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The TGF-beta1 target WISP1 is highly expressed in liver cirrhosis and cirrhotic HCC microenvironment and involved in pro- and anti-tumorigenic effects.

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INTRODUCTION: WNT1-inducible signalling pathway protein 1 (WISP1) promotes progression of several tumor entities often correlating with worse prognosis. Here its expression regulation and role in the … progression of chronic liver diseases (CLD) was investigated. METHODS: WISP1 expression was analyzed in human HCC datasets, in biopsies and serum samples and an HCC patient tissue microarray (TMA) including correlation to clinicopathological parameters. Spatial distribution of WISP1 expression was determined using RNAscope analysis. Regulation of WISP1 expression was investigated in cytokine-stimulated primary mouse hepatocytes (PMH) by array analysis and qRT-PCR. Outcome of WISP1 stimulation was analyzed by IncuCyte S3-live cell imaging, qRT-PCR, and immunoblotting in murine AML12 cells. RESULTS: In a TMA, high WISP1 expression was positively correlated with early HCC stages and male sex. Highest WISP1 expression levels were detected in patients with cirrhosis as compared to healthy individuals, patients with early fibrosis, and non-cirrhotic HCC in liver biopsies, expression datasets and serum samples. WISP1 transcripts were predominantly detected in hepatocytes of cirrhotic rather than tumorous liver tissue. High WISP1 expression was associated with better survival. In PMH, AML12 and HepaRG, WISP1 was identified as a specific TGF-beta1 target gene. Accordingly, expression levels of both cytokines positively correlated in human HCC patient samples. WISP1-stimulation induced the expression of Bcl-xL, PCNA and p21 in AML12 cells. CONCLUSIONS: WISP1 expression is induced by TGF-beta1 in hepatocytes and is associated with cirrhotic liver disease. We propose a crucial role of WISP1 in balancing pro- and anti-tumorigenic effects during premalignant stages of CLD.

Authors: A. Dropmann, S. Alex, K. Schorn, C. Tong, T. Caccamo, P. Godoy, I. Ilkavets, R. Liebe, D. Gonzalez, J. G. Hengstler, A. Piiper, L. Quagliata, M. S. Matter, O. Waidmann, F. Finkelmeier, T. Feng, T. S. Weiss, N. Rahbari, E. Birgin, E. Rasbach, S. Roessler, K. Breuhahn, M. Toth, M. P. Ebert, S. Dooley, S. Hammad, N. M. Meindl-Beinker

Date Published: 5th Nov 2024

Publication Type: Journal

Direct Ingestion of Oxidized Red Blood Cells (Efferocytosis) by Hepatocytes.

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PURPOSE: Both hepatic iron accumulation and hemolysis have been identified as independent prognostic factor in alcohol-related liver disease (ALD); however, the mechanisms still remain poorly understood. … We here demonstrate that hepatocytes are able to directly ingest aged and ethanol-primed red blood cells (RBCs), a process termed efferocytosis. METHODS: Efferocytosis of RBCs was directly studied in vitro and observed by live microscopy for real-time visualization. RBCs pretreated with either CuSO(4) or ethanol following co-incubation with Huh7 cells and murine primary hepatocytes. Heme oxygenase-1 (HO-1) and other targets were measured by q-PCR. RESULTS: As shown by live microscopy, oxidized RBCs, but not intact RBCs, are rapidly ingested by both Huh7 cells and murine primary hepatocytes within 10 minutes. In some cases, more than 10 RBCs were seen within hepatocytes, surrounding the nucleus. RBC efferocytosis also rapidly induces HO1, its upstream regulator Nuclear factor erythroid 2-related factor 2 (Nrf2) and ferritin, indicating efficient heme degradation. Preliminary data further suggest that hepatocyte efferocytosis of oxidized RBCs is, at least in part, mediated by scavenging receptors such as ASGPR1. Of note, pretreatment of RBCs with ethanol but also heme and bilirubin also initiated efferocytosis. In a cohort of heavy human drinkers, a significant correlation of hepatic ASGPR1 with the heme degradation pathway was observed. CONCLUSION: We here demonstrate that hepatocytes can directly ingest and degrade oxidized RBCs through efferocytosis, a process that can be also triggered by ethanol, heme and bilirubin. Our findings are highly suggestive for a novel mechanism of hepatic iron overload in ALD patients.

Authors: C. Zheng, Xiaojia Li, H. Lyu, C. Chen, J. Mueller, A. Dropmann, S. Hammad, S. Dooley, S. He, S. Mueller

Date Published: 9th Sep 2024

Publication Type: Journal

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

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BACKGROUND: When massive necrosis occurs in acute liver failure (ALF), rapid expansion of HSCs called liver progenitor cells (LPCs) in a process called ductular reaction is required for survival. The … underlying mechanisms governing this process are not entirely known to date. In ALF, high levels of retinoic acid (RA), a molecule known for its pleiotropic roles in embryonic development, are secreted by activated HSCs. We hypothesized that RA plays a key role in ductular reaction during ALF. METHODS: RNAseq was performed to identify molecular signaling pathways affected by all-trans retinoid acid (atRA) treatment in HepaRG LPCs. Functional assays were performed in HepaRG cells treated with atRA or cocultured with LX-2 cells and in the liver tissue of patients suffering from ALF. RESULTS: Under ALF conditions, activated HSCs secreted RA, inducing RARalpha nuclear translocation in LPCs. RNAseq data and investigations in HepaRG cells revealed that atRA treatment activated the WNT-beta-Catenin pathway, enhanced stemness genes (SOX9, AFP, and others), increased energy storage, and elevated the expression of ATP-binding cassette transporters in a RARalpha nuclear translocation-dependent manner. Further, atRA treatment-induced pathways were confirmed in a coculture system of HepaRG with LX-2 cells. Patients suffering from ALF who displayed RARalpha nuclear translocation in the LPCs had significantly better MELD scores than those without. CONCLUSIONS: During ALF, RA secreted by activated HSCs promotes LPC activation, a prerequisite for subsequent LPC-mediated liver regeneration.

Authors: S. Wang, F. Link, S. Munker, W. Wang, R. Feng, R. Liebe, Y. Li, Y. Yao, H. Liu, C. Shao, M. P. A. Ebert, H. Ding, S. Dooley, H. L. Weng, S. S. Wang

Date Published: 1st Aug 2024

Publication Type: Journal

Tumour-specific activation of a tumour-blood transport improves the diagnostic accuracy of blood tumour markers in mice.

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BACKGROUND: The accuracy of blood-based early tumour recognition is compromised by signal production at non-tumoral sites, low amount of signal produced by small tumours, and variable tumour production. … Here we examined whether tumour-specific enhancement of vascular permeability by the particular tumour homing peptide, iRGD, which carries dual function of binding to integrin receptors overexpressed in the tumour vasculature and is known to promote extravasation via neuropilin-1 receptor upon site-specific cleavage, might be useful to improve blood-based tumour detection by inducing a yet unrecognised vice versa tumour-to-blood transport. METHODS: To detect an iRGD-induced tumour-to-blood transport, we examined the effect of intravenously injected iRGD on blood levels of alpha-fetoprotein (AFP) and autotaxin in several mouse models of hepatocellular carcinoma (HCC) or in mice with chronic liver injury without HCC, and on prostate-specific antigen (PSA) levels in mice with prostate cancer. FINDINGS: Intravenously injected iRGD rapidly and robustly elevated the blood levels of AFP in several mouse models of HCC, but not in mice with chronic liver injury. The effect was primarily seen in mice with small tumours and normal basal blood AFP levels, was attenuated by an anti-neuropilin-1 antibody, and depended on the concentration gradient between tumour and blood. iRGD treatment was also able to increase blood levels of autotaxin in HCC mice, and of PSA in mice with prostate cancer. INTERPRETATION: We conclude that iRGD induces a tumour-to-blood transport in a tumour-specific fashion that has potential of improving diagnosis of early stage cancer. FUNDING: Deutsche Krebshilfe, DKTK, LOEWE-Frankfurt Cancer Institute.

Authors: C. Schmithals, B. Kakoschky, D. Denk, M. von Harten, J. H. Klug, E. Hintermann, A. Dropmann, E. Hamza, A. C. Jacomin, J. U. Marquardt, S. Zeuzem, P. Schirmacher, E. Herrmann, U. Christen, T. J. Vogl, O. Waidmann, S. Dooley, F. Finkelmeier, A. Piiper

Date Published: 13th Jul 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

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

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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

A liver digital twin for in silico testing of cellular and inter-cellular mechanisms in regeneration after drug-induced damage.

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This communication presents a mathematical mechanism-based model of the regenerating liver after drug-induced pericentral lobule damage resolving tissue microarchitecture. The consequence of alternative … hypotheses about the interplay of different cell types on regeneration was simulated. Regeneration dynamics has been quantified by the size of the damage-induced dead cell area, the hepatocyte density and the spatial-temporal profile of the different cell types. We use deviations of observed trajectories from the simulated system to identify branching points, at which the systems behavior cannot be explained by the underlying set of hypotheses anymore. Our procedure reflects a successful strategy for generating a fully digital liver twin that, among others, permits to test perturbations from the molecular up to the tissue scale. The model simulations are complementing current knowledge on liver regeneration by identifying gaps in mechanistic relationships and guiding the system toward the most informative (lacking) parameters that can be experimentally addressed.

Authors: J. Zhao, A. Ghallab, R. Hassan, S. Dooley, J. G. Hengstler, D. Drasdo

Date Published: 16th Feb 2024

Publication Type: Journal

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

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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

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

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

Direct Ingestion of Oxidized Red Blood Cells (Efferocytosis) by Hepatocytes

Abstract

Not specified

Authors: Chaowen Zheng, Siyuan Li, Huanran Lyu, Cheng Chen, Johannes Mueller, Anne Dropmann, Seddik Hammad, Steven Dooley, Songqing He, Sebastian Mueller

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

Insulin Determines Transforming Growth Factor β Effects on Hepatocyte Nuclear Factor 4α Transcription in Hepatocytes

Abstract (Expand)

Loss of hepatocyte nuclear factor 4α (HNF4α) expression is frequently observed in end-stage liver disease and associated with loss of vital liver functions, thus increasjng mortality. Loss of HNF4α … expression is mediated by inflammatory cytokines, such as transforming growth factor (TGF)-β. However, details of how HNF4α is suppressed are largely unknown to date. This study reports that TGF-β does not directly inhibit HNF4α but contributes to its transcriptional regulation by SMAD2/3 recruiting acetyltransferase CREB-binding protein/p300 to the HNF4α promoter. The recruitment of CREB-binding protein/p300 is indispensable for CCAAT/enhancer-binding protein α (C/EBPα) binding, another essential requirement for constitutive HNF4α expression in hepatocytes. Consistent with the in vitro observation, 67 of 98 patients with hepatic HNF4α express both phospho-SMAD2 and C/EBPα, whereas 22 patients without HNF4α expression lack either phospho-SMAD2 or C/EBPα. In contrast to the observed induction of HNF4α, SMAD2/3 inhibits C/EBPα transcription. Therefore, long-term TGF-β incubation results in C/EBPα depletion, which abrogates HNF4α expression. Intriguingly, SMAD2/3 inhibitory binding to the C/EBPα promoter is abolished by insulin. Two-thirds of patients without C/EBPα lack membrane glucose transporter type 2 expression in hepatocytes, indicating insulin resistance. Taken together, hepatic insulin sensitivity is essential for hepatic HNF4α expression in the condition of inflammation.

Authors: Rilu Feng, Chenhao Tong, Tao Lin, Hui Liu, Chen Shao, Yujia Li, Carsten Sticht, Kejia Kan, Xiaofeng Li, Rui Liu, Sai Wang, Shanshan Wang, Stefan Munker, Hanno Niess, Christoph Meyer, Roman Liebe, Matthias P. Ebert, Steven Dooley, Hua Wang, Huiguo Ding, Hong-Lei Weng

Date Published: 1st Oct 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

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

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

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

Transcriptomic Cross‐Species Analysis of Chronic Liver Disease Reveals Consistent Regulation Between Humans and Mice

Abstract

Not specified

Authors: Christian H. Holland, Ricardo O. Ramirez Flores, Maiju Myllys, Reham Hassan, Karolina Edlund, Ute Hofmann, Rosemarie Marchan, Cristina Cadenas, Jörg Reinders, Stefan Hoehme, Abdel‐latif Seddek, Steven Dooley, Verena Keitel, Patricio Godoy, Brigitte Begher‐Tibbe, Christian Trautwein, Christian Rupp, Sebastian Mueller, Thomas Longerich, Jan G. Hengstler, Julio Saez‐Rodriguez, Ahmed Ghallab

Date Published: 28th Aug 2021

Publication Type: Journal

Liver sinusoidal endothelial cells suppress BMP2 production in response to TGFβ pathway activation

Abstract

Not specified

Authors: Silvia Colucci, Sandro Altamura, Oriana Marques, Anne Dropmann, Natalie K. Horvat, Katja Müdder, Seddik Hammad, Steven Dooley, Martina U. Muckenthaler

Date Published: 13th May 2021

Publication Type: Journal

Orphan nuclear receptor ERR-γ regulates hepatic FGF23 production in acute kidney injury.

Abstract (Expand)

Fibroblast growth factor 23 (FGF23), a hormone generally derived from bone, is important in phosphate and vitamin D homeostasis. In acute kidney injury (AKI) patients, high-circulating FGF23 levels are … associated with disease progression and mortality. However, the organ and cell type of FGF23 production in AKI and the molecular mechanism of its excessive production are still unidentified. For insight, we investigated folic acid (FA)-induced AKI in mice. Interestingly, simultaneous with FGF23, orphan nuclear receptor ERR-γ expression is increased in the liver of FA-treated mice, and ectopic overexpression of ERR-γ was sufficient to induce hepatic FGF23 production. In patients and in mice, AKI is accompanied by up-regulated systemic IL-6, which was previously identified as an upstream regulator of ERR-γ expression in the liver. Administration of IL-6 neutralizing antibody to FA-treated mice or of recombinant IL-6 to healthy mice confirms IL-6 as an upstream regulator of hepatic ERR-γ-mediated FGF23 production. A significant (<i>P</i> &lt; 0.001) interconnection between high IL-6 and FGF23 levels as a predictor of AKI in patients that underwent cardiac surgery was also found, suggesting the clinical relevance of the finding. Finally, liver-specific depletion of ERR-γ or treatment with an inverse ERR-γ agonist decreased hepatic FGF23 expression and plasma FGF23 levels in mice with FA-induced AKI. Thus, inverse agonist of ERR-γ may represent a therapeutic strategy to reduce adverse plasma FGF23 levels in AKI.

Authors: Kamalakannan Radhakrishnan, Yong-Hoon Kim, Yoon Seok Jung, Don-Kyu Kim, Soon-Young Na, Daejin Lim, Dong Hun Kim, Jina Kim, Hyung-Seok Kim, Hyon E Choy, Sung Jin Cho, In-Kyu Lee, Şamil Ayvaz, Stefanie Nittka, Danilo Fliser, Stefan J Schunk, Thimoteus Speer, Steven Dooley, Chul-Ho Lee, Hueng-Sik Choi

Date Published: 20th Apr 2021

Publication Type: Journal

Abcb4KO mice upon chemical intoxication represent features of acute-on-chronic liver failure in patients

Abstract

Not specified

Authors: P Erdoesi, E Karatayli, F Lammert, S Dooley, S Hammad

Date Published: 2021

Publication Type: Proceedings

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

Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance.

Abstract (Expand)

BACKGROUND: The extracellular signal-regulated kinase (ERK) pathway regulates cell growth, and is hyper-activated and associated with drug resistance in hepatocellular carcinoma (HCC). Metabolic pathways … are profoundly dysregulated in HCC. Whether an altered metabolic state is linked to activated ERK pathway and drug response in HCC is unaddressed. METHODS: We deprived HCC cells of glutamine to induce metabolic alterations and performed various assays, including metabolomics (with (13)C-glucose isotope tracing), microarray analysis, and cell proliferation assays. Glutamine-deprived cells were also treated with kinase inhibitors (e.g. Sorafenib, Erlotinib, U0126 amongst other MEK inhibitors). We performed bioinformatics analysis and stratification of HCC tumour microarrays to determine upregulated ERK gene signatures in patients. FINDINGS: In a subset of HCC cells, the withdrawal of glutamine triggers a severe metabolic alteration and ERK phosphorylation (pERK). This is accompanied by resistance to the anti-proliferative effect of kinase inhibitors, despite pERK inhibition. High intracellular serine is a consistent feature of an altered metabolic state and contributes to pERK induction and the kinase inhibitor resistance. Blocking the ERK pathway facilitates cell proliferation by reprogramming metabolism, notably enhancing aerobic glycolysis. We have identified 24 highly expressed ERK gene signatures that their combined expression strongly indicates a dysregulated metabolic gene network in human HCC tissues. INTERPRETATION: A severely compromised metabolism lead to ERK pathway induction, and primes some HCC cells to pro-survival phenotypes upon ERK pathway blockade. Our findings offer novel insights for understanding, predicting and overcoming drug resistance in liver cancer patients. FUND: DFG, BMBF and Sino-German Cooperation Project.

Authors: Z. C. Nwosu, W. Pioronska, N. Battello, A. D. Zimmer, B. Dewidar, M. Han, S. Pereira, B. Blagojevic, D. Castven, V. Charlestin, P. Holenya, J. Lochead, C. De La Torre, N. Gretz, P. Sajjakulnukit, L. Zhang, M. H. Ward, J. U. Marquardt, M. P. di Magliano, C. A. Lyssiotis, J. Sleeman, S. Wolfl, M. P. Ebert, C. Meyer, U. Hofmann, S. Dooley

Date Published: 25th Apr 2020

Publication Type: Not specified

TGF-β2 silencing to target biliary-derived liver diseases

Abstract

Not specified

Authors: Anne Dropmann, Steven Dooley, Bedair Dewidar, Seddik Hammad, Tatjana Dediulia, Julia Werle, Vanessa Hartwig, Shahrouz Ghafoory, Stefan Woelfl, Hanna Korhonen, Michel Janicot, Katja Wosikowski, Timo Itzel, Andreas Teufel, Detlef Schuppan, Ana Stojanovic, Adelheid Cerwenka, Stefanie Nittka, Albrecht Piiper, Timo Gaiser, Naiara Beraza, Malgorzata Milkiewicz, Piotr Milkiewicz, John G Brain, David E J Jones, Thomas S Weiss, Ulrich M Zanger, Matthias Ebert, Nadja M Meindl-Beinker

Date Published: 28th Jan 2020

Publication Type: Not specified

Editorial: Systems Biology and Bioinformatics in Gastroenterology and Hepatology

Abstract

Not specified

Authors: Peter L. M. Jansen, Kai Breuhahn, Andreas Teufel, Steven Dooley

Date Published: 22nd Nov 2019

Publication Type: Not specified

TGF-beta in Hepatic Stellate Cell Activation and Liver Fibrogenesis-Updated 2019.

Abstract (Expand)

Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment … is mainly the removal of the causative factor. Transforming growth factor (TGF)-beta is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-beta has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-beta and its upstream and downstream regulatory mechanisms will help to design better TGF-beta based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-beta signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-beta on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-beta. Finally, we discuss new approaches to target the TGF-beta pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed.

Authors: B. Dewidar, C. Meyer, S. Dooley, A. N. Meindl-Beinker

Date Published: 11th Nov 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

Adenovirusmediated overexpression of bone morphogenetic protein9 promotes methionine choline deficiencyinduced nonalcoholic steatohepatitis in nonobese mice.

Abstract (Expand)

Liver inflammation and macrophage infiltration are critical steps in the progression of nonalcoholic fatty liver to the development of nonalcoholic steatohepatitis. Bone morphogenetic protein9 is a … cytokine involved in the regulation of chemokines and lipogenesis. However, the function of bone morphogenetic protein9 in nonalcoholic steatohepatitis is still unknown. The present study hypothesized that bone morphogenetic protein9 may contribute to steatohepatitis in mice fed a methionine choline deficiency diet (MCD). C57BL/6 mice overexpressing bone morphogenetic protein9 and control mice were fed the MCD diet for 4 weeks. Liver tissue and serum samples were obtained for subsequent measurements. Bone morphogenetic protein9 overexpression exacerbated steatohepatitis in mice on the MCD diet, as indicated by liver histopathology, increased serum alanine aminotransferase activity, aspartate transaminase activity, hepatic inflammatory gene expression and M1 macrophage recruitment. Although bone morphogenetic protein9 overexpression did not affect the expression of profibrogenic genes, including Collagen I (alpha)1 or matrix metalloproteinase (MMP) 9, it did upregulate the expression of transforming growth factorbeta and plasminogen activator inhibitor 1, and downregulated the expression of MMP2. The above results indicate that bone morphogenetic protein9 exerts a proinflammatory role in MCD dietinduced nonalcoholic steatohepatitis.

Authors: Q. Li, B. Liu, K. Breitkopf-Heinlein, H. Weng, Q. Jiang, P. Dong, S. Dooley, K. Xu, H. Ding

Date Published: 20th Jul 2019

Publication Type: Not specified

Glial cell line-derived neurotrophic factor (GDNF) mediates hepatic stellate cell activation via ALK5/Smad signalling.

Abstract (Expand)

OBJECTIVE: Although glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-beta superfamily, its function in liver fibrosis has rarely been studied. Here, we … investigated the role of GDNF in hepatic stellate cell (HSC) activation and liver fibrosis in humans and mice. DESIGN: GDNF expression was examined in liver biopsies and sera from patients with liver fibrosis. The functional role of GDNF in liver fibrosis was examined in mice with adenoviral delivery of the GDNF gene, GDNF sgRNA CRISPR/Cas9 and the administration of GDNF-blocking antibodies. GDNF was examined on HSC activation using human and mouse primary HSCs. The binding of activin receptor-like kinase 5 (ALK5) to GDNF was determined using surface plasmon resonance (SPR), molecular docking, mutagenesis and co-immunoprecipitation. RESULTS: GDNF mRNA and protein levels are significantly upregulated in patients with stage F4 fibrosis. Serum GDNF content correlates positively with alpha-smooth muscle actin (alpha-SMA) and Col1A1 mRNA in human fibrotic livers. Mice with overexpressed GDNF display aggravated liver fibrosis, while mice with silenced GDNF expression or signalling inhibition by GDNF-blocking antibodies have reduced fibrosis and HSC activation. GDNF is confined mainly to HSCs and contributes to HSC activation through ALK5 at His(39) and Asp(76) and through downstream signalling via Smad2/3, but not through GDNF family receptor alpha-1 (GFRalpha1). GDNF, ALK5 and alpha-SMA colocalise in human and mouse HSCs, as demonstrated by confocal microscopy. CONCLUSIONS: GDNF promotes HSC activation and liver fibrosis through ALK5/Smad signalling. Inhibition of GDNF could be a novel therapeutic strategy to combat liver fibrosis.

Authors: L. Tao, W. Ma, L. Wu, M. Xu, Y. Yang, W. Zhang, W. Sha, H. Li, J. Xu, R. Feng, D. Xue, J. Zhang, S. Dooley, E. Seki, P. Liu, C. Liu

Date Published: 6th Jun 2019

Publication Type: Not specified

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

Aged Abcb4-/- mice upon acute sublethal chemical insult recapitulate features of acute-on-chronic liver failure in patients

Abstract

Not specified

Authors: S Hammad, JG Hengstler, S Dooley

Date Published: 2019

Publication Type: Not specified

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

Simultaneous isolation of parenchymal and non-parenchymal cells from healthy and diseased mice liver

Abstract

Not specified

Authors: B Dewidar, A Dropmann, K Gould, V Hartwig, C Dormann, S Dooley, S Hammad

Date Published: 2019

Publication Type: Not specified

Jagged-1 upregulation in stressed hepatocytes is crucial for liver regeneration

Abstract

Not specified

Authors: B Dewidar, S Hammad, MP Ebert, JG Hengstler, S Dooley

Date Published: 2019

Publication Type: Not specified

Cellular and nuclear hepatocyte ploidy represent a repository in regenerating livers

Abstract

Not specified

Authors: S Hammad, U Dahmen, A Othman, I Recklinghausen, JG Hengstler, U Klingmüller, S Dooley

Date Published: 2019

Publication Type: Not specified

Liver cell type specific discrimination of TGF-beta signaling and outcome in vitro and in vivo

Abstract

Not specified

Authors: M Han, ZC Nwosu, MP Ebert, S Hammad, S Dooley, C Meyer

Date Published: 2019

Publication Type: Not specified

CYP2E1 recovery is associated with a pericentral fibrosis pattern after repeated CCl4 insults

Abstract

Not specified

Authors: S Hammad, J Zhao, Y Yin, A Zaza, D Drasdo, JG Hengstler, S Dooley

Date Published: 2019

Publication Type: Not specified

Transcription factor TRIM33 controls liver progenitor cell towards hepatocyte differentiation through synergizing with phosphorylated Smad2/3 in liver cirrhosis

Abstract

Not specified

Authors: T Lin, S Wang, C Shao, X Yuan, F Wandrer, H Bantel, MP Ebert, H Ding, S Dooley, HL Weng

Date Published: 2019

Publication Type: Not specified

Maintenance of functional hepatocellular polarity determines recovery in acute-on-chronic liver failure

Abstract

Not specified

Authors: S Wang, R Feng, X Yuan, F Wandrer, MP Ebert, H Bantel, H Li, S Dooley, HL Weng

Date Published: 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

Focused scores enable reliable discrimination of small differences in steatosis.

Abstract (Expand)

BACKGROUND: Automated image analysis enables quantitative measurement of steatosis in histological images. However, spatial heterogeneity of steatosis can make quantitative steatosis scores unreliable. … To improve the reliability, we have developed novel scores that are "focused" on steatotic tissue areas. METHODS: Focused scores use concepts of tile-based hotspot analysis in order to compute statistics about steatotic tissue areas in an objective way. We evaluated focused scores on three data sets of images of rodent liver sections exhibiting different amounts of dietary-induced steatosis. The same evaluation was conducted with the standard steatosis score computed by most image analysis methods. RESULTS: The standard score reliably discriminated large differences in steatosis (intraclass correlation coefficient ICC = 0.86), but failed to discriminate small (ICC = 0.54) and very small (ICC = 0.14) differences. With an appropriate tile size, mean-based focused scores reliably discriminated large (ICC = 0.92), small (ICC = 0.86) and very small (ICC = 0.83) differences. Focused scores based on high percentiles showed promise in further improving the discrimination of very small differences (ICC = 0.93). CONCLUSIONS: Focused scores enable reliable discrimination of small differences in steatosis in histological images. They are conceptually simple and straightforward to use in research studies.

Authors: A. Homeyer, S. Hammad, L. O. Schwen, U. Dahmen, H. Hofener, Y. Gao, S. Dooley, A. Schenk

Date Published: 20th Sep 2018

Publication Type: Not specified

Liver cancer cell lines distinctly mimic the metabolic gene expression pattern of the corresponding human tumours.

Abstract (Expand)

BACKGROUND: Although metabolism is profoundly altered in human liver cancer, the extent to which experimental models, e.g. cell lines, mimic those alterations is unresolved. Here, we aimed to determine … the resemblance of hepatocellular carcinoma (HCC) cell lines to human liver tumours, specifically in the expression of deregulated metabolic targets in clinical tissue samples. METHODS: We compared the overall gene expression profile of poorly-differentiated (HLE, HLF, SNU-449) to well-differentiated (HUH7, HEPG2, HEP3B) HCC cell lines in three publicly available microarray datasets. Three thousand and eighty-five differentially expressed genes in >/=2 datasets (P < 0.05) were used for pathway enrichment and gene ontology (GO) analyses. Further, we compared the topmost gene expression, pathways, and GO from poorly differentiated cell lines to the pattern from four human HCC datasets (623 tumour tissues). In well- versus poorly differentiated cell lines, and in representative models HLE and HUH7 cells, we specifically assessed the expression pattern of 634 consistently deregulated metabolic genes in human HCC. These data were complemented by quantitative PCR, proteomics, metabolomics and assessment of response to thirteen metabolism-targeting compounds in HLE versus HUH7 cells. RESULTS: We found that poorly-differentiated HCC cells display upregulated MAPK/RAS/NFkB signaling, focal adhesion, and downregulated complement/coagulation cascade, PPAR-signaling, among pathway alterations seen in clinical tumour datasets. In HLE cells, 148 downregulated metabolic genes in liver tumours also showed low gene/protein expression - notably in fatty acid beta-oxidation (e.g. ACAA1/2, ACADSB, HADH), urea cycle (e.g. CPS1, ARG1, ASL), molecule transport (e.g. SLC2A2, SLC7A1, SLC25A15/20), and amino acid metabolism (e.g. PHGDH, PSAT1, GOT1, GLUD1). In contrast, HUH7 cells showed a higher expression of 98 metabolic targets upregulated in tumours (e.g. HK2, PKM, PSPH, GLUL, ASNS, and fatty acid synthesis enzymes ACLY, FASN). Metabolomics revealed that the genomic portrait of HLE cells co-exist with profound reliance on glutamine to fuel tricarboxylic acid cycle, whereas HUH7 cells use both glucose and glutamine. Targeting glutamine pathway selectively suppressed the proliferation of HLE cells. CONCLUSIONS: We report a yet unappreciated distinct expression pattern of clinically-relevant metabolic genes in HCC cell lines, which could enable the identification and therapeutic targeting of metabolic vulnerabilities at various liver cancer stages.

Authors: Z. C. Nwosu, N. Battello, M. Rothley, W. Pioronska, B. Sitek, M. P. Ebert, U. Hofmann, J. Sleeman, S. Wolfl, C. Meyer, D. A. Megger, S. Dooley

Date Published: 5th Sep 2018

Publication Type: Not specified

Bile micro-infarcts in cholestasis are initiated by rupture of the apical hepatocyte membrane and cause shunting of bile to sinusoidal blood

Abstract

Not specified

Authors: Ahmed Ghallab, Ute Hofmann, Selahaddin Sezgin, Nachiket Vartak, Reham Hassan, Ayham Zaza, Patricio Godoy, Kai Markus Schneider, Georgia Guenther, Yasser A Ahmed, Aya A Abbas, Verena Keitel, Lars Kuepfer, Steven Dooley, Frank Lammert, Christian Trautwein, Michael Spiteller, Dirk Drasdo, Alan F Hofmann, Peter L M Jansen, Jan G Hengstler, Raymond Reif

Date Published: 13th Aug 2018

Publication Type: Not specified

MicroRNA-942 mediates hepatic stellate cell activation by regulating BAMBI expression in human liver fibrosis.

Abstract (Expand)

MicroRNA (miRNA)-mediated gene regulation contributes to liver pathophysiology, including hepatic stellate cell (HSC) activation and fibrosis progression. Here, we investigated the role of miR-942 in … human liver fibrosis. The expression of miR-942, HSC activation markers, transforming growth factor-beta pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI), as well as collagen deposition, were investigated in 100 liver specimens from patients with varying degree of hepatitis B virus (HBV)-related fibrosis. Human primary HSCs and the immortalized cell line (LX2 cells) were used for functional studies. We found that miR-942 expression was upregulated in activated HSCs and correlated inversely with BAMBI expression in liver fibrosis progression. Transforming growth factor beta (TGF-beta) and lipopolyssacharide (LPS), two major drivers of liver fibrosis and inflammation, induce miR-942 expression in HSCs via Smad2/3 respective NF-kappaB/p50 binding to the miR-942 promoter. Mechanistically, the induced miR-942 degrades BAMBI mRNA in HSCs, thereby sensitizing the cells for fibrogenic TGF-beta signaling and also partly mediates LPS-induced proinflammatory HSC fate. In conclusion, the TGF-beta and LPS-induced miR-942 mediates HSC activation through downregulation of BAMBI in human liver fibrosis. Our study provides new insights on the molecular mechanism of HSC activation and fibrosis.

Authors: L. Tao, D. Xue, D. Shen, W. Ma, J. Zhang, X. Wang, W. Zhang, L. Wu, K. Pan, Y. Yang, Z. C. Nwosu, S. Dooley, E. Seki, C. Liu

Date Published: 12th Aug 2018

Publication Type: Not specified

Inverse agonist of ERRgamma reduces cannabinoid receptor type 1-mediated induction of fibrinogen synthesis in mice with a high-fat diet-intoxicated liver.

Abstract (Expand)

Upon liver intoxication with malnutrition or high-fat diet feeding, fibrinogen is synthesized by hepatocytes and secreted into the blood in human and mouse. Its primary function is to occlude blood … vessels upon damage and thereby stop excessive bleeding. High fibrinogen levels may contribute to the development of pathological thrombosis, which is one mechanism linking fatty liver disease with cardiovascular disease. Our previous results present ERRgamma as key regulator of hepatocytic fibrinogen gene expression in human. In a therapeutic approach, we now tested ERRgamma inverse agonist GSK5182 as regulator of fibrinogen levels in mouse hyperfibrinogenemia caused by diet-induced obesity and in mouse hepatocytes. ACEA, a CB1R agonist, up-regulated transcription of mouse fibrinogen via induction of ERRgamma, whereas knockdown of ERRgamma attenuated the effect of ACEA (10 microM) on fibrinogen expression in AML12 mouse hepatocytes. Deletion analyses of the mouse fibrinogen gamma (FGG) gene promoter and ChIP assays revealed binding sites for ERRgamma on the mouse FGG promoter. ACEA or adenovirus ERRgamma injection induced FGA, FGB and FGG mRNA and protein expression in mouse liver, while ERRgamma knockdown with Ad-shERRgamma attenuated ACEA-mediated induction of fibrinogen gene expression. Moreover, mice maintained on a high-fat diet (HFD) expressed higher levels of fibrinogen, whereas cannabinoid receptor type 1 (CB1R)-KO mice fed an HFD had nearly normal fibrinogen levels. Finally, GSK5182 (40 mg/kg) strongly inhibits the ACEA (10 mg/kg) or HFD-mediated induction of fibrinogen level in mice. Taken together, targeting ERRgamma with its inverse agonist GSK5182 represents a promising therapeutic strategy for ameliorating hyperfibrinogenemia.

Authors: Y. Zhang, D. K. Kim, Y. S. Jung, Y. H. Kim, Y. S. Lee, J. Kim, W. I. Jeong, I. K. Lee, S. J. Cho, S. Dooley, C. H. Lee, H. S. Choi

Date Published: 19th Jul 2018

Publication Type: Not specified

Confounding influence of tamoxifen in mouse models of Cre recombinase-induced gene activity or modulation

Abstract (Expand)

Tamoxifen (TAM) is commonly used for cell type specific Cre recombinase-induced gene inactivation and in cell fate tracing studies. Inducing a gene knockout by TAM and using non-TAM exposed mice as … controls lead to a situation where differences are interpreted as consequences of the gene knockout but in reality result from TAM-induced changes in hepatic metabolism. The degree to which TAM may compromise the interpretation of animal experiments with inducible gene expression still has to be elucidated. Here, we report that TAM strongly attenuates CCl4-induced hepatotoxicity in male C57Bl/6N mice, even after a 10 days TAM exposure-free period. TAM decreased (p < 0.0001) the necrosis index and the level of aspartate- and alanine transaminases in CCl4-treated compared to vehicle-exposed mice. TAM pretreatment also led to the downregulation of CYP2E1 (p = 0.0045) in mouse liver tissue, and lowered its activity in CYP2E1 expressing HepG2 cell line. Furthermore, TAM increased the level of the antioxidant ascorbate, catalase, SOD2, and methionine, as well as phase II metabolizing enzymes GSTM1 and UGT1A1 in CCl4-treated livers. Finally, we found that TAM increased the presence of resident macrophages and recruitment of immune cells in necrotic areas of the livers as indicated by F4/80 and CD45 staining. In conclusion, we reveal that TAM increases liver resistance to CCl4-induced toxicity. This finding is of high relevance for studies using the tamoxifen-inducible expression system particularly if this system is used in combination with hepatotoxic compounds such as CCl4.

Authors: Seddik Hammad, Amnah Othman, Christoph Meyer, Ahmad Telfah, Joerg Lambert, Bedair Dewidar, Julia Werle, Zeribe Chike Nwosu, Abdo Mahli, Christof Dormann, Yan Gao, Kerry Gould, Mei Han, Xiaodong Yuan, Mikheil Gogiashvili, Roland Hergenröder, Claus Hellerbrand, Maria Thomas, Matthias Philip Ebert, Salah Amasheh, Jan G. Hengstler, Steven Dooley

Date Published: 4th Jul 2018

Publication Type: Not specified

Galunisertib modifies the liver fibrotic composition in the Abcb4Ko mouse model

Abstract (Expand)

Transforming growth factor (TGF)-β stimulates extracellular matrix (ECM) deposition during development of liver fibrosis and cirrhosis, the most important risk factor for the onset of hepatocellular … carcinoma. In liver cancer, TGF-β is responsible for a more aggressive and invasive phenotype, orchestrating remodeling of the tumor microenvironment and triggering epithelial-mesenchymal transition of cancer cells. This is the scientific rationale for targeting the TGF-β pathway via a small molecule, galunisertib (intracellular inhibitor of ALK5) in clinical trials to treat liver cancer patients at an advanced disease stage. In this study, the hypothesis that galunisertib modifies the tissue microenvironment via inhibition of the TGF-β pathway is tested in an experimental preclinical model. At the age of 6 months, Abcb4ko mice-a well-established model for chronic liver disease development and progression-are treated twice daily with galunisertib (150 mg/kg) via oral gavage for 14 consecutive days. Two days after the last treatment, blood plasma and livers are harvested for further assessment, including fibrosis scoring and ECM components. The reduction of Smad2 phosphorylation in both parenchymal and non-parenchymal liver cells following galunisertib administration confirms the treatment effectiveness. Damage-related galunisertib does not change cell proliferation, macrophage numbers and leucocyte recruitment. Furthermore, no clear impact on the amount of fibrosis is evident, as documented by PicroSirius red and Gomori-trichome scoring. On the other hand, several fibrogenic genes, e.g., collagens (Col1α1 and Col1α2), Tgf-β1 and Timp1, mRNA levels are significantly downregulated by galunisertib administration when compared to controls. Most interestingly, ECM/stromal components, fibronectin and laminin-332, as well as the carcinogenic β-catenin pathway, are remarkably reduced by galunisertib-treated Abcb5ko mice. In conclusion, TGF-β inhibition by galunisertib interferes, to some extent, with chronic liver progression, not by reducing the stage of liver fibrosis as measured by different scoring systems, but rather by modulating the biochemical composition of the deposited ECM, likely affecting the fate of non-parenchymal cells.

Authors: Seddik Hammad, Elisabetta Cavalcanti, Julia Werle, Maria Lucia Caruso, Anne Dropmann, Antonia Ignazzi, Matthias Philip Ebert, Steven Dooley, Gianluigi Giannelli

Date Published: 28th May 2018

Publication Type: Not specified

Hepatic Smad7 overexpression causes severe iron overload in mice

Abstract

Not specified

Authors: Dilay Lai, Feng Teng, Seddik Hammad, Julia Werle, Thorsten Maas, Andreas Teufel, Martina U. Muckenthaler, Steven Dooley, Maja Vujić Spasić

Date Published: 1st Feb 2018

Publication Type: Not specified

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

Adverse outcome pathways: opportunities, limitations and open questions.

Abstract (Expand)

Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory … purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field.

Authors: M. Leist, A. Ghallab, R. Graepel, R. Marchan, R. Hassan, S. H. Bennekou, A. Limonciel, M. Vinken, S. Schildknecht, T. Waldmann, E. Danen, B. van Ravenzwaay, H. Kamp, I. Gardner, P. Godoy, F. Y. Bois, A. Braeuning, R. Reif, F. Oesch, D. Drasdo, S. Hohme, M. Schwarz, T. Hartung, T. Braunbeck, J. Beltman, H. Vrieling, F. Sanz, A. Forsby, D. Gadaleta, C. Fisher, J. Kelm, D. Fluri, G. Ecker, B. Zdrazil, A. Terron, P. Jennings, B. van der Burg, S. Dooley, A. H. Meijer, E. Willighagen, M. Martens, C. Evelo, E. Mombelli, O. Taboureau, A. Mantovani, B. Hardy, B. Koch, S. Escher, C. van Thriel, C. Cadenas, D. Kroese, B. van de Water, J. G. Hengstler

Date Published: 19th Oct 2017

Publication Type: Not specified

The level of caveolin-1 expression determines response to TGF-β as a tumour suppressor in hepatocellular carcinoma cells

Abstract

Not specified

Authors: Joaquim Moreno-Càceres, Daniel Caballero-Díaz, Zeribe Chike Nwosu, Christoph Meyer, Judit López-Luque, Andrea Malfettone, Raquel Lastra, Teresa Serrano, Emilio Ramos, Steven Dooley, Isabel Fabregat

Date Published: 12th Oct 2017

Publication Type: Not specified

Identification of the Consistently Altered Metabolic Targets in Human Hepatocellular Carcinoma

Abstract

Not specified

Authors: Zeribe Chike Nwosu, Dominik Andre Megger, Seddik Hammad, Barbara Sitek, Stephanie Roessler, Matthias Philip Ebert, Christoph Meyer, Steven Dooley

Date Published: 1st Sep 2017

Publication Type: Not specified

A frequent misinterpretation in current research on liver fibrosis: the vessel in the center of CCl4-induced pseudolobules is a portal vein.

Abstract (Expand)

Carbon tetrachloride-induced liver injury is a thoroughly studied model for regeneration and fibrosis in rodents. Nevertheless, its pattern of liver fibrosis is frequently misinterpreted as portal type. … To clarify this, we show that collagen type IV+ "streets" and alpha-SMA+ cells accumulate pericentrally and extend to neighbouring central areas of the liver lobule, forming a 'pseudolobule'. Blood vessels in the center of such pseudolobules are portal veins as indicated by the presence of bile duct cells (CK19+) and the absence of pericentral hepatocytes (glutamine synthetase+). It is critical to correctly describe this pattern of fibrosis, particulary for metabolic zonation studies.

Authors: S. Hammad, A. Braeuning, C. Meyer, F. E. Z. A. Mohamed, J. G. Hengstler, S. Dooley

Date Published: 22nd Aug 2017

Publication Type: Not specified

Orphan nuclear receptor ERRγ is a key regulator of human fibrinogen gene expression

Abstract

Not specified

Authors: Yaochen Zhang, Don-Kyu Kim, Yan Lu, Yoon Seok Jung, Ji-min Lee, Young-Hoon Kim, Yong Soo Lee, Jina Kim, Bedair Dewidar, Won-IL Jeong, In-Kyu Lee, Sung Jin Cho, Steven Dooley, Chul-Ho Lee, Xiaoying Li, Hueng-Sik Choi

Date Published: 27th Jul 2017

Publication Type: Not specified

Robust detection and segmentation of cell nuclei in biomedical images based on a computational topology framework

Abstract

Not specified

Authors: Rodrigo Rojas-Moraleda, Wei Xiong, Niels Halama, Katja Breitkopf-Heinlein, Steven Dooley, Luis Salinas, Dieter W. Heermann, Nektarios A. Valous

Date Published: 1st May 2017

Publication Type: Not specified

Quantification of substrate and cellular strains in stretchable 3D cell cultures: an experimental and computational framework

Abstract

Not specified

Authors: P. GONZÁLEZ-AVALOS, M. MÜRNSEER, J. DEEG, A. BACHMANN, J. SPATZ, S. DOOLEY, R. EILS, E. GLADILIN

Date Published: 1st May 2017

Publication Type: Not specified

Global Transcriptional Response of Human Liver Cells to Ethanol Stress of Different Strength Reveals Hormetic Behavior

Abstract

Not specified

Authors: Wolfgang Schmidt-Heck, Eva C. Wönne, Thomas Hiller, Uwe Menzel, Dirk Koczan, Georg Damm, Daniel Seehofer, Fanny Knöspel, Nora Freyer, Reinhard Guthke, Steven Dooley, Katrin Zeilinger

Date Published: 1st May 2017

Publication Type: Not specified

BMP-9 interferes with liver regeneration and promotes liver fibrosis.

Abstract (Expand)

OBJECTIVE: Bone morphogenetic protein (BMP)-9, a member of the transforming growth factor-beta family of cytokines, is constitutively produced in the liver. Systemic levels act on many organs and tissues … including bone and endothelium, but little is known about its hepatic functions in health and disease. DESIGN: Levels of BMP-9 and its receptors were analysed in primary liver cells. Direct effects of BMP-9 on hepatic stellate cells (HSCs) and hepatocytes were studied in vitro, and the role of BMP-9 was examined in acute and chronic liver injury models in mice. RESULTS: Quiescent and activated HSCs were identified as major BMP-9 producing liver cell type. BMP-9 stimulation of cultured hepatocytes inhibited proliferation, epithelial to mesenchymal transition and preserved expression of important metabolic enzymes such as cytochrome P450. Acute liver injury caused by partial hepatectomy or single injections of carbon tetrachloride (CCl4) or lipopolysaccharide (LPS) into mice resulted in transient downregulation of hepatic BMP-9 mRNA expression. Correspondingly, LPS stimulation led to downregulation of BMP-9 expression in cultured HSCs. Application of BMP-9 after partial hepatectomy significantly enhanced liver damage and disturbed the proliferative response. Chronic liver damage in BMP-9-deficient mice or in mice adenovirally overexpressing the selective BMP-9 antagonist activin-like kinase 1-Fc resulted in reduced deposition of collagen and subsequent fibrosis. CONCLUSIONS: Constitutive expression of low levels of BMP-9 stabilises hepatocyte function in the healthy liver. Upon HSC activation, endogenous BMP-9 levels increase in vitro and in vivo and high levels of BMP-9 cause enhanced damage upon acute or chronic injury.

Authors: K. Breitkopf-Heinlein, C. Meyer, C. Konig, H. Gaitantzi, A. Addante, M. Thomas, E. Wiercinska, C. Cai, Q. Li, F. Wan, C. Hellerbrand, N. A. Valous, M. Hahnel, C. Ehlting, J. G. Bode, S. Muller-Bohl, U. Klingmuller, J. Altenoder, I. Ilkavets, M. J. Goumans, L. J. Hawinkels, S. J. Lee, M. Wieland, C. Mogler, M. P. Ebert, B. Herrera, H. Augustin, A. Sanchez, S. Dooley, P. Ten Dijke

Date Published: 25th Mar 2017

Publication Type: Not specified

BMP-9 interferes with liver regeneration and promotes liver fibrosis.

Abstract (Expand)

OBJECTIVE: Bone morphogenetic protein (BMP)-9, a member of the transforming growth factor-beta family of cytokines, is constitutively produced in the liver. Systemic levels act on many organs and tissues … including bone and endothelium, but little is known about its hepatic functions in health and disease. DESIGN: Levels of BMP-9 and its receptors were analysed in primary liver cells. Direct effects of BMP-9 on hepatic stellate cells (HSCs) and hepatocytes were studied in vitro, and the role of BMP-9 was examined in acute and chronic liver injury models in mice. RESULTS: Quiescent and activated HSCs were identified as major BMP-9 producing liver cell type. BMP-9 stimulation of cultured hepatocytes inhibited proliferation, epithelial to mesenchymal transition and preserved expression of important metabolic enzymes such as cytochrome P450. Acute liver injury caused by partial hepatectomy or single injections of carbon tetrachloride (CCl4) or lipopolysaccharide (LPS) into mice resulted in transient downregulation of hepatic BMP-9 mRNA expression. Correspondingly, LPS stimulation led to downregulation of BMP-9 expression in cultured HSCs. Application of BMP-9 after partial hepatectomy significantly enhanced liver damage and disturbed the proliferative response. Chronic liver damage in BMP-9-deficient mice or in mice adenovirally overexpressing the selective BMP-9 antagonist activin-like kinase 1-Fc resulted in reduced deposition of collagen and subsequent fibrosis. CONCLUSIONS: Constitutive expression of low levels of BMP-9 stabilises hepatocyte function in the healthy liver. Upon HSC activation, endogenous BMP-9 levels increase in vitro and in vivo and high levels of BMP-9 cause enhanced damage upon acute or chronic injury.

Authors: K. Breitkopf-Heinlein, C. Meyer, C. Konig, H. Gaitantzi, A. Addante, M. Thomas, E. Wiercinska, C. Cai, Q. Li, F. Wan, C. Hellerbrand, N. A. Valous, M. Hahnel, C. Ehlting, J. G. Bode, S. Muller-Bohl, U. Klingmuller, J. Altenoder, I. Ilkavets, M. J. Goumans, L. J. Hawinkels, S. J. Lee, M. Wieland, C. Mogler, M. P. Ebert, B. Herrera, H. Augustin, A. Sanchez, S. Dooley, P. Ten Dijke

Date Published: 23rd Mar 2017

Publication Type: Not specified

Quantitative and integrative analysis of paracrine hepatocyte activation by nonparenchymal cells upon lipopolysaccharide induction

Abstract

Not specified

Authors: Katharina Beuke, Frank A. Schildberg, Federico Pinna, Ute Albrecht, Roman Liebe, Michaela Bissinger, Peter Schirmacher, Steven Dooley, Johannes G. Bode, Percy A. Knolle, Ursula Kummer, Kai Breuhahn, Sven Sahle

Date Published: 1st Mar 2017

Publication Type: Not specified

Global Transcriptional Response of Human Liver Cells to Ethanol Stress of Different Strength Reveals Hormetic Behavior.

Abstract (Expand)

BACKGROUND: The liver is the major site for alcohol metabolism in the body and therefore the primary target organ for ethanol (EtOH)-induced toxicity. In this study, we investigated the in vitro response … of human liver cells to different EtOH concentrations in a perfused bioartificial liver device that mimics the complex architecture of the natural organ. METHODS: Primary human liver cells were cultured in the bioartificial liver device and treated for 24 hours with medium containing 150 mM (low), 300 mM (medium), or 600 mM (high) EtOH, while a control culture was kept untreated. Gene expression patterns for each EtOH concentration were monitored using Affymetrix Human Gene 1.0 ST Gene chips. Scaled expression profiles of differentially expressed genes (DEGs) were clustered using Fuzzy c-means algorithm. In addition, functional classification methods, KEGG pathway mapping and also a machine learning approach (Random Forest) were utilized. RESULTS: A number of 966 (150 mM EtOH), 1,334 (300 mM EtOH), or 4,132 (600 mM EtOH) genes were found to be differentially expressed. Dose-response relationships of the identified clusters of co-expressed genes showed a monotonic, threshold, or nonmonotonic (hormetic) behavior. Functional classification of DEGs revealed that low or medium EtOH concentrations operate adaptation processes, while alterations observed for the high EtOH concentration reflect the response to cellular damage. The genes displaying a hormetic response were functionally characterized by overrepresented "cellular ketone metabolism" and "carboxylic acid metabolism." Altered expression of the genes BAHD1 and H3F3B was identified as sufficient to classify the samples according to the applied EtOH doses. CONCLUSIONS: Different pathways of metabolic and epigenetic regulation are affected by EtOH exposition and partly undergo hormetic regulation in the bioartificial liver device. Gene expression changes observed at high EtOH concentrations reflect in some aspects the situation of alcoholic hepatitis in humans.

Authors: W. Schmidt-Heck, E. C. Wonne, T. Hiller, U. Menzel, D. Koczan, G. Damm, D. Seehofer, F. Knospel, N. Freyer, R. Guthke, S. Dooley, K. Zeilinger

Date Published: 23rd Feb 2017

Publication Type: Not specified

Hepatocyte-specific Smad7 deletion accelerates DEN-induced HCC via activation of STAT3 signaling in mice

Abstract

Not specified

Authors: T Feng, J Dzieran, X Yuan, A Dropmann, T Maass, A Teufel, S Marhenke, T Gaiser, F Rückert, I Kleiter, S Kanzler, M P Ebert, A Vogel, P ten Dijke, S Dooley, N M Meindl-Beinker

Date Published: 2017

Publication Type: Not specified

Caveolin-1 in the regulation of cell metabolism: a cancer perspective.

Abstract (Expand)

Caveolin-1 (CAV1) is an oncogenic membrane protein associated with endocytosis, extracellular matrix organisation, cholesterol distribution, cell migration and signaling. Recent studies reveal that … CAV1 is involved in metabolic alterations - a critical strategy adopted by cancer cells to their survival advantage. Consequently, research findings suggest that CAV1, which is altered in several cancer types, influences tumour development or progression by controlling metabolism. Understanding the molecular interplay between CAV1 and metabolism could help uncover druggable metabolic targets or pathways of clinical relevance in cancer therapy. Here we review from a cancer perspective, the findings that CAV1 modulates cell metabolism with a focus on glycolysis, mitochondrial bioenergetics, glutaminolysis, fatty acid metabolism, and autophagy.

Authors: Z. C. Nwosu, M. P. Ebert, S. Dooley, C. Meyer

Date Published: 18th Nov 2016

Publication Type: Not specified

Orphan nuclear receptor SHP regulates iron metabolism through inhibition of BMP6-mediated hepcidin expression.

Abstract (Expand)

Small heterodimer partner (SHP) is a transcriptional corepressor regulating diverse metabolic processes. Here, we show that SHP acts as an intrinsic negative regulator of iron homeostasis. SHP-deficient … mice maintained on a high-iron diet showed increased serum hepcidin levels, decreased expression of the iron exporter ferroportin as well as iron accumulation compared to WT mice. Conversely, overexpression of either SHP or AMP-activated protein kinase (AMPK), a metabolic sensor inducing SHP expression, suppressed BMP6-induced hepcidin expression. In addition, an inhibitory effect of AMPK activators metformin and AICAR on BMP6-mediated hepcidin gene expression was significantly attenuated by ablation of SHP expression. Interestingly, SHP physically interacted with SMAD1 and suppressed BMP6-mediated recruitment of the SMAD complex to the hepcidin gene promoter by inhibiting the formation of SMAD1 and SMAD4 complex. Finally, overexpression of SHP and metformin treatment of BMP6 stimulated mice substantially restored hepcidin expression and serum iron to baseline levels. These results reveal a previously unrecognized role for SHP in the transcriptional control of iron homeostasis.

Authors: D. K. Kim, Y. H. Kim, Y. S. Jung, K. S. Kim, J. H. Jeong, Y. S. Lee, J. M. Yuk, B. C. Oh, H. E. Choy, S. Dooley, M. U. Muckenthaler, C. H. Lee, H. S. Choi

Date Published: 1st Oct 2016

Publication Type: Not specified

Delta-Like Ligand 4 Modulates Liver Damage by Down-Regulating Chemokine Expression

Abstract

Not specified

Authors: Zhe Shen, Yan Liu, Bedair Dewidar, Junhao Hu, Ogyi Park, Teng Feng, Chengfu Xu, Chaohui Yu, Qi Li, Christoph Meyer, Iryna Ilkavets, Alexandra Müller, Carolin Stump-Guthier, Stefan Munker, Roman Liebe, Vincent Zimmer, Frank Lammert, Peter R. Mertens, Hai Li, Peter ten Dijke, Hellmut G. Augustin, Jun Li, Bin Gao, Matthias P. Ebert, Steven Dooley, Youming Li, Hong-Lei Weng

Date Published: 1st Jul 2016

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

Transforming Growth Factor β1 (TGF-β1) Activates Hepcidin mRNA Expression in Hepatocytes

Abstract

Not specified

Authors: Simeng Chen, Teng Feng, Maja Vujić Spasić, Sandro Altamura, Katja Breitkopf-Heinlein, Jutta Altenöder, Thomas S. Weiss, Steven Dooley, Martina U. Muckenthaler

Date Published: 17th Jun 2016

Publication Type: Not specified

TGF-&#x3B2;1 and TGF-&#x3B2;2 abundance in liver diseases of mice and men

Abstract

Not specified

Authors: Anne Dropmann, Tatjana Dediulia, Katja Breitkopf-Heinlein, Hanna Korhonen, Michel Janicot, Susanne N. Weber, Maria Thomas, Albrecht Piiper, Esther Bertran, Isabel Fabregat, Kerstin Abshagen, Jochen Hess, Peter Angel, Cédric Coulouarn, Steven Dooley, Nadja M. Meindl-Beinker

Date Published: 12th Apr 2016

Publication Type: Not specified

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