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377 Publications visible to you, out of a total of 377
Evolving Insights on Metabolism, Autophagy, and Epigenetics in Liver Myofibroblasts.

Abstract (Expand)

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

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

Date Published: 18th Jun 2016

Publication Type: Not specified

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

Abstract

Not specified

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

Date Published: 17th Jun 2016

Publication Type: Not specified

Gender, Contraceptives and Individual Metabolic Predisposition Shape a Healthy Plasma Lipidome.

Abstract (Expand)

Lipidomics of human blood plasma is an emerging biomarker discovery approach that compares lipid profiles under pathological and physiologically normal conditions, but how a healthy lipidome varies … within the population is poorly understood. By quantifying 281 molecular species from 27 major lipid classes in the plasma of 71 healthy young Caucasians whose 35 clinical blood test and anthropometric indices matched the medical norm, we provided a comprehensive, expandable and clinically relevant resource of reference molar concentrations of individual lipids. We established that gender is a major lipidomic factor, whose impact is strongly enhanced by hormonal contraceptives and mediated by sex hormone-binding globulin. In lipidomics epidemiological studies should avoid mixed-gender cohorts and females taking hormonal contraceptives should be considered as a separate sub-cohort. Within a gender-restricted cohort lipidomics revealed a compositional signature that indicates the predisposition towards an early development of metabolic syndrome in ca. 25% of healthy male individuals suggesting a healthy plasma lipidome as resource for early biomarker discovery.

Authors: S. Sales, J. Graessler, S. Ciucci, R. Al-Atrib, T. Vihervaara, K. Schuhmann, D. Kauhanen, M. Sysi-Aho, S. R. Bornstein, M. Bickle, C. V. Cannistraci, K. Ekroos, A. Shevchenko

Date Published: 14th Jun 2016

Publication Type: Not specified

A targeted analysis reveals relevant shifts in the methylation and transcription of genes responsible for bile acid homeostasis and drug metabolism in non-alcoholic fatty liver disease.

Abstract (Expand)

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is associated with a high risk for liver cirrhosis and cancer. Recent studies demonstrate that NAFLD significantly impacts on the genome wide … methylation and expression reporting top hit genes to be associated with e.g. diabetes mellitus. In a targeted analysis we specifically investigate to what extent NAFLD is associated with methylation and transcriptional changes in gene networks responsible for drug metabolism (DM) and bile acid (BA) homeostasis, which may trigger liver and system toxic events. METHODS: We performed a systematic analysis of 73 genes responsible for BA homeostasis and DM based on liver derived methylation and expression data from three cohort studies including 103 NAFLD and 75 non-NAFLD patients. Using multiple linear regression models, we detected methylation differences in proximity to the transcriptional start site of these genes in two NAFLD cohorts and correlated the methylation of significantly changed CpG sites to transcriptional expression in a third cohort using robust multiple linear regression approaches. RESULTS: We detected 64 genes involved in BA homeostasis and DM to be significantly differentially methylated. In 26 of these genes, methylation significantly correlated with RNA expression, detecting i.e. genes such as CYP27A1, OSTa, and SLC27A5 (BA homeostasis), and SLCO2B1, SLC47A1, and several UGT and CYP genes (DM) to be NAFLD dependently modulated. CONCLUSIONS: NAFLD is associated with significant shifts in the methylation of key genes responsible for BA and DM that are associated with transcriptional modulations. These findings have implications for BA composition, BA regulated metabolic pathways and for drug safety and efficacy.

Authors: H. B. Schioth, A. Bostrom, S. K. Murphy, W. Erhart, J. Hampe, C. Moylan, J. Mwinyi

Date Published: 14th Jun 2016

Publication Type: Not specified

Toward Community Standards and Software for Whole-Cell Modeling.

Abstract (Expand)

OBJECTIVE: Whole-cell (WC) modeling is a promising tool for biological research, bioengineering, and medicine. However, substantial work remains to create accurate comprehensive models of complex cells. … METHODS: We organized the 2015 Whole-Cell Modeling Summer School to teach WC modeling and evaluate the need for new WC modeling standards and software by recoding a recently published WC model in the Systems Biology Markup Language. RESULTS: Our analysis revealed several challenges to representing WC models using the current standards. CONCLUSION: We, therefore, propose several new WC modeling standards, software, and databases. SIGNIFICANCE: We anticipate that these new standards and software will enable more comprehensive models.

Authors: D. Waltemath, J. R. Karr, F. T. Bergmann, V. Chelliah, M. Hucka, M. Krantz, W. Liebermeister, P. Mendes, C. J. Myers, P. Pir, B. Alaybeyoglu, N. K. Aranganathan, K. Baghalian, A. T. Bittig, P. E. Burke, M. Cantarelli, Y. H. Chew, R. S. Costa, J. Cursons, T. Czauderna, A. P. Goldberg, H. F. Gomez, J. Hahn, T. Hameri, D. F. Gardiol, D. Kazakiewicz, I. Kiselev, V. Knight-Schrijver, C. Knupfer, M. Konig, D. Lee, A. Lloret-Villas, N. Mandrik, J. K. Medley, B. Moreau, H. Naderi-Meshkin, S. K. Palaniappan, D. Priego-Espinosa, M. Scharm, M. Sharma, K. Smallbone, N. J. Stanford, J. H. Song, T. Theile, M. Tokic, N. Tomar, V. Toure, J. Uhlendorf, T. M. Varusai, L. H. Watanabe, F. Wendland, M. Wolfien, J. T. Yurkovich, Y. Zhu, A. Zardilis, A. Zhukova, F. Schreiber

Date Published: 10th Jun 2016

Publication Type: Not specified

Hedgehog signaling is a potent regulator of liver lipid metabolism and reveals a GLI-code associated with steatosis.

Abstract (Expand)

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and is increasing in prevalence. The pathomechanisms, however, are poorly understood. This study … assessed the unexpected role of the Hedgehog pathway in adult liver lipid metabolism. Using transgenic mice with conditional hepatocyte-specific deletion of Smoothened in adult mice, we showed that hepatocellular inhibition of Hedgehog signaling leads to steatosis by altering the abundance of the transcription factors GLI1 and GLI3. This steatotic 'Gli-code' caused the modulation of a complex network of lipogenic transcription factors and enzymes, including SREBP1 and PNPLA3, as demonstrated by microarray analysis and siRNA experiments and could be confirmed in other steatotic mouse models as well as in steatotic human livers. Conversely, activation of the Hedgehog pathway reversed the "Gli-code" and mitigated hepatic steatosis. Collectively, our results reveal that dysfunctions in the Hedgehog pathway play an important role in hepatic steatosis and beyond.

Authors: M. Matz-Soja, C. Rennert, K. Schonefeld, S. Aleithe, J. Boettger, W. Schmidt-Heck, T. S. Weiss, A. Hovhannisyan, S. Zellmer, N. Kloting, A. Schulz, J. Kratzsch, R. Guthke, R. Gebhardt

Date Published: 17th May 2016

Publication Type: Not specified

DNA Methylation of ADME Genes.

Abstract (Expand)

The epigenetic regulation of expression of genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs contributes to interindividual variability in drug response. Epigenetic … mechanisms include DNA methylation, histone modifications, and miRNAs. This review systematically outlines the influence of DNA methylation on ADME gene expression and highlights the consequences for interindividual variability in drug response or drug-induced toxicity and the implications for personalized medicine.

Authors: P. Fisel, E. Schaeffeler, M. Schwab

Date Published: 12th Apr 2016

Publication Type: Not specified

TGF-β1 and TGF-β2 abundance in liver diseases of mice and men

Abstract

Not specified

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

Date Published: 12th Apr 2016

Publication Type: Not specified

The Human Physiome: how standards, software and innovative service infrastructures are providing the building blocks to make it achievable

Abstract (Expand)

Reconstructing and understanding the Human Physiome virtually is a complex mathematical problem, and a highly demanding computational challenge. Mathematical models spanning from the molecular level … through to whole populations of individuals must be integrated, then personalized. This requires interoperability with multiple disparate and geographically separated data sources, and myriad computational software tools. Extracting and producing knowledge from such sources, even when the databases and software are readily available, is a challenging task. Despite the difficulties, researchers must frequently perform these tasks so that available knowledge can be continually integrated into the common framework required to realize the Human Physiome. Software and infrastructures that support the communities that generate these, together with their underlying standards to format, describe and interlink the corresponding data and computer models, are pivotal to the Human Physiome being realized. They provide the foundations for integrating, exchanging and re-using data and models efficiently, and correctly, while also supporting the dissemination of growing knowledge in these forms. In this paper, we explore the standards, software tooling, repositories and infrastructures that support this work, and detail what makes them vital to realizing the Human Physiome.

Authors: D. Nickerson, K. Atalag, B. de Bono, J. Geiger, C. Goble, S. Hollmann, J. Lonien, W. Muller, B. Regierer, N. J. Stanford, M. Golebiewski, P. Hunter

Date Published: 7th Apr 2016

Publication Type: Not specified

Model-guided identification of a therapeutic strategy to reduce hyperammonemia in liver diseases

Abstract (Expand)

BACKGROUND & AIMS: Recently, spatial-temporal/metabolic mathematical models have been established that allow the simulation of metabolic processes in tissues. We applied these models to decipher …er ammonia detoxification mechanisms in the liver. METHODS: An integrated metabolic-spatial-temporal model was used to generate hypotheses of ammonia metabolism. Predicted mechanisms were validated using time-resolved analyses of nitrogen metabolism, activity analyses, immunostaining and gene expression after induction of liver damage in mice. Moreover, blood from the portal vein, liver vein and mixed venous blood was analyzed in a time dependent manner. RESULTS: Modeling revealed an underestimation of ammonia consumption after liver damage when only the currently established mechanisms of ammonia detoxification were simulated. By iterative cycles of modeling and experiments, the reductive amidation of alpha-ketoglutarate (α-KG) via glutamate dehydrogenase (GDH) was identified as the lacking component. GDH is released from damaged hepatocytes into the blood where it consumes ammonia to generate glutamate, thereby providing systemic protection against hyperammonemia. This mechanism was exploited therapeutically in a mouse model of hyperammonemia by injecting GDH together with optimized doses of cofactors. Intravenous injection of GDH (720 U/kg), α-KG (280 mg/kg) and NADPH (180 mg/kg) reduced the elevated blood ammonia concentrations (>200 μM) to levels close to normal within only 15 min. CONCLUSION: If successfully translated to patients the GDH-based therapy might provide a less aggressive therapeutic alternative for patients with severe hyperammonemia.

Authors: Ahmed Ghallab, Géraldine Cellière, Sebastian G. Henkel, Dominik Driesch, Stefan Hoehme, Ute Hofmann, Sebastian Zellmer, Patricio Godoy, Agapios Sachinidis, Meinolf Blaszkewicz, Raymond Reif, Rosemarie Marchan, Lars Kuepfer, Dieter Häussinger, Dirk Drasdo, Rolf Gebhardt, Jan G. Hengstler

Date Published: 1st Apr 2016

Publication Type: Not specified

The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism--insights from mathematical modeling.

Abstract (Expand)

BACKGROUND: Adaptation of the cellular metabolism to varying external conditions is brought about by regulated changes in the activity of enzymes and transporters. Hormone-dependent reversible enzyme … phosphorylation and concentration changes of reactants and allosteric effectors are the major types of rapid kinetic enzyme regulation, whereas on longer time scales changes in protein abundance may also become operative. Here, we used a comprehensive mathematical model of the hepatic glucose metabolism of rat hepatocytes to decipher the relative importance of different regulatory modes and their mutual interdependencies in the hepatic control of plasma glucose homeostasis. RESULTS: Model simulations reveal significant differences in the capability of liver metabolism to counteract variations of plasma glucose in different physiological settings (starvation, ad libitum nutrient supply, diabetes). Changes in enzyme abundances adjust the metabolic output to the anticipated physiological demand but may turn into a regulatory disadvantage if sudden unexpected changes of the external conditions occur. Allosteric and hormonal control of enzyme activities allow the liver to assume a broad range of metabolic states and may even fully reverse flux changes resulting from changes of enzyme abundances alone. Metabolic control analysis reveals that control of the hepatic glucose metabolism is mainly exerted by enzymes alone, which are differently controlled by alterations in enzyme abundance, reversible phosphorylation, and allosteric effects. CONCLUSION: In hepatic glucose metabolism, regulation of enzyme activities by changes of reactants, allosteric effects, and reversible phosphorylation is equally important as changes in protein abundance of key regulatory enzymes.

Authors: S. Bulik, H. G. Holzhutter, N. Berndt

Date Published: 2nd Mar 2016

Publication Type: Not specified

Cholestasis-induced adaptive remodeling of interlobular bile ducts.

Abstract (Expand)

UNLABELLED: Cholestasis is a common complication in liver diseases that triggers a proliferative response of the biliary tree. Bile duct ligation (BDL) is a frequently used model of cholestasis in … rodents. To determine which changes occur in the three-dimensional (3D) architecture of the interlobular bile duct during cholestasis, we used 3D confocal imaging, surface reconstructions, and automated image quantification covering a period up to 28 days after BDL. We show a highly reproducible sequence of interlobular duct remodeling, where cholangiocyte proliferation initially causes corrugation of the luminal duct surface, leading to an approximately five-fold increase in surface area. This is analogous to the function of villi in the intestine or sulci in the brain, where an expansion of area is achieved within a restricted volume. The increase in surface area is further enhanced by duct branching, branch elongation, and loop formation through self-joining, whereby an initially relatively sparse mesh surrounding the portal vein becomes five-fold denser through elongation, corrugation, and ramification. The number of connections between the bile duct and the lobular bile canalicular network by the canals of Hering decreases proportionally to the increase in bile duct length, suggesting that no novel connections are established. The diameter of the interlobular bile duct remains constant after BDL, a response that is qualitatively distinct from that of large bile ducts, which tend to enlarge their diameters. Therefore, volume enhancement is only due to net elongation of the ducts. Because curvature and tortuosity of the bile duct are unaltered, this enlargement of the biliary tree is caused by branching and not by convolution. CONCLUSION: BDL causes adaptive remodeling that aims at optimizing the intraluminal surface area by way of corrugation and branching.

Authors: N. Vartak, A. Damle-Vartak, B. Richter, O. Dirsch, U. Dahmen, S. Hammad, J. G. Hengstler

Date Published: 27th Nov 2015

Publication Type: Not specified

A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis.

Abstract (Expand)

Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related … cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 x 10(-9)) and TM6SF2 (P = 7.89 x 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 x 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.

Authors: S. Buch, F. Stickel, E. Trepo, M. Way, A. Herrmann, H. D. Nischalke, M. Brosch, J. Rosendahl, T. Berg, M. Ridinger, M. Rietschel, A. McQuillin, J. Frank, F. Kiefer, S. Schreiber, W. Lieb, M. Soyka, N. Semmo, E. Aigner, C. Datz, R. Schmelz, S. Bruckner, S. Zeissig, A. M. Stephan, N. Wodarz, J. Deviere, N. Clumeck, C. Sarrazin, F. Lammert, T. Gustot, P. Deltenre, H. Volzke, M. M. Lerch, J. Mayerle, F. Eyer, C. Schafmayer, S. Cichon, M. M. Nothen, M. Nothnagel, D. Ellinghaus, K. Huse, A. Franke, S. Zopf, C. Hellerbrand, C. Moreno, D. Franchimont, M. Y. Morgan, J. Hampe

Date Published: 21st Oct 2015

Publication Type: Journal

Optimality in COVID-19 vaccination strategies determined by heterogeneity in human-human interaction networks

Abstract (Expand)

Interactions between humans cause transmission of SARS-CoV-2. We demonstrate that heterogeneity in human-human interactions give rise to non-linear infection networks that gain complexity with time. … Consequently, targeted vaccination strategies are challenged as such effects are not accurately captured by epidemiological models assuming homogeneous mixing. With vaccines being prepared for global deployment determining optimality for swiftly reaching population level immunity in heterogeneous local communities world-wide is critical. We introduce a model that predicts the effect of vaccination into an ongoing COVID-19 outbreak using precision simulation of human-human interaction and infection networks. We show that simulations incorporating non-linear network complexity and local heterogeneity can enable governance with performance-quantified vaccination strategies. Vaccinating highly interactive people diminishes the risk for an infection wave, while vaccinating the elderly reduces fatalities at low population level immunity. Interestingly, a combined strategy is not better due to non-linear effects. While risk groups should be vaccinated first to minimize fatalities, significant optimality branching is observed with increasing population level immunity. Importantly, we demonstrate that regardless of immunization strategy non-pharmaceutical interventions are required to prevent ICU overload and breakdown of healthcare systems. The approach, adaptable in real-time and applicable to other viruses, provides a highly valuable platform for the current and future pandemics.

Authors: Bjoern Goldenbogen, Stephan O. Adler, Oliver Bodeit, Judith AH Wodke, Ximena Escalera-Fanjul, Aviv Korman, Maria Krantz, Lasse Bonn, Rafael U Morán-Torres, Johanna E L Haffner, Maxim Karnetzki, Ivo Maintz, Lisa Mallis, Patrick S Segelitz, Martin Seeger, Rune Linding, Edda Klipp

Date Published: No date defined

Publication Type: Unpublished

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

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