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In this study, we investigated the in\u00a0vitro response of human liver cells to different EtOH concentrations in a perfused bioartificial liver device that mimics the complex architecture of the natural organ.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Primary human liver cells were cultured in the bioartificial liver device and treated for 24\u00a0hours with medium containing 150\u00a0mM (low), 300\u00a0mM (medium), or 600\u00a0mM (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\u2010means algorithm. In addition, functional classification methods, KEGG pathway mapping and also a machine learning approach (Random Forest) were utilized.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A number of 966 (150\u00a0mM EtOH), 1,334 (300\u00a0mM EtOH), or 4,132 (600\u00a0mM EtOH) genes were found to be differentially expressed. Dose\u2013response relationships of the identified clusters of co\u2010expressed 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 \u201ccellular ketone metabolism\u201d and \u201ccarboxylic acid metabolism.\u201d Altered expression of the genes <jats:italic>BAHD1<\/jats:italic> and <jats:italic>H3F3B<\/jats:italic> was identified as sufficient to classify the samples according to the applied EtOH doses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.13361","type":"journal-article","created":{"date-parts":[[2017,2,22]],"date-time":"2017-02-22T20:12:43Z","timestamp":1487794363000},"page":"883-894","source":"Crossref","is-referenced-by-count":8,"title":["Global Transcriptional Response of Human Liver Cells to Ethanol Stress of Different Strength Reveals Hormetic Behavior"],"prefix":"10.1111","volume":"41","author":[{"given":"Wolfgang","family":"Schmidt\u2010Heck","sequence":"first","affiliation":[{"name":"Leibniz Institute for Natural Product Research and Infection Biology \u2013 Hans\u2010Kn\u00f6ll\u2010Institute (HKI) Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva C.","family":"W\u00f6nne","sequence":"additional","affiliation":[{"name":"Bioreactor Group  Berlin\u2010Brandenburg Center for Regenerative Therapies (BCRT) Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Hiller","sequence":"additional","affiliation":[{"name":"Bioreactor Group  Berlin\u2010Brandenburg Center for Regenerative Therapies (BCRT) Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Menzel","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Natural Product Research and Infection Biology \u2013 Hans\u2010Kn\u00f6ll\u2010Institute (HKI) Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Koczan","sequence":"additional","affiliation":[{"name":"Institute for Immunology  University of Rostock Rostock Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Damm","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery  Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin Berlin Germany"},{"name":"Department of Hepatobiliary Surgery and Visceral Transplantation  University of Leipzig Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Seehofer","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery  Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin Berlin Germany"},{"name":"Department of Hepatobiliary Surgery and Visceral Transplantation  University of Leipzig Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny","family":"Kn\u00f6spel","sequence":"additional","affiliation":[{"name":"Bioreactor Group  Berlin\u2010Brandenburg Center for Regenerative Therapies (BCRT) Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora","family":"Freyer","sequence":"additional","affiliation":[{"name":"Bioreactor Group  Berlin\u2010Brandenburg Center for Regenerative Therapies (BCRT) Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard","family":"Guthke","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Natural Product Research and Infection Biology \u2013 Hans\u2010Kn\u00f6ll\u2010Institute (HKI) Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Dooley","sequence":"additional","affiliation":[{"name":"II. 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