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70 Publications visible to you, out of a total of 70
BMP-9 interferes with liver regeneration and promotes liver fibrosis.

Abstract (Expand)

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

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

Date Published: 23rd Mar 2017

Publication Type: Not specified

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

Abstract

Not specified

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

Date Published: 1st Mar 2017

Publication Type: Not specified

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

Abstract (Expand)

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

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

Date Published: 23rd Feb 2017

Publication Type: Not specified

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

Abstract

Not specified

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

Date Published: 2017

Publication Type: Not specified

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

Abstract (Expand)

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

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

Date Published: 18th Nov 2016

Publication Type: Not specified

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

Abstract (Expand)

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

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

Date Published: 1st Oct 2016

Publication Type: Not specified

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

Abstract

Not specified

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

Date Published: 1st Jul 2016

Publication Type: Not specified

Evolving Insights on Metabolism, Autophagy, and Epigenetics in Liver Myofibroblasts.

Abstract (Expand)

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

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

Date Published: 18th Jun 2016

Publication Type: Not specified

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

Abstract

Not specified

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

Date Published: 17th Jun 2016

Publication Type: Not specified

TGF-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

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