title: Variable responses of small and large human hepatocytes to hypoxia and hypoxia/reoxygenation (H-R).
abstract: Hypoxia and hypoxia-reoxygenation (H-R) regulate human hepatocyte cell death by mediating the accumulation of reactive oxygen species (ROS). Hepatocytes within the liver are organised into peri-portal (PP) and peri-venous (PV) subpopulations. PP and PV hepatocytes differ in size and function. We investigated whether PP and PV human hepatocytes exhibit differential susceptibility to hypoxic stress. Isolated hepatocytes were used in an in vitro model of hypoxia and H-R. ROS production and cell death were assessed using flow cytometry. PV, and not PP hepatocytes, accumulate intracellular ROS in a mitochondrial dependent manner during hypoxia and H-R. This increased ROS regulates hepatocyte apoptosis and necrosis via a mitochondrial pathway. These findings have implications on the understanding of liver injury and application of potential therapeutic strategies.
authors.affiliation: Centre for Liver Research, School of Infection and Immunity, Institute of Biomedical Research, The Medical School, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. balsin@hotmail.com
authors.forename: Ricky H
authors.initials: RH
authors.lastname: Bhogal
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Weston
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Curbishley
authors.forename: Anand N
authors.initials: AN
authors.lastname: Bhatt
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
authors.forename: Simon C
authors.initials: SC
authors.lastname: Afford
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia; D048429:Cell Size; D002478:Cells, Cultured; D005434:Flow Cytometry; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis; D010100:Oxygen / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D012402:Rotenone; D010100:Oxygen