title: Reducing Hepatocyte Injury and Necrosis in Response to Paracetamol Using Noncoding RNAs.
abstract: The liver performs multiple functions within the human body. It is composed of numerous cell types, which play important roles in organ physiology. Our study centers on the major metabolic cell type of the liver, the hepatocyte, and its susceptibility to damage during drug overdose. In these studies, hepatocytes were generated from a renewable and genetically defined resource. In vitro-derived hepatocytes were extensively profiled and exposed to varying levels of paracetamol and plasma isolated from liver-failure patients, with a view to identifying noncoding microRNAs that could reduce drug- or serum-induced hepatotoxicity. We identified a novel anti-microRNA, which reduced paracetamol-induced hepatotoxicity and glutathione depletion. Additionally, we identified a prosurvival role for anti-microRNA-324 following exposure to plasma collected from liver failure patients. We believe that these studies represent an important advance for the field, demonstrating the power of stem cell-derived systems to model human biology "in a dish" and identify novel noncoding microRNAs, which could be translated to the clinic in the future.
  
  
  CONCLUSIONS
  The liver performs vital functions within the human body and is composed of numerous cell types. The major metabolic cell type of the liver, the hepatocyte, is susceptible to damage during drug overdose. In these studies, hepatocytes were generated from a renewable resource and exposed to varying levels of paracetamol, with a view to identifying interventions that could reduce or attenuate drug-induced liver toxicity. A novel noncoding RNA that reduced paracetamol-induced hepatocyte toxicity was identified. These findings may represent an important advance for the field.
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Dagmara
authors.initials: D
authors.lastname: Szkolnicka
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Baltasar
authors.initials: B
authors.lastname: Lucendo-Villarin
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Joanna K
authors.initials: JK
authors.lastname: Moore
authors.affiliation: Division of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Simpson
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Forbes
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom davehay@talktalk.net.
authors.forename: David C
authors.initials: DC
authors.lastname: Hay
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000328:Adult; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000628:therapy; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000627:therapeutic use*; D009336:Necrosis / Q000235:genetics / Q000628:therapy*; D061251:Primary Cell Culture; D022661:RNA, Untranslated / Q000235:genetics / Q000627:therapeutic use*
chemical_list: C000599310:MIRN324 microRNA, human; D035683:MicroRNAs; D022661:RNA, Untranslated; D000082:Acetaminophen
keywords: Apoptosis; Drug-induced liver injury; Hepatocyte; MicroRNA; Necrosis; Paracetamol