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81 Publications visible to you, out of a total of 81
ECM1 is a gatekeeper that restrains TGF-β activation to maintain liver homeostasis and prevent fibrogenesis

Abstract

Not specified

Authors: S Dooley, W Fan, S Hammad, K Gould, T Longerich, T Liu, W Chen, C Liu, J Hou, J Jia, B Sun

Date Published: 2019

Publication Type: Not specified

ECM1 Prevents Activation of Transforming Growth Factor beta, Hepatic Stellate Cells, and Fibrogenesis in Mice.

Abstract (Expand)

BACKGROUND & AIMS: Activation of transforming growth factor beta (TGFB) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanism of TGFB activation are not clear. We … investigated the role of extracellular matrix protein 1 (ECM1), which interacts with extracellular and structural proteins, in TGFB activation in livers of mice. METHODS: We performed studies with e C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1Deltahep). ECM1 or soluble TGFB receptor 2 (TGFBR2) were expressed in livers of mice following injection of an adeno-associated virus vector. Liver fibrosis was induced by carbon tetrachloride (CCl4) administration. Livers were collected from mice and analyzed by histology, immunohistochemistry, in situ hybridization, and immunofluorescence analyses. Hepatocytes and HSCs were isolated from livers of mice and incubated with ECM1; production of cytokines and activation of reporter genes were quantified. Liver tissues from patients with viral or alcohol-induced hepatitis (with different stages of fibrosis) and individuals with healthy liver were analyzed by immunohistochemistry and in situ hybridization. RESULTS: ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix-deposited TGFB in its inactive form by interacting with alphav integrins to prevent activation of HSCs. In liver tissues from patients and in mice with CCl4-induced liver fibrosis, we found an inverse correlation between level of ECM1 and severity of fibrosis. CCl4-induced liver fibrosis was accelerated in ECM1Deltahep mice compared with control mice. Hepatocytes produced the highest levels of ECM1 in livers of mice. Ectopic expression of ECM1 or soluble TGFBR2 in liver prevented fibrogenesis in ECM1-KO mice and prolonged their survival. Ectopic expression of ECM1 in liver also reduced the severity of CCl4-induced fibrosis in mice. CONCLUSIONS: ECM1, produced by hepatocytes, inhibits activation of TGFB and its activation of HSCs to prevent fibrogenesis in mouse liver. Strategies to increase levels of ECM1 in liver might be developed for treatment of fibrosis.

Authors: W. Fan, T. Liu, W. Chen, S. Hammad, T. Longerich, Y. Fu, N. Li, Y. He, C. Liu, Y. Zhang, Q. Lian, X. Zhao, C. Yan, L. Li, C. Yi, Z. Ling, L. Ma, X. Zhao, H. Xu, P. Wang, M. Cong, H. You, Z. Liu, Y. Wang, J. Chen, D. Li, L. Hui, S. Dooley, J. Hou, J. Jia, B. Sun

Date Published: 27th Jul 2019

Publication Type: Not specified

ECM1 stabilizes matrix deposited latent TGF-β to maintain liver homeostasis and prevent fibrogenesis

Abstract

Not specified

Authors: S Hammad, W Fan, T Liu, W Chen, K Gould, T Longerich, I Haußer-Siller, J Hou, J Jia, B Sun, S Dooely

Date Published: 2019

Publication Type: Not specified

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

Abstract

Not specified

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

Effect of alcohol on the interleukin 6-mediated inflammatory response in a new mouse model of acute-on-chronic liver injury

Abstract

Not specified

Authors: Ersin Karatayli, Rabea A. Hall, Susanne N. Weber, Steven Dooley, Frank Lammert

Date Published: 1st Feb 2019

Publication Type: Not specified

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

ERRγ-inducible FGF23 promotes alcoholic liver injury through enhancing CYP2E1 mediated hepatic oxidative stress

Abstract

Not specified

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

Ethanol sensitizes hepatocytes for TGF-beta-triggered apoptosis.

Abstract (Expand)

Alcohol abuse is a global health problem causing a substantial fraction of chronic liver diseases. Abundant TGF-beta-a potent pro-fibrogenic cytokine-leads to disease progression. Our aim was to elucidate … the crosstalk of TGF-beta and alcohol on hepatocytes. Primary murine hepatocytes were challenged with ethanol and TGF-beta and cell fate was determined. Fluidigm RNA analyses revealed transcriptional effects that regulate survival and apoptosis. Mechanistic insights were derived from enzyme/pathway inhibition experiments and modulation of oxidative stress levels. To substantiate findings, animal model specimens and human liver tissue cultures were investigated. RESULTS: On its own, ethanol had no effect on hepatocyte apoptosis, whereas TGF-beta increased cell death. Combined treatment led to massive hepatocyte apoptosis, which could also be recapitulated in human HCC liver tissue treated ex vivo. Alcohol boosted the TGF-beta pro-apoptotic gene signature. The underlying mechanism of pathway crosstalk involves SMAD and non-SMAD/AKT signaling. Blunting CYP2E1 and ADH activities did not prevent this effect, implying that it was not a consequence of alcohol metabolism. In line with this, the ethanol metabolite acetaldehyde did not mimic the effect and glutathione supplementation did not prevent the super-induction of cell death. In contrast, blocking GSK-3beta activity, a downstream mediator of AKT signaling, rescued the strong apoptotic response triggered by ethanol and TGF-beta. This study provides novel information on the crosstalk between ethanol and TGF-beta. We give evidence that ethanol directly leads to a boost of TGF-beta's pro-apoptotic function in hepatocytes, which may have implications for patients with chronic alcoholic liver disease.

Authors: H. Gaitantzi, C. Meyer, P. Rakoczy, M. Thomas, K. Wahl, F. Wandrer, H. Bantel, H. Alborzinia, S. Wolfl, S. Ehnert, A. Nussler, I. Bergheim, L. Ciuclan, M. Ebert, K. Breitkopf-Heinlein, S. Dooley

Date Published: 21st Jan 2018

Publication Type: Not specified

Ethanol sensitizes hepatocytes for TGF-β-triggered apoptosis

Abstract

Not specified

Authors: Haristi Gaitantzi, Christoph Meyer, Pia Rakoczy, Maria Thomas, Kristin Wahl, Franziska Wandrer, Heike Bantel, Hamed Alborzinia, Stefan Wölfl, Sabrina Ehnert, Andreas Nüssler, Ina Bergheim, Loredana Ciuclan, Matthias Ebert, Katja Breitkopf-Heinlein, Steven Dooley

Date Published: 1st Feb 2018

Publication Type: Not specified

Evolving Insights on Metabolism, Autophagy, and Epigenetics in Liver Myofibroblasts.

Abstract (Expand)

Liver myofibroblasts (MFB) are crucial mediators of extracellular matrix (ECM) deposition in liver fibrosis. They arise mainly from hepatic stellate cells (HSCs) upon a process termed "activation." … To a lesser extent, and depending on the cause of liver damage, portal fibroblasts, mesothelial cells, and fibrocytes may also contribute to the MFB population. Targeting MFB to reduce liver fibrosis is currently an area of intense research. Unfortunately, a clog in the wheel of antifibrotic therapies is the fact that although MFB are known to mediate scar formation, and participate in liver inflammatory response, many of their molecular portraits are currently unknown. In this review, we discuss recent understanding of MFB in health and diseases, focusing specifically on three evolving research fields: metabolism, autophagy, and epigenetics. We have emphasized on therapeutic prospects where applicable and mentioned techniques for use in MFB studies. Subsequently, we highlighted uncharted territories in MFB research to help direct future efforts aimed at bridging gaps in current knowledge.

Authors: Z. C. Nwosu, H. Alborzinia, S. Wolfl, S. Dooley, Y. Liu

Date Published: 18th Jun 2016

Publication Type: Not specified

Expression of TLR-2 in hepatocellular carcinoma is associated with tumour proliferation, angiogenesis and Caspase-3 expression

Abstract

Not specified

Authors: Fatma El-Zahraa Ammar Mohamed, Seddik Hammad, Tu Vinh Luong, Bedair Dewidar, Rajai Al-Jehani, Nathan Davies, Steven Dooley, Rajiv Jalan

Date Published: 1st Aug 2020

Publication Type: Journal

Expression of TLR-2 in hepatocellular carcinoma is associated with tumour proliferation, angiogenesis and Caspase-3 expression.

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

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

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