title: Enhanced expression of c-myc in hepatocytes promotes initiation and progression of alcoholic liver disease.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Germany. Electronic address: ynevzorova@ukaachen.de.
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Nevzorova
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Germany.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Cubero
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Germany.
authors.forename: Fengjie
authors.initials: F
authors.lastname: Hao
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Haas
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Germany.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Ramadori
authors.affiliation: Institute of Pathology, Klinikum Braunschweig, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.affiliation: Electron Microscopic Facility, Medical Faculty, University Hospital RWTH, Aachen, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Hoss
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Germany; Interdisciplinary Center for Clinical Research (IZKF) Aachen, Germany.
authors.forename: Pavel
authors.initials: P
authors.lastname: Strnad
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Germany.
authors.forename: Henning W
authors.initials: HW
authors.lastname: Zimmermann
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Germany. Electronic address: cliedtke@ukaachen.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Liedtke
mesh_terms: D000818:Animals; D002453:Cell Cycle; D018450:Disease Progression; D059865:Endoplasmic Reticulum Stress; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D016259:Genes, myc / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000209:etiology*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D005230:Fatty Acids, Nonesterified; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt
keywords: Cell cycle regulation; Ethanol; Lieber-DeCarli diet; ROS; p53