, Steven Dooley

Date Published: 15th Aug 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

Acute liver injury induces expression of FGF23 in hepatocytes via orphan nuclear receptor ERRγ signaling

Abstract

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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

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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

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

Abstract

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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

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

Abstract

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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

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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

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