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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

Follistatin‐controlled activin‐HNF4α‐coagulation factor axis in liver progenitor cells determines outcome of acute liver failure

Abstract

Not specified

Authors: Tao Lin, Shanshan Wang, Stefan Munker, Kyounghwa Jung, Ricardo U. Macías‐Rodríguez, Astrid Ruiz‐Margáin, Robert Schierwagen, Hui Liu, Chen Shao, Chunlei Fan, Rilu Feng, Xiaodong Yuan, Sai Wang, Franziska Wandrer, Christoph Meyer, Ralf Wimmer, Roman Liebe, Jens Kroll, Long Zhang, Tobias Schiergens, Peter ten Dijke, Andreas Teufel, Alexander Marx, Peter R. Mertens, Hua Wang, Matthias P.A. Ebert, Heike Bantel, Enrico De Toni, Jonel Trebicka, Steven Dooley, Donghun Shin, Huiguo Ding, Hong‐Lei Weng

Date Published: 1st Feb 2022

Publication Type: Journal

FOXA2 inhibits hyperbilirubinemia through maintaining apical MRP2 expression in acute liver failure

Abstract

Not specified

Authors: Sai Wang, Rilu Feng, Shanshan Wang, Hui Liu, Chen Shao, Yujia Li, Link Frederik, Stefan Munker, Roman Liebe, Christoph Meyer, Elke Burgermeister, Matthias Ebert, Steven Dooley, Huiguo Ding, Honglei Weng

Date Published: 2022

Publication Type: Journal

Circulating miR-148a is a precipitant independent biomarker of acute-on-chronic liver failure (ACLF)

Abstract

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Authors: Maximilian Tessenyi, SusanneN Weber, Matthias Reichert, SenemC. Karatayli, RabeaA Hall, Tony Bruns, Sen Qiao, Ulrich Boehm, Steven Dooley, Frank Lammert, Ersin Karatayli

Date Published: 2022

Publication Type: Journal

Multi-omics profiling identifies molecular signatures of acute-on-chronic liver failure in Abcb4KO mice upon chemical intoxication

Abstract

Not specified

Authors: Pia Erdoesi, Maren Buettner, Matthias Meyer-Bender, Rizqah Kamies, IoannisK. Deligiannis, MichaelP. Menden, Steven Dooley, CeliaP. Martinez-Jimenez, Christoph Ogris, Seddik Hammad

Date Published: 2022

Publication Type: Journal

Spatio-Temporal Multiscale Analysis of Western Diet-Fed Mice Reveals a Translationally Relevant Sequence of Events during NAFLD Progression

Abstract (Expand)

Mouse models of non-alcoholic fatty liver disease (NAFLD) are required to define therapeutic targets, but detailed time-resolved studies to establish a sequence of events are lacking. Here, we fed male …e, we fed male C57Bl/6N mice a Western or standard diet over 48 weeks. Multiscale time-resolved characterization was performed using RNA-seq, histopathology, immunohistochemistry, intravital imaging, and blood chemistry; the results were compared to human disease. Acetaminophen toxicity and ammonia metabolism were additionally analyzed as functional readouts. We identified a sequence of eight key events: formation of lipid droplets; inflammatory foci; lipogranulomas; zonal reorganization; cell death and replacement proliferation; ductular reaction; fibrogenesis; and hepatocellular cancer. Functional changes included resistance to acetaminophen and altered nitrogen metabolism. The transcriptomic landscape was characterized by two large clusters of monotonously increasing or decreasing genes, and a smaller number of ‘rest-and-jump genes’ that initially remained unaltered but became differentially expressed only at week 12 or later. Approximately 30% of the genes altered in human NAFLD are also altered in the present mouse model and an increasing overlap with genes altered in human HCC occurred at weeks 30–48. In conclusion, the observed sequence of events recapitulates many features of human disease and offers a basis for the identification of therapeutic targets.

Authors: Ahmed Ghallab, Maiju Myllys, Adrian Friebel, Julia Duda, Karolina Edlund, Emina Halilbasic, Mihael Vucur, Zaynab Hobloss, Lisa Brackhagen, Brigitte Begher-Tibbe, Reham Hassan, Michael Burke, Erhan Genc, Lynn Johann Frohwein, Ute Hofmann, Christian H. Holland, Daniela González, Magdalena Keller, Abdel-latif Seddek, Tahany Abbas, Elsayed S. I. Mohammed, Andreas Teufel, Timo Itzel, Sarah Metzler, Rosemarie Marchan, Cristina Cadenas, Carsten Watzl, Michael A. Nitsche, Franziska Kappenberg, Tom Luedde, Thomas Longerich, Jörg Rahnenführer, Stefan Hoehme, Michael Trauner, Jan G. Hengstler

Date Published: 1st Oct 2021

Publication Type: Journal

Cell-to-cell variability in JAK2/STAT5 pathway components and cytoplasmic volumes defines survival threshold in erythroid progenitor cells.

Abstract (Expand)

Survival or apoptosis is a binary decision in individual cells. However, at the cell-population level, a graded increase in survival of colony-forming unit-erythroid (CFU-E) cells is observed upon … stimulation with erythropoietin (Epo). To identify components of Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5) signal transduction that contribute to the graded population response, we extended a cell-population-level model calibrated with experimental data to study the behavior in single cells. The single-cell model shows that the high cell-to-cell variability in nuclear phosphorylated STAT5 is caused by variability in the amount of Epo receptor (EpoR):JAK2 complexes and of SHP1, as well as the extent of nuclear import because of the large variance in the cytoplasmic volume of CFU-E cells. 24-118 pSTAT5 molecules in the nucleus for 120 min are sufficient to ensure cell survival. Thus, variability in membrane-associated processes is sufficient to convert a switch-like behavior at the single-cell level to a graded population-level response.

Authors: L. Adlung, P. Stapor, C. Tonsing, L. Schmiester, L. E. Schwarzmuller, L. Postawa, D. Wang, J. Timmer, U. Klingmuller, J. Hasenauer, M. Schilling

Date Published: 10th Aug 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

Isolated bacterial infection without decompensation has no impact on survival of compensated patients with cirrhosis.

Abstract (Expand)

BACKGROUND & AIMS: Bacterial infections (BI) affect the natural course of cirrhosis and were suggested to be a landmark event marking the transition to the decompensated stage. Our specific aim was … to evaluate the impact of BI on the natural history of compensated cirrhosis. METHODS: We analyzed 858 patients with cirrhosis, evaluated for the INCA trial (EudraCT 2013-001626-26) in 2 academic medical centers between February 2014 and May 2019. Only patients with previously compensated disease were included. They were divided into 4 groups: compensated without BI, compensated with BI, 1st decompensation without BI, and 1st decompensation with BI. RESULTS: About 425 patients (median 61 [53-69] years) were included in the final prospective analysis. At baseline, 257 patients were compensated (12 [4.7%] with BI), whereas 168 patients presented with their 1st decompensation (42 [25.0%] with BI). In patients who remained compensated MELD scores were similar in those with and without BI. Patients with their first decompensation and BI had higher MELD scores than those without BI. Amongst patients who remained compensated, BI had no influence on transplant-free survival, whereas patients with their 1st decompensation and concurrent BI had significantly reduced transplant-free survival as compared with those without BI. The development of BI or decompensation during follow-up had a greater impact on survival than each of these complications at baseline. CONCLUSIONS: In compensated patients with cirrhosis, the 1st decompensation associated to BI has worse survival than decompensation without BI. By contrast, BI without decompensation does not negatively impact survival of patients with compensated cirrhosis.

Authors: M. C. Reichert, C. Schneider, R. Greinert, M. Casper, F. Grunhage, A. Wienke, A. Zipprich, F. Lammert, C. Ripoll

Date Published: 1st Mar 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

Simulation of a detoxifying organ function: Focus on hemodynamics modeling and convection-reaction numerical simulation in microcirculatory networks.

Abstract (Expand)

When modeling a detoxifying organ function, an important component is the impact of flow on the metabolism of a compound of interest carried by the blood. We here study the effects of red blood cells … (such as the Fahraeus-Lindqvist effect and plasma skimming) on blood flow in typical microcirculatory components such as tubes, bifurcations and entire networks, with particular emphasis on the liver as important representative of detoxifying organs. In one of the plasma skimming models, under certain conditions, oscillations between states are found and analyzed in a methodical study to identify their causes and influencing parameters. The flow solution obtained is then used to define the velocity at which a compound would be transported. A convection-reaction equation is studied to simulate the transport of a compound in blood and its uptake by the surrounding cells. Different types of signal sharpness have to be handled depending on the application to address different temporal compound concentration profiles. To permit executing the studied models numerically stable and accurate, we here extend existing transport schemes to handle converging bifurcations, and more generally multi-furcations. We study the accuracy of different numerical schemes as well as the effect of reactions and of the network itself on the bolus shape. Even though this study is guided by applications in liver micro-architecture, the proposed methodology is general and can readily be applied to other capillary network geometries, hence to other organs or to bioengineered network designs.

Authors: N. Boissier, D. Drasdo, I. E. Vignon-Clementel

Date Published: 29th Nov 2020

Publication Type: Journal

rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis.

Abstract (Expand)

BACKGROUND & AIMS: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been … consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. METHODS: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. RESULTS: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], pz = 4.8x10(-5)) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], pz = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], pz = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz = 0.002) and lower serum triglycerides (pz = 1.5x10(-4)). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. CONCLUSIONS: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. LAY SUMMARY: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.

Authors: K. Teo, K. W. M. Abeysekera, L. Adams, E. Aigner, Q. M. Anstee, J. M. Banales, R. Banerjee, P. Basu, T. Berg, P. Bhatnagar, S. Buch, A. Canbay, S. Caprio, A. Chatterjee, Y. D. Ida Chen, A. Chowdhury, A. K. Daly, C. Datz, D. de Gracia Hahn, J. K. DiStefano, J. Dong, A. Duret, C. Emdin, M. Fairey, G. S. Gerhard, X. Guo, J. Hampe, M. Hickman, L. Heintz, C. Hudert, H. Hunter, M. Kelly, J. Kozlitina, M. Krawczyk, F. Lammert, C. Langenberg, J. Lavine, L. Li, H. K. Lim, R. Loomba, P. K. Luukkonen, P. E. Melton, T. A. Mori, N. D. Palmer, C. A. Parisinos, S. G. Pillai, F. Qayyum, M. C. Reichert, S. Romeo, J. I. Rotter, Y. R. Im, N. Santoro, C. Schafmayer, E. K. Speliotes, S. Stender, F. Stickel, C. D. Still, P. Strnad, K. D. Taylor, A. Tybjaerg-Hansen, G. R. Umano, M. Utukuri, L. Valenti, L. E. Wagenknecht, N. J. Wareham, R. M. Watanabe, J. Wattacheril, H. Yaghootkar, H. Yki-Jarvinen, K. A. Young, J. P. Mann

Date Published: 4th Sep 2020

Publication Type: Journal

Volume-Function Analysis (LiMAx Test) in Patients with HCC and Cirrhosis Undergoing TACE-A Feasibility Study.

Abstract (Expand)

BACKGROUND: Transarterial chemoembolization (TACE) is an important therapy for hepatocellular carcinoma (HCC) in cirrhosis. In particular in advanced cirrhosis, post-TACE hepatic failure liver (PTHF) … failure may develop. Currently, there is no standardization for the periinterventional risk assessment. The liver maximum capacity (LiMAx) test assesses the functional liver capacity, but has not been investigated in this setting. AIMS: The aim of this study was to prospectively evaluate periinterventional LiMAx and CT volumetry measurements in patients with cirrhosis and HCC undergoing repetitive TACE. METHODS: From 06/2016 to 11/2017, eleven patients with HCC and cirrhosis undergoing TACE were included. LiMAx measurements (n = 42) were conducted before and after each TACE. Laboratory parameters were correlated with the volume-function data. RESULTS: The median LiMAx levels before (276 +/- 166 microg/kg/h) were slightly reduced after TACE (251 +/- 122 microg/kg/h; p = 0.08). This corresponded to a median drop of 7.1%. Notably, there was a significant correlation between LiMAx levels before TACE and bilirubin (but not albumin nor albumin-bilirubin [ALBI] score) increase after TACE (p = 0.02, k = 0.56). Furthermore, a significantly higher increase in bilirubin in patients with LiMAx </= 150 microg/kg/h was observed (p = 0.011). LiMAx levels at different time points in single patients were similar (p = 0.2). CONCLUSION: In our prospective pilot study in patients with HCC and cirrhosis undergoing multiple TACE, robust and reliable LiMAx measurements were demonstrated. Lower LiMAx levels before TACE were associated with surrogate markers (bilirubin) of liver failure after TACE. Specific subgroups at high risk of PTHF should be investigated. This might facilitate the future development of strategies to prevent occurrence of PTHF.

Authors: M. C. Reichert, A. Massmann, A. Schulz, A. Buecker, M. Glanemann, F. Lammert, M. Malinowski

Date Published: 21st Aug 2020

Publication Type: Journal

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

Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction.

Abstract (Expand)

Tightly interlinked feedback regulators control the dynamics of intracellular responses elicited by the activation of signal transduction pathways. Interferon alpha (IFNalpha) orchestrates antiviral … responses in hepatocytes, yet mechanisms that define pathway sensitization in response to prestimulation with different IFNalpha doses remained unresolved. We establish, based on quantitative measurements obtained for the hepatoma cell line Huh7.5, an ordinary differential equation model for IFNalpha signal transduction that comprises the feedback regulators STAT1, STAT2, IRF9, USP18, SOCS1, SOCS3, and IRF2. The model-based analysis shows that, mediated by the signaling proteins STAT2 and IRF9, prestimulation with a low IFNalpha dose hypersensitizes the pathway. In contrast, prestimulation with a high dose of IFNalpha leads to a dose-dependent desensitization, mediated by the negative regulators USP18 and SOCS1 that act at the receptor. The analysis of basal protein abundance in primary human hepatocytes reveals high heterogeneity in patient-specific amounts of STAT1, STAT2, IRF9, and USP18. The mathematical modeling approach shows that the basal amount of USP18 determines patient-specific pathway desensitization, while the abundance of STAT2 predicts the patient-specific IFNalpha signal response.

Authors: F. Kok, M. Rosenblatt, M. Teusel, T. Nizharadze, V. Goncalves Magalhaes, C. Dachert, T. Maiwald, A. Vlasov, M. Wasch, S. Tyufekchieva, K. Hoffmann, G. Damm, D. Seehofer, T. Boettler, M. Binder, J. Timmer, M. Schilling, U. Klingmuller

Date Published: 23rd Jul 2020

Publication Type: Journal

Lipid-encapsulated siRNA for hepatocyte-directed treatment of advanced liver disease

Abstract (Expand)

Lipid-based RNA nanocarriers have been recently accepted as a novel therapeutic option in humans, thus increasing the therapeutic options for patients. Tailored nanomedicines will enable to treat chronic … liver disease (CLD) and end-stage liver cancer, disorders with high mortality and few treatment options. Here, we investigated the curative potential of gene therapy of a key molecule in CLD, the c-Jun N-terminal kinase-2 (Jnk2). Delivery to hepatocytes was achieved using a lipid-based clinically employable siRNA formulation that includes a cationic aminolipid to knockdown Jnk2 (named siJnk2). After assessing the therapeutic potential of siJnk2 treatment, non-invasive imaging demonstrated reduced apoptotic cell death and improved hepatocarcinogenesis was evidenced by improved liver parenchyma as well as ameliorated markers of hepatic damage, reduced fibrogenesis in 1-year-old mice. Strikingly, chronic siJnk2 treatment reduced premalignant nodules, indicative of tumor initiation. Furthermore, siJnk2 treatment led to a significant activation of the immune cell compartment. In conclusion, Jnk2 knockdown in hepatocytes ameliorated hepatitis, fibrogenesis, and initiation of hepatocellular carcinoma (HCC), and hence might be a suitable therapeutic option, to define novel molecular targets for precision medicine in CLD.

Authors: Marius Maximilian Woitok, Miguel Eugenio Zoubek, Dennis Doleschel, Matthias Bartneck, Mohamed Ramadan Mohamed, Fabian Kießling, Wiltrud Lederle, Christian Trautwein, Francisco Javier Cubero

Date Published: 1st May 2020

Publication Type: Journal

Predictive Power of Liver Maximum Function Capacity Test in Transjugular Intrahepatic Portosystemic Shunt Patients: A Pilot Study.

Abstract (Expand)

BACKGROUND: Transjugular intrahepatic shunt (TIPSS) is placed in patients with variceal bleeding, refractory ascites, and for other indications. Postprocedural liver function-associated complications … (LFAC), including hepatic encephalopathy (HE) and liver failure, represent a major setback. Current methods to predict complications are insufficient. OBJECTIVES: We investigated in a pilot study of patients prior TIPSS placement whether the risk of LFAC correlates with the functional reserve of the liver, as assessed by liver maximum function capacity (LiMAx) test. METHODS: Prospectively we included patients prior TIPSS placement between June 2016 and November 2017 at Saarland University Medical Center. LiMAx was conducted before and after TIPSS placement. Patients with HE prior TIPSS, as well as other factors predisposing to HE, including concomitant sedative drugs, current bacterial infections and sepsis, were excluded. Overt HE (OHE), LiMAx, and laboratory values were assessed before and after TIPSS placement. Data were analyzed in multivariate regression and AUROC models. RESULTS: Mean age was 60 +/- 8 years. Patients (n = 20) were mainly men (65%), and presented predominantly with Child-Pugh class B (90%). Indications for TIPSS were most commonly refractory ascites or recurrent variceal bleeding. In total, 40% of the patients developed LFAC after TIPSS placement. Expectedly, LiMAx decreased and serum bilirubin increased after TIPSS. LiMAx drop >/=20% was the only parameter predicting the development of LFAC after TIPSS in multivariate regression and AUROC analysis. CONCLUSIONS: In multivariate regression models and AUROC analysis, a drop in LiMAx predicted the development of LFAC after TIPSS placement. Additional larger studies assessing OHE and early liver failure separately are warranted.

Authors: M. C. Reichert, A. Schulz, A. Massmann, A. Buecker, M. Glanemann, F. Lammert, M. Malinowski

Date Published: 17th Oct 2019

Publication Type: Journal

Transient elastography for screening of liver fibrosis: Cost-effectiveness analysis from six prospective cohorts in Europe and Asia.

Abstract (Expand)

BACKGROUND & AIMS: Non-alcoholic fatty liver disease and alcohol-related liver disease pose an important challenge to current clinical healthcare pathways because of the large number of at-risk … patients. Therefore, we aimed to explore the cost-effectiveness of transient elastography (TE) as a screening method to detect liver fibrosis in a primary care pathway. METHODS: Cost-effectiveness analysis was performed using real-life individual patient data from 6 independent prospective cohorts (5 from Europe and 1 from Asia). A diagnostic algorithm with conditional inference trees was developed to explore the relationships between liver stiffness, socio-demographics, comorbidities, and hepatic fibrosis, the latter assessed by fibrosis scores (FIB-4, NFS) and liver biopsies in a subset of 352 patients. We compared the incremental cost-effectiveness of a screening strategy against standard of care alongside the numbers needed to screen to diagnose a patient with fibrosis stage >/=F2. RESULTS: The data set encompassed 6,295 participants (mean age 55+/-12years, BMI 27+/-5kg/m(2), liver stiffness 5.6+/-5.0kPa). A 9.1kPa TE cut-off provided the best accuracy for the diagnosis of significant fibrosis (>/=F2) in general population settings, whereas a threshold of 9.5kPa was optimal for populations at-risk of alcohol-related liver disease. TE with the proposed cut-offs outperformed fibrosis scores in terms of accuracy. Screening with TE was cost-effective with mean incremental cost-effectiveness ratios ranging from 2,570 euro/QALY (95% CI 2,456-2,683) for a population at-risk of alcohol-related liver disease (age >/=45years) to 6,217 euro/QALY (95% CI 5,832-6,601) in the general population. Overall, there was a 12% chance of TE screening being cost saving across countries and populations. CONCLUSIONS: Screening for liver fibrosis with TE in primary care is a cost-effective intervention for European and Asian populations and may even be cost saving. LAY SUMMARY: The lack of optimized public health screening strategies for the detection of liver fibrosis in adults without known liver disease presents a major healthcare challenge. Analyses from 6 independent international cohorts, with transient elastography measurements, show that a community-based risk-stratification strategy for alcohol-related and non-alcoholic fatty liver diseases is cost-effective and potentially cost saving for our healthcare systems, as it leads to earlier identification of patients.

Authors: M. Serra-Burriel, I. Graupera, P. Toran, M. Thiele, D. Roulot, V. Wai-Sun Wong, I. Neil Guha, N. Fabrellas, A. Arslanow, C. Exposito, R. Hernandez, G. Lai-Hung Wong, D. Harman, S. Darwish Murad, A. Krag, G. Pera, P. Angeli, P. Galle, G. P. Aithal, L. Caballeria, L. Castera, P. Gines, F. Lammert

Date Published: 31st Aug 2019

Publication Type: Not specified

Cooperative and distinct functions of MK2 and MK3 in the regulation of the macrophage transcriptional response to lipopolysaccharide.

Abstract (Expand)

The p38(MAPK) downstream targets MAPKAP kinases (MK) 2 and 3 are critical for the regulation of the macrophage response to LPS. The extents to which these two kinases act cooperatively and distinctly … in regulating LPS-induced inflammatory cytokine expression are still unclear. To address this uncertainty, whole transcriptome analyses were performed using bone marrow-derived macrophages (BMDM) generated from MK2(-/-) or MK2/3(-/-) animals and their wild-type littermates. The results suggest that in BMDM, MK2 and MK3 not only cooperatively regulate the transcript expression of signaling intermediates, including IL-10, IL-19, CXCL2 and the IL-4 receptor (IL-4R)alpha subunit, they also exert distinct regulatory effects on the expression of specific transcripts. Based on the differential regulation of gene expression by MK2 and MK3, at least six regulatory patterns were identified. Importantly, we confirmed our previous finding, which showed that in the absence of MK2, MK3 negatively regulates IFN-beta. Moreover, this genome-wide analysis identified the regulation of Cr1A, NOD1 and Serpina3f as similar to that of IFN-beta. In the absence of MK2, MK3 also delayed the nuclear translocation of NFkappaB by delaying the ubiquitination and subsequent degradation of IkappaBbeta, reflecting the substantial plasticity of the response of BMDM to LPS.

Authors: C. Ehlting, J. Rex, U. Albrecht, R. Deenen, C. Tiedje, K. Kohrer, O. Sawodny, M. Gaestel, D. Haussinger, J. G. Bode

Date Published: 30th Jul 2019

Publication Type: Not specified

Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation.

Abstract (Expand)

BACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) is among the most common genetic disorders. Severe AATD is caused by a homozygous mutation in the SERPINA1 gene that encodes the Glu342Lys … substitution (called the Pi*Z mutation, Pi*ZZ genotype). Pi*ZZ carriers may develop lung and liver diseases. Mutation-associated lung disorders have been well studied, but less is known about the effects in liver. We assessed the liver disease burden and associated features in adults with this form of AATD. METHODS: We collected data from 554 Pi*ZZ adults (403 in an exploratory cohort, 151 in a confirmatory cohort), in 9 European countries, with AATD who were homozygous for the Pi*Z mutation, and 234 adults without the Pi*Z mutation (controls), all without pre-existing liver disease. We collected data on demographic parameters, comorbidities, lung- and liver-related health, and blood samples for laboratory analysis. Liver fibrosis was assessed non-invasively via the serum tests Aspartate Aminotransferase to Platelet Ratio Index and HepaScore and via transient elastography. Liver steatosis was determined via transient elastography-based controlled attenuation parameter. We performed histologic analyses of livers from transgenic mice that overexpress the AATD-associated Pi*Z variant. RESULTS: Serum levels of liver enzymes were significantly higher in Pi*ZZ carriers vs controls. Based on non-invasive tests for liver fibrosis, significant fibrosis was suspected in 20%-36% of Pi*ZZ carriers, whereas signs of advanced fibrosis were 9- to 20-fold more common in Pi*ZZ carriers compared to non-carriers. Male sex; age older than 50 years; increased levels of alanine aminotransferase, aspartate aminotransferase, or gamma-glutamyl transferase; and low numbers of platelets were associated with higher liver fibrosis burden. We did not find evidence for a relationship between lung function and liver fibrosis. Controlled attenuation parameter >/=280 dB/m, suggesting severe steatosis, was detected in 39% of Pi*ZZ carriers vs 31% of controls. Carriers of Pi*ZZ had lower serum concentrations of triglyceride and low- and very-low-density lipoprotein cholesterol than controls, suggesting impaired hepatic secretion of lipid. Livers from Pi*Z-overexpressing mice had steatosis and down-regulation of genes involved in lipid secretion. CONCLUSIONS: In studies of AATD adults with the Pi*ZZ mutation, and of Pi*Z-overexpressing mice, we found evidence of liver steatosis and impaired lipid secretion. We identified factors associated with significant liver fibrosis in patients, which could facilitate hepatologic assessment and counseling of individuals who carry the Pi*ZZ mutation. ClinicalTrials.gov Number NCT02929940.

Authors: K. Hamesch, M. Mandorfer, V. M. Pereira, L. S. Moeller, M. Pons, G. E. Dolman, M. C. Reichert, C. V. Schneider, V. Woditsch, J. Voss, C. Lindhauer, M. Fromme, I. Spivak, N. Guldiken, B. Zhou, A. Arslanow, B. Schaefer, H. Zoller, E. Aigner, T. Reiberger, M. Wetzel, B. Siegmund, C. Simoes, R. Gaspar, L. Maia, D. Costa, M. Bento-Miranda, J. van Helden, E. Yagmur, D. Bzdok, J. Stolk, W. Gleiber, V. Knipel, W. Windisch, R. Mahadeva, R. Bals, R. Koczulla, M. Barrecheguren, M. Miravitlles, S. Janciauskiene, F. Stickel, F. Lammert, R. Liberal, J. Genesca, W. J. Griffiths, M. Trauner, A. Krag, C. Trautwein, P. Strnad

Date Published: 24th May 2019

Publication Type: Not specified

Second exposure to acetaminophen overdose is associated with liver fibrosis in mice

Abstract (Expand)

Repeated administration of hepatotoxicants is usually accompanied by liver fibrosis. However, the difference in response as a result of repeated exposures of acetaminophen (APAP) compared to a single … dose is not well-studied. Therefore, in the current study, the liver response after a second dose of APAP was investigated. Adult fasted Balb/C mice were exposed to two toxic doses of 300 mg/kg APAP, which were administered 72 h apart from each other. Subsequently, blood and liver from the treated mice were collected 24 h and 72 h after both APAP admin-istrations. Liver transaminase, i.e. alanine amino transferase (ALT) and aspartate amino transferase (AST) levels revealed that the fulminant liver damage was reduced after the second APAP administration compared to that observed at the same time point after the first treatment. These results correlated with the necrotic areas as indicated by histological analyses. Surprisingly, Picro Sirius Red (PSR) staining showed that the accumulation of extracel-lular matrix after the second dose coincides with the upregulation of some fibrogenic signatures, e.g., alpha smooth muscle actin. Non-targeted liver tissue metabolic profiling indicates that most alterations occur 24 h after the first dose of APAP. However, the levels of most metabolites recover to basal values over time. This organ adaptation process is also confirmed by the upregulation of antioxidative systems like e.g. superoxide dismutase and catalase. From the results, it can be concluded that there is a different response of the liver to APAP toxic doses, if the liver has already been exposed to APAP. A necroinflammatory process followed by a liver regeneration was observed after the first APAP exposure. However, fibrogenesis through the accumulation of extracellular matrix is observed after a second challenge. Therefore, further studies are required to mechanistically understand the so called “liver memory”

Author: Mohammad AlWahsh, Amnah Othman, Lama Hamadneh, Ahmad Telfah, Jörg Lambert, Suhair Hikmat, Amin Alassi, Fatma El Zahraa Mohamed, Roland Hergenröder, Tariq Al-Qirim, Steven Dooley, Seddik Hammad

Date Published: 6th Feb 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

Common NOD2 Risk Variants as Major Susceptibility Factors for Bacterial Infections in Compensated Cirrhosis.

Abstract (Expand)

OBJECTIVES: Common nucleotide-binding oligomerization domain containing 2 (NOD2) gene variants have been associated with bacterial infections (BIs) in cirrhosis, in particular, spontaneous bacterial … peritonitis, and mortality. Our aim was to evaluate the independent association of NOD2 variants with BI according to the decompensation stage. METHODS: Consecutive patients with cirrhosis in 2 academic medical centers were included and genotyped for the NOD2 variants p.R702W, p.G908R, and c.3020insC. Electronic medical records were screened for BI (requiring antibiotic therapy) and past and present decompensation (as defined by variceal bleeding, encephalopathy, ascites, and/or jaundice). Clinically significant portal hypertension (CSPH) was assessed with liver stiffness and/or hepatic venous pressure gradient measurements. RESULTS: Overall, 735 patients were recruited (men 65%; interquartile age range 53-68 years). Alcoholic cirrhosis was the predominant etiology (n = 406, 55%), and most patients were in the decompensated stage (n = 531, 72%). In total, 158 patients (21%) carried at least one NOD2 variant. BIs were detected in 263 patients (36%), and NOD2 variants were associated with BI (odds ratio = 1.58; 95% confidence interval 1.11-2.27; P = 0.02). In compensated patients, the combination of NOD2 variants and presence of CSPH was the best independent predictors of BI, whereas other factors, such as spleen size and hemoglobin, and decompensations including hepatic encephalopathy or jaundice, gained relevance in decompensated patients. CONCLUSIONS: NOD2 risk variants are associated with BI in cirrhosis. The genetic effect on BI is strongest in compensated patients, whereas in decompensated patients their presence is less relevant. In this situation, CSPH becomes an independent factor associated with BI.

Authors: M. C. Reichert, C. Ripoll, M. Casper, R. Greinert, E. Vandieken, F. Grunhage, B. Appenrodt, A. Zipprich, F. 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

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

ABCB4 Gene Aberrations in Human Liver Disease: An Evolving Spectrum

Abstract

Not specified

Authors: Matthias Reichert, Frank Lammert

Date Published: 24th Oct 2018

Publication Type: Not specified

Raf kinase inhibitor protein mediates myocardial fibrosis under conditions of enhanced myocardial oxidative stress.

Abstract (Expand)

Fibrosis is a hallmark of maladaptive cardiac remodelling. Here we report that genome-wide quantitative trait locus (QTL) analyses in recombinant inbred mouse lines of C57BL/6 J and DBA2/J strains … identified Raf Kinase Inhibitor Protein (RKIP) as genetic marker of fibrosis progression. C57BL/6 N-RKIP(-/-) mice demonstrated diminished fibrosis induced by transverse aortic constriction (TAC) or CCl(4) (carbon tetrachloride) treatment compared with wild-type controls. TAC-induced expression of collagen Ialpha2 mRNA, Ki67(+) fibroblasts and marker of oxidative stress 8-hydroxyguanosine (8-dOHG)(+) fibroblasts as well as the number of fibrocytes in the peripheral blood and bone marrow were markedly reduced in C57BL/6 N-RKIP(-/-) mice. RKIP-deficient cardiac fibroblasts demonstrated decreased migration and fibronectin production. This was accompanied by a two-fold increase of the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), the main transcriptional activator of antioxidative proteins, and reduced expression of its inactivators. To test the importance of oxidative stress for this signaling, C57BL/6 J mice were studied. C57BL/6 J, but not the C57BL/6 N-strain, is protected from TAC-induced oxidative stress due to mutation of the nicotinamide nucleotide transhydrogenase gene (Nnt). After TAC surgery, the hearts of Nnt-deficient C57BL/6 J-RKIP(-/-) mice revealed diminished oxidative stress, increased left ventricular (LV) fibrosis and collagen Ialpha2 as well as enhanced basal nuclear expression of Nrf2. In human LV myocardium from both non-failing and failing hearts, RKIP-protein correlated negatively with the nuclear accumulation of Nrf2. In summary, under conditions of Nnt-dependent enhanced myocardial oxidative stress induced by TAC, RKIP plays a maladaptive role for fibrotic myocardial remodeling by suppressing the Nrf2-related beneficial effects.

Authors: A. Kazakov, R. A. Hall, C. Werner, T. Meier, A. Trouvain, S. Rodionycheva, A. Nickel, F. Lammert, C. Maack, M. Bohm, U. Laufs

Date Published: 6th Sep 2018

Publication Type: Journal

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

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

Model-based identification of TNFalpha-induced IKKbeta-mediated and IkappaBalpha-mediated regulation of NFkappaB signal transduction as a tool to quantify the impact of drug-induced liver injury compounds.

Abstract (Expand)

Drug-induced liver injury (DILI) has become a major problem for patients and for clinicians, academics and the pharmaceutical industry. To date, existing hepatotoxicity test systems are only poorly … predictive and the underlying mechanisms are still unclear. One of the factors known to amplify hepatotoxicity is the tumor necrosis factor alpha (TNFalpha), especially due to its synergy with commonly used drugs such as diclofenac. However, the exact mechanism of how diclofenac in combination with TNFalpha induces liver injury remains elusive. Here, we combined time-resolved immunoblotting and live-cell imaging data of HepG2 cells and primary human hepatocytes (PHH) with dynamic pathway modeling using ordinary differential equations (ODEs) to describe the complex structure of TNFalpha-induced NFkappaB signal transduction and integrated the perturbations of the pathway caused by diclofenac. The resulting mathematical model was used to systematically identify parameters affected by diclofenac. These analyses showed that more than one regulatory module of TNFalpha-induced NFkappaB signal transduction is affected by diclofenac, suggesting that hepatotoxicity is the integrated consequence of multiple changes in hepatocytes and that multiple factors define toxicity thresholds. Applying our mathematical modeling approach to other DILI-causing compounds representing different putative DILI mechanism classes enabled us to quantify their impact on pathway activation, highlighting the potential of the dynamic pathway model as a quantitative tool for the analysis of DILI compounds.

Authors: A. Oppelt, D. Kaschek, S. Huppelschoten, R. Sison-Young, F. Zhang, M. Buck-Wiese, F. Herrmann, S. Malkusch, C. L. Kruger, M. Meub, B. Merkt, L. Zimmermann, A. Schofield, R. P. Jones, H. Malik, M. Schilling, M. Heilemann, B. van de Water, C. E. Goldring, B. K. Park, J. Timmer, U. Klingmuller

Date Published: 15th Jun 2018

Publication Type: Not specified

Effects of Gene Variants Controlling Vitamin D Metabolism and Serum Levels on Hepatic Steatosis.

Abstract (Expand)

BACKGROUND/AIMS: Common genetic variations in vitamin D metabolism are associated with liver stiffness. Whether these genes are implicated in hepatic steatosis remains unclear. Here we aimed to analyse … the association of common vitamin D pathway gene variants with liver steatosis. METHODS: Liver steatosis was assessed non-invasively in 241 patients with chronic liver conditions by controlled attenuation parameter (CAP). The following polymorphisms were genotyped using TaqMan assays: group-specific component (GC) rs7041, 7-dehydrocholesterol reductase (DHCR7) rs12785878, cytochrome P450 2R1 (CYP2R1) rs10741657, -vitamin D receptor (VDR) rs7974353. Chemiluminescence immunoassay determined serum 25-hydroxyvitamin D (25(OH) D) concentrations. RESULTS: Vitamin D deficiency (defined by 25(OH)D concentrations <20 ng/mL) occurred in 66% of patients. Median CAP was 296 (100-400) dB/m. Patients with advanced steatosis (CAP >/=280 dB/m) had significantly (p = 0.033) lower 25(OH)D levels as compared to patients with CAP <280 dB/m. Moreover, the rare allele [T] in GC rs7041 was significantly (p = 0.018) associated with higher 25(OH)D levels in patients with CAP <280 dB/m. However, GC, DHCR7, CYP2R1, and VDR polymorphisms were not related to liver steatosis and obesity traits. CONCLUSIONS: Higher CAP values are associated with low serum 25(OH)D concentrations but not with common vitamin D pathway gene variants.

Authors: M. Jamka, A. Arslanow, A. Bohner, M. Krawczyk, S. N. Weber, F. Grunhage, F. Lammert, C. S. Stokes

Date Published: 8th Mar 2018

Publication Type: Not specified

Could inherited predisposition drive non-obese fatty liver disease? Results from German tertiary referral centers.

Abstract (Expand)

Non-alcoholic fatty liver disease (NAFLD) is frequent among obese individuals with metabolic syndrome. Variants PNPLA3 p.I148M, TM6SF2 p.E167K and MBOAT7 rs641738 are associated with higher liver fat … contents. Here we analyzed 63 biopsied non-obese, non-diabetic patients with NAFLD (39 men, age: 20-72 years) recruited within the German NAFLD CSG program. The frequencies of the PNPLA3, TM6SF2 and MBOAT7 polymorphisms were compared with the remaining patients in the NAFLD CSG cohort and with a control population (n = 174). Serum CK18-M30 was measured by ELISA. In non-obese NAFLD patients, the frequency of the PNPLA3 p.I148M allele (74.6%), but not of the TM6SF2 or MBOAT7 polymorphisms, was significantly (P < 0.05) higher as compared to the other patients in the NAFLD CSG cohort (54.9%) or controls (40.2%). The presence of the minor PNPLA3 p.I148M risk allele increased the risk of developing NAFLD (OR = 3.29, P < 0.001) and was associated with higher steatosis, fibrosis, and serum CK18-M30 levels (all P < 0.05). According to the population attributable fraction (PAF), 49.8% of NAFLD cases could be eliminated if the PNPLA3 mutation was absent. The MBOAT7 polymorphism was more frequent (P = 0.019) in patients with severe hepatic steatosis. In conclusion, PNPLA3, and to a lesser extent, MBOAT7 variants are associated with NAFLD risk and modulate liver injury in non-obese patients without diabetes.

Authors: M. Krawczyk, H. Bantel, M. Rau, J. M. Schattenberg, F. Grunhage, A. Pathil, M. Demir, J. Kluwe, T. Boettler, S. N. Weber, A. Geier, F. Lammert

Date Published: 28th Feb 2018

Publication Type: Not specified

Resolving the Combinatorial Complexity of Smad Protein Complex Formation and Its Link to Gene Expression.

Abstract (Expand)

Upon stimulation of cells with transforming growth factor beta (TGF-beta), Smad proteins form trimeric complexes and activate a broad spectrum of target genes. It remains unresolved which of the possible … Smad complexes are formed in cellular contexts and how these contribute to gene expression. By combining quantitative mass spectrometry with a computational selection strategy, we predict and provide experimental evidence for the three most relevant Smad complexes in the mouse hepatoma cell line Hepa1-6. Utilizing dynamic pathway modeling, we specify the contribution of each Smad complex to the expression of representative Smad target genes, and show that these contributions are conserved in human hepatoma cell lines and primary hepatocytes. We predict, based on gene expression data of patient samples, increased amounts of Smad2/3/4 proteins and Smad2 phosphorylation as hallmarks of hepatocellular carcinoma and experimentally verify this prediction. Our findings demonstrate that modeling approaches can disentangle the complexity of transcription factor complex formation and its impact on gene expression.

Authors: P. Lucarelli, M. Schilling, C. Kreutz, A. Vlasov, M. E. Boehm, N. Iwamoto, B. Steiert, S. Lattermann, M. Wasch, M. Stepath, M. S. Matter, M. Heikenwalder, K. Hoffmann, D. Deharde, G. Damm, D. Seehofer, M. Muciek, N. Gretz, W. D. Lehmann, J. Timmer, U. Klingmuller

Date Published: 19th Feb 2018

Publication Type: Not specified

Model Based Targeting of IL-6-Induced Inflammatory Responses in Cultured Primary Hepatocytes to Improve Application of the JAK Inhibitor Ruxolitinib.

Abstract (Expand)

IL-6 is a central mediator of the immediate induction of hepatic acute phase proteins (APP) in the liver during infection and after injury, but increased IL-6 activity has been associated with multiple … pathological conditions. In hepatocytes, IL-6 activates JAK1-STAT3 signaling that induces the negative feedback regulator SOCS3 and expression of APPs. While different inhibitors of IL-6-induced JAK1-STAT3-signaling have been developed, understanding their precise impact on signaling dynamics requires a systems biology approach. Here we present a mathematical model of IL-6-induced JAK1-STAT3 signaling that quantitatively links physiological IL-6 concentrations to the dynamics of IL-6-induced signal transduction and expression of target genes in hepatocytes. The mathematical model consists of coupled ordinary differential equations (ODE) and the model parameters were estimated by a maximum likelihood approach, whereas identifiability of the dynamic model parameters was ensured by the Profile Likelihood. Using model simulations coupled with experimental validation we could optimize the long-term impact of the JAK-inhibitor Ruxolitinib, a therapeutic compound that is quickly metabolized. Model-predicted doses and timing of treatments helps to improve the reduction of inflammatory APP gene expression in primary mouse hepatocytes close to levels observed during regenerative conditions. The concept of improved efficacy of the inhibitor through multiple treatments at optimized time intervals was confirmed in primary human hepatocytes. Thus, combining quantitative data generation with mathematical modeling suggests that repetitive treatment with Ruxolitinib is required to effectively target excessive inflammatory responses without exceeding doses recommended by the clinical guidelines.

Authors: S. Sobotta, A. Raue, X. Huang, J. Vanlier, A. Junger, S. Bohl, U. Albrecht, M. J. Hahnel, S. Wolf, N. S. Mueller, L. A. D'Alessandro, S. Mueller-Bohl, M. E. Boehm, P. Lucarelli, S. Bonefas, G. Damm, D. Seehofer, W. D. Lehmann, S. Rose-John, F. van der Hoeven, N. Gretz, F. J. Theis, C. Ehlting, J. G. Bode, J. Timmer, M. Schilling, U. Klingmuller

Date Published: 9th 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

Genetic determinants of cholangiopathies: Molecular and systems genetics.

Abstract (Expand)

Familial cholangiopathies are rare but potentially severe diseases. Their spectrum ranges from fairly benign conditions as, for example, benign recurrent intrahepatic cholestasis to low-phospholipid … associated cholelithiasis and progressive familial intrahepatic cholestasis (PFIC). Many cholangiopathies such as primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) affect first the bile ducts ("ascending pathophysiology") but others, such as PFIC, start upstream in hepatocytes and cause progressive damage "descending" down the biliary tree and leading to end-stage liver disease. In recent years our understanding of cholestatic diseases has improved, since we have been able to pinpoint numerous disease-causing mutations that cause familial cholangiopathies. Accordingly, six PFIC subtypes (PFIC type 1-6) have now been defined. Given the availability of genotyping resources, these findings can be introduced in the diagnostic work-up of patients with peculiar cholestasis. In addition, functional studies have defined the pathophysiological consequences of some of the detected variants. Furthermore, ABCB4 variants do not only cause PFIC type 3 but confer an increased risk for chronic liver disease in general. In the near future these findings will serve to develop new therapeutic strategies for patients with liver diseases. Here we present the latest data on the genetic background of familial cholangiopathies and discuss their application in clinical practice for the differential diagnosis of cholestasis of unknown aetiology. As look in the future we present "system genetics" as a novel experimental tool for the study of cholangiopathies and disease-modifying genes. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Authors: M. C. Reichert, R. A. Hall, M. Krawczyk, F. Lammert

Date Published: 2nd Aug 2017

Publication Type: Journal

Large-scale computational models of liver metabolism: How far from the clinics?

Abstract (Expand)

Understanding the dynamics of human liver metabolism is fundamental for effective diagnosis and treatment of liver diseases in general and the metabolism of drugs in particular. This knowledge can be … obtained with systems biology/medicine approaches that account for the complexity of hepatic responses and their systemic consequences in other organs. Computational modelling can reveal hidden principles of the system by classification of individual components, analysing their interactions and simulating the effects that are difficult to investigate experimentally. Herein we review the state-of-the-art computational models that describe liver dynamics from the metabolic, gene regulatory and signal transduction perspectives. We focus especially on large-scale liver models described either by genome scale metabolic networks (GSMN) or object-oriented approach. We also discuss the benefits and limitations of each modelling approach and their value for clinical applications in diagnosis, therapy and prevention of liver diseases as well as precision medicine in hepatology. This article is protected by copyright. All rights reserved.

Authors: T. Cvitanovic, M. C. Reichert, M. Moskon, M. Mraz, F. Lammert, D. Rozman

Date Published: 19th 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: 23rd Mar 2017

Publication Type: Not specified

Panel of three novel serum markers predicts liver stiffness and fibrosis stages in patients with chronic liver disease.

Abstract (Expand)

Latest data suggest that placental growth factor (PLGF), growth differentiation factor-15 (GDF-15) and hepatic growth factor (HGF) are involved in hepatic fibrogenesis. Diagnostic performance of these … markers for non-invasive liver fibrosis prediction was evaluated based on liver histology and stiffness. In total 834 patients were recruited. Receiver-operating-characteristics were used to define cut-offs for markers correlating to fibrosis stages. Odds-ratios were calculated for the presence/absence of fibrosis/cirrhosis and confirmed in the sub-group of patients phenotyped by elastography only. Logistic and uni- and multivariate regression analyses were used to test for association of markers with liver fibrosis stages and for independent prediction of liver histology and stiffness. Marker concentrations correlated significantly (P<0.001) with histology and stiffness. Cut-offs for liver fibrosis (>/=F2) were PLGF = 20.20 pg/ml, GDF15 = 1582.76 pg/ml and HGF = 2598.00 pg/ml. Logistic regression confirmed an increase of ORs from 3.6 over 33.0 to 108.4 with incremental (1-3) markers positive for increased liver stiffness (>/=12.8kPa; all P<0.05). Subgroup analysis revealed associations with advanced fibrosis for HCV (three markers positive: OR = 59.9, CI 23.4-153.4, P<0.001) and non-HCV patients (three markers positive: OR = 144, CI 59-3383, P<0.001). Overall, serum markers identified additional 50% of patients at risk for advanced fibrosis presenting with low elastography results. In conclusion, this novel combination of markers reflects the presence of significant liver fibrosis detected by elastography and histology and may also identify patients at risk presenting with low elastography values.

Authors: M. Krawczyk, S. Zimmermann, G. Hess, R. Holz, M. Dauer, J. Raedle, F. Lammert, F. Grunhage

Date Published: 17th 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

L1 regularization facilitates detection of cell type-specific parameters in dynamical systems.

Abstract (Expand)

MOTIVATION: A major goal of drug development is to selectively target certain cell types. Cellular decisions influenced by drugs are often dependent on the dynamic processing of information. Selective … responses can be achieved by differences between the involved cell types at levels of receptor, signaling, gene regulation or further downstream. Therefore, a systematic approach to detect and quantify cell type-specific parameters in dynamical systems becomes necessary. RESULTS: Here, we demonstrate that a combination of nonlinear modeling with L1 regularization is capable of detecting cell type-specific parameters. To adapt the least-squares numerical optimization routine to L1 regularization, sub-gradient strategies as well as truncation of proposed optimization steps were implemented. Likelihood-ratio tests were used to determine the optimal regularization strength resulting in a sparse solution in terms of a minimal number of cell type-specific parameters that is in agreement with the data. By applying our implementation to a realistic dynamical benchmark model of the DREAM6 challenge we were able to recover parameter differences with an accuracy of 78%. Within the subset of detected differences, 91% were in agreement with their true value. Furthermore, we found that the results could be improved using the profile likelihood. In conclusion, the approach constitutes a general method to infer an overarching model with a minimum number of individual parameters for the particular models. AVAILABILITY AND IMPLEMENTATION: A MATLAB implementation is provided within the freely available, open-source modeling environment Data2Dynamics. Source code for all examples is provided online at http://www.data2dynamics.org/ CONTACT: bernhard.steiert@fdm.uni-freiburg.de.

Authors: B. Steiert, J. Timmer, C. Kreutz

Date Published: 3rd Sep 2016

Publication Type: Not specified

Driving the Model to Its Limit: Profile Likelihood Based Model Reduction.

Abstract (Expand)

In systems biology, one of the major tasks is to tailor model complexity to information content of the data. A useful model should describe the data and produce well-determined parameter estimates and … predictions. Too small of a model will not be able to describe the data whereas a model which is too large tends to overfit measurement errors and does not provide precise predictions. Typically, the model is modified and tuned to fit the data, which often results in an oversized model. To restore the balance between model complexity and available measurements, either new data has to be gathered or the model has to be reduced. In this manuscript, we present a data-based method for reducing non-linear models. The profile likelihood is utilised to assess parameter identifiability and designate likely candidates for reduction. Parameter dependencies are analysed along profiles, providing context-dependent suggestions for the type of reduction. We discriminate four distinct scenarios, each associated with a specific model reduction strategy. Iterating the presented procedure eventually results in an identifiable model, which is capable of generating precise and testable predictions. Source code for all toy examples is provided within the freely available, open-source modelling environment Data2Dynamics based on MATLAB available at http://www.data2dynamics.org/, as well as the R packages dMod/cOde available at https://github.com/dkaschek/. Moreover, the concept is generally applicable and can readily be used with any software capable of calculating the profile likelihood.

Authors: T. Maiwald, H. Hass, B. Steiert, J. Vanlier, R. Engesser, A. Raue, F. Kipkeew, H. H. Bock, D. Kaschek, C. Kreutz, J. Timmer

Date Published: 3rd Sep 2016

Publication Type: Not specified

Identification of Cell Type-Specific Differences in Erythropoietin Receptor Signaling in Primary Erythroid and Lung Cancer Cells.

Abstract (Expand)

Lung cancer, with its most prevalent form non-small-cell lung carcinoma (NSCLC), is one of the leading causes of cancer-related deaths worldwide, and is commonly treated with chemotherapeutic drugs … such as cisplatin. Lung cancer patients frequently suffer from chemotherapy-induced anemia, which can be treated with erythropoietin (EPO). However, studies have indicated that EPO not only promotes erythropoiesis in hematopoietic cells, but may also enhance survival of NSCLC cells. Here, we verified that the NSCLC cell line H838 expresses functional erythropoietin receptors (EPOR) and that treatment with EPO reduces cisplatin-induced apoptosis. To pinpoint differences in EPO-induced survival signaling in erythroid progenitor cells (CFU-E, colony forming unit-erythroid) and H838 cells, we combined mathematical modeling with a method for feature selection, the L1 regularization. Utilizing an example model and simulated data, we demonstrated that this approach enables the accurate identification and quantification of cell type-specific parameters. We applied our strategy to quantitative time-resolved data of EPO-induced JAK/STAT signaling generated by quantitative immunoblotting, mass spectrometry and quantitative real-time PCR (qRT-PCR) in CFU-E and H838 cells as well as H838 cells overexpressing human EPOR (H838-HA-hEPOR). The established parsimonious mathematical model was able to simultaneously describe the data sets of CFU-E, H838 and H838-HA-hEPOR cells. Seven cell type-specific parameters were identified that included for example parameters for nuclear translocation of STAT5 and target gene induction. Cell type-specific differences in target gene induction were experimentally validated by qRT-PCR experiments. The systematic identification of pathway differences and sensitivities of EPOR signaling in CFU-E and H838 cells revealed potential targets for intervention to selectively inhibit EPO-induced signaling in the tumor cells but leave the responses in erythroid progenitor cells unaffected. Thus, the proposed modeling strategy can be employed as a general procedure to identify cell type-specific parameters and to recommend treatment strategies for the selective targeting of specific cell types.

Authors: R. Merkle, B. Steiert, F. Salopiata, S. Depner, A. Raue, N. Iwamoto, M. Schelker, H. Hass, M. Wasch, M. E. Bohm, O. Mucke, D. B. Lipka, C. Plass, W. D. Lehmann, C. Kreutz, J. Timmer, M. Schilling, U. Klingmuller

Date Published: 6th Aug 2016

Publication Type: Not specified

Identification of miRNA148a-3p as a novel non-invasive potential biomarker for ACLF

Abstract

Not specified

Author: M. TESSENYI, S.N. WEBER, M.C. REICHERT, S.C. KARATAYLI, R.A. HALL, S. QIAO, U. BOEHM, T. BRUNS, S. DOOLEY, F. LAMMERT, E. KARATAYLI

Date Published: No date defined

Publication Type: Journal

Fibroblast growth factor 21 response in a preclinical alcohol model of acute-on-chronic liver injury

Abstract

Not specified

Author: G. Christidis, E. Karatayli1, R.A. Hall, S.N. Weber, M.C. Reichert, M. Hohl, S. Qiao, U. Boehm, D. Lütjohann, F. Lammert, S.C. Karatayli

Date Published: No date defined

Publication Type: Journal

Protective effects of statin therapy in cirrhosis are limited by a common SLCO1B1 transporter variant.

Abstract

Not specified

Author: Melissa Merkel, Christina Schneider, Robin Greinert, Alexander Zipprich, Cristina Ripoll, Frank Lammert1 and Matthias C. Reichert1

Date Published: No date defined

Publication Type: Journal

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