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377 Publications visible to you, out of a total of 377
beta-Catenin and Yes-Associated Protein 1 Cooperate in Hepatoblastoma Pathogenesis.

Abstract (Expand)

Hepatoblastoma (HB), the most common pediatric primary liver neoplasm, shows nuclear localization of beta-catenin and yes-associated protein 1 (YAP1) in almost 80% of the cases. Co-expression of … constitutively active S127A-YAP1 and DeltaN90 deletion-mutant beta-catenin (YAP1-DeltaN90-beta-catenin) causes HB in mice. Because heterogeneity in downstream signaling is being identified owing to mutational differences even in the beta-catenin gene alone, we investigated if co-expression of point mutants of beta-catenin (S33Y or S45Y) with S127A-YAP1 led to similar tumors as YAP1-DeltaN90-beta-catenin. Co-expression of S33Y/S45Y-beta-catenin and S127A-YAP1 led to activation of Yap and Wnt signaling and development of HB, with 100% mortality by 13 to 14 weeks. Co-expression with YAP1-S45Y/S33Y-beta-catenin of the dominant-negative T-cell factor 4 or dominant-negative transcriptional enhanced associate domain 2, the respective surrogate transcription factors, prevented HB development. Although histologically similar, HB in YAP1-S45Y/S33Y-beta-catenin, unlike YAP1-DeltaN90-beta-catenin HB, was glutamine synthetase (GS) positive. However, both DeltaN90-beta-catenin and point-mutant beta-catenin comparably induced GS-luciferase reporter in vitro. Finally, using a previously reported 16-gene signature, it was shown that YAP1-DeltaN90-beta-catenin HB tumors exhibited genetic similarities with more proliferative, less differentiated, GS-negative HB patient tumors, whereas YAP1-S33Y/S45Y-beta-catenin HB exhibited heterogeneity and clustered with both well-differentiated GS-positive and proliferative GS-negative patient tumors. Thus, we demonstrate that beta-catenin point mutants can also collaborate with YAP1 in HB development, albeit with a distinct molecular profile from the deletion mutant, which may have implications in both biology and therapy.

Authors: Q. Min, L. Molina, J. Li, A. O. Adebayo Michael, J. O. Russell, M. E. Preziosi, S. Singh, M. Poddar, M. Matz-Soja, S. Ranganathan, A. W. Bell, R. Gebhardt, F. Gaunitz, J. Yu, J. Tao, S. P. Monga

Date Published: 23rd Feb 2019

Publication Type: Not specified

Non-invasive structure-function assessment of the liver by 2D time-harmonic elastography and the dynamic Liver MAximum capacity (LiMAx) test.

Abstract (Expand)

BACKGROUND AND AIM: Accurate assessment of structural and functional characteristics of the liver could improve the diagnosis and the clinical management of patients with chronic liver diseases. However, … the structure-function relationship in the progression of chronic liver disease remains elusive. The aim of this study is the combined measurement of liver function by the (13) C-methacetin Liver MAximum capacity (LiMAx) test and tissue-structure related stiffness by 2D time-harmonic elastography for the assessment of liver disease progression. METHODS: LiMAx test and time-harmonic elastography were applied, and the serological scores fibrosis 4 index and aspartate aminotransferase to platelet ratio index were calculated in patients with chronic liver diseases (n = 75) and healthy control subjects (n = 22). In 47 patients who underwent surgery, fibrosis was graded by histological examination of the resected liver tissue. RESULTS: LiMAx values correlated negatively with liver stiffness (r = -0.747), aminotransferase to platelet ratio index (r = -0.604), and fibrosis 4 (r = -0.573). Median (interquartile range) LiMAx values decreased with fibrosis progression from 395 mug/kg/h (371-460 mug/kg/h) in participants with no fibrosis to 173 mug/kg/h (126-309 mug/kg/h) in patients with severe fibrosis. Median liver stiffness increased progressively with the stage of fibrosis from no fibrosis (1.56 m/s [1.52-1.63 m/s]) to moderate fibrosis (1.60 m/s [1.54-1.67 m/s]) to severe fibrosis (1.85 m/s [1.76-1.92 m/s]). CONCLUSION: Our findings show that structural changes in the liver due to progressing liver diseases and reflected by increased tissue stiffness correlate with a functional decline of the organ as reflected by a decreased metabolic capacity of the liver.

Authors: N. Heucke, T. Wuensch, J. Mohr, M. Kaffarnik, R. Arsenic, B. Sinn, T. Muller, J. Pratschke, M. Stockmann, I. Sack, H. Tzschatzsch

Date Published: 13th Feb 2019

Publication Type: Not specified

The predictive value of future liver remnant function after liver resection for HCC in noncirrhotic and cirrhotic patients.

Abstract (Expand)

BACKGROUND: Surgical procedures in patients with underlying liver disease are still burdened by a high rate of postoperative morbidity, especially posthepatectomy liver failure (PHLF), ranging from 1.2 … to 33.8%. The aim of this study was to investigate the prognostic value of volume/function analysis for the prediction of hepatectomy-related morbidity in patients with hepatocellular carcinoma. METHODS: Clinicopathological data were analysed in 261 patients who underwent liver resection for HCC between 2001 and 2014. Future liver remnant volume (FLRV) and future liver remnant function (FLRF) based on LiMAx test were obtained retrospectively. A subgroup analysis for high-risk patients with impaired liver function was conducted. Univariate and multivariate regression analysis was performed to identify risk factors for major complications, defined by Dindo >/= IIIb and PHLF grade >/= B. RESULTS: In the total cohort, FLRF was independently associated with major complications. FLRV, resected liver volume, and FLRF were independent risk factors for PHLF. In a subgroup analysis of high-risk patients, FLRF was identified as the only independent risk factor for major complications and PHLF development. DISCUSSION: These results suggest the superior value of FLRF to FLRV in predicting postoperative complications as well as PHLF in patients with chronic liver disease.

Authors: E. Bluthner, M. Jara, R. Shrestha, W. Faber, J. Pratschke, M. Stockmann, M. Malinowski

Date Published: 9th Feb 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

Tick-tock hedgehog-mutual crosstalk with liver circadian clock promotes liver steatosis.

Abstract (Expand)

BACKGROUND & AIMS: The mammalian circadian clock controls various aspects of liver metabolism and integrates nutritional signals. Recently, we described Hedgehog (Hh) signaling as a novel regulator … of liver lipid metabolism. Herein, we investigated crosstalk between hepatic Hh signaling and circadian rhythm. METHODS: Diurnal rhythms of Hh signaling were investigated in liver and hepatocytes from mice with ablation of Smoothened (SAC-KO) and crossbreeds with PER2::LUC reporter mice. By using genome-wide screening, qPCR, immunostaining, ELISA and RNAi experiments in vitro we identified relevant transcriptional regulatory steps. Shotgun lipidomics and metabolic cages were used for analysis of metabolic alterations and behavior. RESULTS: Hh signaling showed diurnal oscillations in liver and hepatocytes in vitro. Correspondingly, the level of Indian Hh, oscillated in serum. Depletion of the clock gene Bmal1 in hepatocytes resulted in significant alterations in the expression of Hh genes. Conversely, SAC-KO mice showed altered expression of clock genes, confirmed by RNAi against Gli1 and Gli3. Genome-wide screening revealed that SAC-KO hepatocytes showed time-dependent alterations in various genes, particularly those associated with lipid metabolism. The clock/hedgehog module further plays a role in rhythmicity of steatosis, and in the response of the liver to a high-fat diet or to differently timed starvation. CONCLUSIONS: For the first time, Hh signaling in hepatocytes was found to be time-of-day dependent and to feed back on the circadian clock. Our findings suggest an integrative role of Hh signaling, mediated mainly by GLI factors, in maintaining homeostasis of hepatic lipid metabolism by balancing the circadian clock. LAY SUMMARY: The results of our investigation show for the first time that the Hh signaling in hepatocytes is time-of-day dependent, leading to differences not only in transcript levels but also in the amount of Hh ligands in peripheral blood. Conversely, Hh signaling is able to feed back to the circadian clock.

Authors: E. Marbach-Breitruck, M. Matz-Soja, U. Abraham, W. Schmidt-Heck, S. Sales, C. Rennert, M. Kern, S. Aleithe, L. Spormann, C. Thiel, R. Gerlini, K. Arnold, N. Kloting, R. Guthke, D. Rozman, R. Teperino, A. Shevchenko, A. Kramer, R. Gebhardt

Date Published: 4th 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

Dynamic Metabolic Zonation of the Hepatic Glucose Metabolism Is Accomplished by Sinusoidal Plasma Gradients of Nutrients and Hormones.

Abstract (Expand)

Being the central metabolic organ of vertebrates, the liver possesses the largest repertoire of metabolic enzymes among all tissues and organs. Almost all metabolic pathways are resident in the parenchymal … cell, hepatocyte, but the pathway capacities may largely differ depending on the localization of hepatocytes within the liver acinus-a phenomenon that is commonly referred to as metabolic zonation. Metabolic zonation is rather dynamic since gene expression patterns of metabolic enzymes may change in response to nutrition, drugs, hormones and pathological states of the liver (e.g., fibrosis and inflammation). This fact has to be ultimately taken into account in mathematical models aiming at the prediction of metabolic liver functions in different physiological and pathological settings. Here we present a spatially resolved kinetic tissue model of hepatic glucose metabolism which includes zone-specific temporal changes of enzyme abundances which are driven by concentration gradients of nutrients, hormones and oxygen along the hepatic sinusoids. As key modulators of enzyme expression we included oxygen, glucose and the hormones insulin and glucagon which also control enzyme activities by cAMP-dependent reversible phosphorylation. Starting with an initially non-zonated model using plasma profiles under fed, fasted and diabetic conditions, zonal patterns of glycolytic and gluconeogenetic enzymes as well as glucose uptake and release rates are created as an emergent property. We show that mechanisms controlling the adaptation of enzyme abundances to varying external conditions necessarily lead to the zonation of hepatic carbohydrate metabolism. To the best of our knowledge, this is the first kinetic tissue model which takes into account in a semi-mechanistic way all relevant levels of enzyme regulation.

Authors: N. Berndt, H. G. Holzhutter

Date Published: 12th Jan 2019

Publication Type: Journal

Data Formats for Systems Biology and Quantitative Modeling

Abstract (Expand)

Data standards support the reliable exchange of information, the interoperability of tools, and the reproducibility of scientific results. In systems biology standards are agreed ways of structuring, … describing, and associating models and data, as well as their respective parts, graphical visualization, and information about applied experimental or computational methods. Such standards also assist with describing how constituent parts interact together, or are linked, and how they are embedded in their environmental and experimental context. Here the focus will be on standards for formatting models and their content, and on metadata checklists and ontologies that support modeling.

Author: Martin Golebiewski

Date Published: 2019

Publication Type: InBook

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

Abstract

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Authors: S Hammad, JG Hengstler, S Dooley

Date Published: 2019

Publication Type: Not specified

ECM1 is a gatekeeper that restrains TGF-β activation to maintain liver homeostasis and prevent fibrogenesis

Abstract

Not specified

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

Date Published: 2019

Publication Type: Not specified

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

Abstract

Not specified

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

Date Published: 2019

Publication Type: Not specified

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

Abstract

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

Date Published: 2019

Publication Type: Not specified

Cellular and nuclear hepatocyte ploidy represent a repository in regenerating livers

Abstract

Not specified

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

Date Published: 2019

Publication Type: Not specified

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

Abstract

Not specified

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

Date Published: 2019

Publication Type: Not specified

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