title: Global Transcriptional Response of Human Liver Cells to Ethanol Stress of Different Strength Reveals Hormetic Behavior.
abstract: 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.affiliation: Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute (HKI), Jena, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schmidt-Heck
authors.affiliation: Bioreactor Group , Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Eva C
authors.initials: EC
authors.lastname: Wönne
authors.affiliation: Bioreactor Group , Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hiller
authors.affiliation: Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute (HKI), Jena, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Menzel
authors.affiliation: Institute for Immunology , University of Rostock, Rostock, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Koczan
authors.affiliation: Department of General, Visceral and Transplantation Surgery , Charité - Universitätsmedizin Berlin, Berlin, Germany.|Department of Hepatobiliary Surgery and Visceral Transplantation , University of Leipzig, Leipzig, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Damm
authors.affiliation: Department of General, Visceral and Transplantation Surgery , Charité - Universitätsmedizin Berlin, Berlin, Germany.|Department of Hepatobiliary Surgery and Visceral Transplantation , University of Leipzig, Leipzig, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Seehofer
authors.affiliation: Bioreactor Group , Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Fanny
authors.initials: F
authors.lastname: Knöspel
authors.affiliation: Bioreactor Group , Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Freyer
authors.affiliation: Leibniz Institute for Natural Product Research and Infection Biology - Hans-Knöll-Institute (HKI), Jena, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Guthke
authors.affiliation: II. Medizinische Klinik, Medizinische Fakultät Mannheim , Universität Heidelberg, Mannheim, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.affiliation: Bioreactor Group , Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Katrin
authors.identifier: http://orcid.org/0000-0001-8448-2470
authors.initials: K
authors.lastname: Zeilinger
mesh_terms: D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology
chemical_list: D000431:Ethanol
keywords: Bioreactor; Ethanol Stress; Hormesis; Human Hepatocytes; Transcriptome