Yulia A Nevzorova1, Francisco J Cubero2, Wei Hu2, Fengjie Hao2, Ute Haas2, Pierluigi Ramadori2, Nikolaus Gassler3, Mareike Hoss4, Pavel Strnad5, Henning W Zimmermann2, Frank Tacke2, Christian Trautwein2, Christian Liedtke6. 1. Department of Internal Medicine III, University Hospital RWTH Aachen, Germany. Electronic address: ynevzorova@ukaachen.de. 2. Department of Internal Medicine III, University Hospital RWTH Aachen, Germany. 3. Institute of Pathology, Klinikum Braunschweig, Germany. 4. Electron Microscopic Facility, Medical Faculty, University Hospital RWTH, Aachen, Germany. 5. Department of Internal Medicine III, University Hospital RWTH Aachen, Germany; Interdisciplinary Center for Clinical Research (IZKF) Aachen, Germany. 6. Department of Internal Medicine III, University Hospital RWTH Aachen, Germany. Electronic address: cliedtke@ukaachen.de.
Abstract
BACKGROUND & AIMS: Progression of alcoholic liver disease (ALD) can be influenced by genetic factors, which potentially include specific oncogenes and tumor suppressors. In the present study, we tested the hypothesis that aberrant expression of the proto-oncogene c-myc might exert a crucial role in the development of ALD. METHODS: Expression of c-myc was measured in biopsies of patients with ALD by quantitative real-time PCR and immunohistochemistry. Mice with transgenic expression of c-myc in hepatocytes (alb-myc(tg)) and wild-type (WT) controls were fed either control or ethanol (EtOH) containing Lieber-DeCarli diet for 4weeks to induce ALD. RESULTS: Hepatic c-myc was strongly upregulated in human patients with advanced ALD and in EtOH-fed WT mice. Transcriptome analysis indicated deregulation of pathways involved in ER-stress, p53 signaling, hepatic fibrosis, cell cycle regulation, ribosomal synthesis and glucose homeostasis in EtOH-fed alb-myc(tg) mice. Transgenic expression of c-myc in hepatocytes with simultaneous EtOH-uptake led to early ballooning degeneration, increased liver collagen deposition and hepatic lipotoxicity, together with excessive CYP2E1-derived reactive oxygen species (ROS) production. Moreover, EtOH-fed alb-myc(tg) mice exhibited substantial changes in mitochondrial morphology associated with energy dysfunction. Pathway analysis revealed that elevated c-myc expression and ethanol uptake synergistically lead to strong AKT activation, Mdm2 phosphorylation and as a consequence to inhibition of p53. CONCLUSIONS: Expression of c-myc and EtOH-uptake synergistically accelerate the progression of ALD most likely due to loss of p53-dependent protection. Thus, c-myc is a new potential marker for the early detection of ALD and identification of risk patients.
BACKGROUND & AIMS: Progression of alcoholic liver disease (ALD) can be influenced by genetic factors, which potentially include specific oncogenes and tumor suppressors. In the present study, we tested the hypothesis that aberrant expression of the proto-oncogene c-myc might exert a crucial role in the development of ALD. METHODS: Expression of c-myc was measured in biopsies of patients with ALD by quantitative real-time PCR and immunohistochemistry. Mice with transgenic expression of c-myc in hepatocytes (alb-myc(tg)) and wild-type (WT) controls were fed either control or ethanol (EtOH) containing Lieber-DeCarli diet for 4weeks to induce ALD. RESULTS: Hepatic c-myc was strongly upregulated in humanpatients with advanced ALD and in EtOH-fed WT mice. Transcriptome analysis indicated deregulation of pathways involved in ER-stress, p53 signaling, hepatic fibrosis, cell cycle regulation, ribosomal synthesis and glucose homeostasis in EtOH-fed alb-myc(tg) mice. Transgenic expression of c-myc in hepatocytes with simultaneous EtOH-uptake led to early ballooning degeneration, increased liver collagen deposition and hepatic lipotoxicity, together with excessive CYP2E1-derived reactive oxygen species (ROS) production. Moreover, EtOH-fed alb-myc(tg) mice exhibited substantial changes in mitochondrial morphology associated with energy dysfunction. Pathway analysis revealed that elevated c-myc expression and ethanol uptake synergistically lead to strong AKT activation, Mdm2 phosphorylation and as a consequence to inhibition of p53. CONCLUSIONS: Expression of c-myc and EtOH-uptake synergistically accelerate the progression of ALD most likely due to loss of p53-dependent protection. Thus, c-myc is a new potential marker for the early detection of ALD and identification of risk patients.
Authors: Tunde Akinyeke; Sydney J Weber; April T Davenport; Erich J Baker; James B Daunais; Jacob Raber Journal: Behav Brain Res Date: 2016-11-08 Impact factor: 3.332
Authors: Mustafa A Barbhuiya; Adam C Mirando; Brian W Simons; Ghali Lemtiri-Chlieh; Jordan J Green; Aleksander S Popel; Niranjan B Pandey; Phuoc T Tran Journal: Oncotarget Date: 2017-09-21
Authors: Pierluigi Ramadori; Francisco Javier Cubero; Christian Liedtke; Christian Trautwein; Yulia A Nevzorova Journal: Cancers (Basel) Date: 2017-09-25 Impact factor: 6.639
Authors: Fengjie Hao; Francisco Javier Cubero; Pierluigi Ramadori; Lijun Liao; Ute Haas; Daniela Lambertz; Roland Sonntag; Jörg-Martin Bangen; Nikolaus Gassler; Mareike Hoss; Konrad L Streetz; Johanna Reissing; Henning W Zimmermann; Christian Trautwein; Christian Liedtke; Yulia A Nevzorova Journal: Cell Death Dis Date: 2017-10-26 Impact factor: 8.469