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37 Publications visible to you, out of a total of 37
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, S. 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

Comprehensive evaluation of phosphoproteomic-based kinase activity inference (preprint)

Abstract (Expand)

Kinases play a central role in regulating cellular processes, making their study essential for understanding cellular function and disease mechanisms. To investigate the regulatory state of a kinase, … numerous methods have been, and continue to be, developed to infer kinase activities from phosphoproteomics data. These methods usually rely on a set of kinase targets collected from various kinase-substrate libraries. However, only a small percentage of measured phosphorylation sites can usually be attributed to an upstream kinase in these libraries, limiting the scope of kinase activity inference. In addition, the inferred activities from different methods can vary making it crucial to evaluate them for accurate interpretation. Here, we present a comprehensive evaluation of kinase activity inference methods using multiple kinase-substrate libraries combined with different inference algorithms. Additionally, we try to overcome the coverage limitations for measured targets in kinase substrate libraries by adding predicted kinase-substrate interactions for activity inference. For the evaluation, in addition to classical cell-based perturbation experiments, we introduce a tumor-based benchmarking approach that utilizes multi-omics data to identify highly active or inactive kinases per tumor type. We show that while most computational algorithms perform comparably regardless of their complexity, the choice of kinase-substrate library can highly impact the inferred kinase activities. Hereby, manually curated libraries, particularly PhosphoSitePlus, demonstrate superior performance in recapitulating kinase activities from phosphoproteomics data. Additionally, in the tumor-based evaluation, adding predicted targets from NetworKIN further boosts the performance, while normalizing sites to host protein levels reduces kinase activity inference performance. We then showcase how kinase activity inference can help in characterizing the response to kinase inhibitors in different cell lines. Overall, the selection of reliable kinase activity inference methods is important in identifying deregulated kinases and novel drug targets. Finally, to facilitate the evaluation of novel methods in the future, we provide both benchmarking approaches in the R package benchmarKIN.

Authors: Sophia Müller-Dott, Eric J. Jaehnig, Khoi Pham Munchic, Wen Jiang, Tomer M. Yaron-Barir, Sara R. Savage, Martin Garrido-Rodriguez, Jared L. Johnson, Alessandro Lussana, Evangelia Petsalaki, Jonathan T. Lei, Aurélien Dugourd, Karsten Krug, Lewis C. Cantley, D. R. Mani, Bing Zhang, Julio Saez-Rodriguez

Date Published: 2nd 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

Lysis buffer selection guidance for mass spectrometry-based global proteomics including studies on the intersection of signal transduction and metabolism (preprint)

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Prerequisite for a successful proteomics experiment is a high-quality lysis of the sample of interest, resulting in a large number of identified proteins as well as a high coverage of protein sequences. … Therefore, the choice of suitable lysis conditions is crucial. Many buffers were previously employed in proteomics studies, yet a comprehensive comparison of lysate preparation conditions was so far missing. In this study, we compared the efficiency of four commonly used lysis buffers, containing the agents NP40, SDS, urea or GdnHCl, in four different types of biological samples (suspension and adherent cell lines, primary mouse cells and mouse liver tissue). After liquid chromatography-mass spectrometry (LC-MS) measurement and MaxQuant analysis, we compared chromatograms, intensities, number of identified proteins and the localization of the identified proteins. Overall, SDS emerged as the most reliable reagent, ensuring stable performance and reproducibility across diverse samples. Furthermore, our data advocated for a dual-sample lysis approach, including that the resulting pellet is lysed again after the initial lysis with a urea lysis buffer and subsequently both lysates are combined for a single LC-MS run to maximize the proteome coverage. However, none of the investigated lysis buffers proved to be superior in every category, indicating that the lysis buffer of choice depends on the proteins of interest and on the biological question. Further, we demonstrated with our systematic studies the establishment of conditions that allows to perform global proteomics and affinity purification-based interactome characterization from the same lysate. In sum our results provide guidance for the best-suited lysis buffer for mass spectrometry-based proteomics depending on the question of interest.

Authors: Barbara Helm, Pauline Hansen, Li Lai, Luisa Schwarzmüller, Simone M. Clas, Annika Richter, Max Ruwolt, Fan Liu, Dario Frey, Lorenza A. D’Alessandro, Wolf-Dieter Lehmann, Marcel Schilling, Dominic Helm, Dorothea Fiedler, Ursula Klingmüller

Date Published: 21st 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

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

Abstract

Not specified

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

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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

Tumour cells can escape antiproliferative pressure by interferon-β through immunoediting of interferon receptor expression

Abstract (Expand)

Abstract Type I interferons (IFNs) play a central role not only in innate immunity against viral infection, but also in the antitumour response, e.g. through a direct impact on cell proliferation. …act on cell proliferation. Particularly for cancer arising in the context of chronic inflammation, constant exposure to IFNs may constitute a strong selective pressure during tumour evolution. Expansion of neoplastic subclones resistant to the antiproliferative effects of IFNs may contribute to immunoediting of tumours, leading to more aggressive disease. Experimental evidence for this development of IFN-insensitivity has been scarce and its molecular mechanism is unclear. In this study we demonstrate that six weeks exposure of cells to IFN-β in vitro reduces their sensitivity to its antiproliferative effects, and that this phenotype was stable for up to four weeks. Furthermore, we observed substantial differences in cellular sensitivity to growth inhibition by IFN-β in a panel of ten different liver cancer cell lines, most prominently in a pair of highly dedifferentiated cell lines, and least in cells from well-differentiated tumours. In both, long-term IFN selection and in dedifferentiated tumour cell lines, we found IFNAR2 expression to be substantially reduced, suggesting the receptor complex to be a sensitive target amenable to immunoediting. Beyond new insights into possible molecular processes in tumour evolution, these findings might prove valuable for the development of biomarkers allowing to stratify tumours for their sensitivity to IFN treatment in the context of patient tailored therapies.

Authors: Felix Hiebinger, Aiste Kudulyte, Huanting Chi, Sebastian Burbano De Lara, Doroteja Ilic, Barbara Helm, Hendrik Welsch, Viet Loan Dao Thi, Ursula Klingmüller, Marco Binder

Date Published: 1st Dec 2023

Publication Type: Journal

Expanding the coverage of regulons from high-confidence prior knowledge for accurate estimation of transcription factor activities

Abstract (Expand)

Abstract Gene regulation plays a critical role in the cellular processes that underlie human health and disease. The regulatory relationship between transcription factors (TFs), key regulators of gene …s), key regulators of gene expression, and their target genes, the so called TF regulons, can be coupled with computational algorithms to estimate the activity of TFs. However, to interpret these findings accurately, regulons of high reliability and coverage are needed. In this study, we present and evaluate a collection of regulons created using the CollecTRI meta-resource containing signed TF–gene interactions for 1186 TFs. In this context, we introduce a workflow to integrate information from multiple resources and assign the sign of regulation to TF–gene interactions that could be applied to other comprehensive knowledge bases. We find that the signed CollecTRI-derived regulons outperform other public collections of regulatory interactions in accurately inferring changes in TF activities in perturbation experiments. Furthermore, we showcase the value of the regulons by examining TF activity profiles in three different cancer types and exploring TF activities at the level of single-cells. Overall, the CollecTRI-derived TF regulons enable the accurate and comprehensive estimation of TF activities and thereby help to interpret transcriptomics data.

Authors: Sophia Müller-Dott, Eirini Tsirvouli, Miguel Vazquez, Ricardo O Ramirez Flores, Pau Badia-i-Mompel, Robin Fallegger, Dénes Türei, Astrid Lægreid, Julio Saez-Rodriguez

Date Published: 10th Nov 2023

Publication Type: Journal

Tumour cells can escape antiproliferative pressure by interferon-β through immunoediting of interferon receptor expression (preprint)

Abstract (Expand)

Type I interferons (IFNs) play a central role not only in innate immunity against viral infection, but also in the antitumour response. Apart from indirect immune-modulatory and anti-angiogenic effects, … they have direct impact on cell proliferation. Particularly for cancer arising in the context of chronic inflammation, constant exposure to IFNs may constitute a strong selective pressure during tumour evolution. Expansion of neoplastic subclones or -populations that developed resistance to the antiproliferative effects of IFNs might constitute an important contribution to immunoediting of the cancer cells leading to more aggressive and metastasising disease. Experimental evidence for this development of IFN-insensitivity has been scarce and its molecular mechanism is unclear. In this study we demonstrate that prolonged (six weeks) exposure of cells to IFN-β in vitro reduces their sensitivity to its antiproliferative effects, and that this phenotype was stable for up to four weeks. Furthermore, we observed substantial differences in cellular sensitivity to growth inhibition by IFN-β in a panel of ten different liver cancer cell lines of varying malignity. IFN-resistance was most prominent in a pair of highly dedifferentiated cell lines, and least in cells from well-differentiated tumours, fostering the hypothesis of IFN-driven immunoediting in advanced cancers. In both settings, long-term IFN selection in vitro as well as in dedifferentiated tumour cell lines, we found IFNAR expression to be substantially reduced, suggesting the receptor complex, in particular IFNAR2, to be a sensitive target amenable to immunoediting. Beyond new insights into possible molecular processes in tumour evolution, these findings might prove valuable for the development of biomarkers allowing to stratify tumours for their sensitivity to IFN treatment in the context of patient tailored therapies.

Authors: Felix Hiebinger, Aiste Kudulyte, Huanting Chi, Sebastian Burbano De Lara, Barbara Helm, Hendrik Welsch, Viet Loan Dao Thi, Ursula Klingmüller, Marco Binder

Date Published: 24th Aug 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

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