title: Autotaxin-lysophosphatidic acid receptor signalling regulates hepatitis C virus replication.
abstract: Chronic hepatitis C is a global health problem with an estimated 170 million hepatitis C virus (HCV) infected individuals at risk of progressive liver disease and hepatocellular carcinoma (HCC). Autotaxin (ATX, gene name: ENPP2) is a phospholipase with diverse roles in the physiological and pathological processes including inflammation and oncogenesis. Clinical studies have reported increased ATX expression in chronic hepatitis C, however, the pathways regulating ATX and its role in the viral life cycle are not well understood.
  
  
  
  In vitro hepatocyte and ex vivo liver culture systems along with chimeric humanized liver mice and HCC tissue enabled us to assess the interplay between ATX and the HCV life cycle.
  
  
  
  HCV infection increased hepatocellular ATX RNA and protein expression. HCV infection stabilizes hypoxia inducible factors (HIFs) and we investigated a role for these transcription factors to regulate ATX. In vitro studies show that low oxygen increases hepatocellular ATX expression and transcriptome analysis showed a positive correlation between ATX mRNA levels and hypoxia gene score in HCC tumour tissue associated with HCV and other aetiologies. Importantly, inhibiting ATX-lysophosphatidic acid (LPA) signalling reduced HCV replication, demonstrating a positive role for this phospholipase in the viral life cycle. LPA activates phosphoinositide-3-kinase that stabilizes HIF-1α and inhibiting the HIF signalling pathway abrogates the pro-viral activity of LPA.
  
  
  
  Our data support a model where HCV infection increases ATX expression which supports viral replication and HCC progression.
  
  
  
  Chronic hepatitis C is a global health problem with infected individuals at risk of developing liver disease that can progress to hepatocellular carcinoma. Autotaxin generates the biologically active lipid lysophosphatidic acid that has been reported to play a tumorigenic role in a wide number of cancers. In this study we show that hepatitis C virus infection increases autotaxin expression via hypoxia inducible transcription factor and provides an environment in the liver that promotes fibrosis and liver injury. Importantly, we show a new role for lysophosphatidic acid in positively regulating hepatitis C virus replication.
authors.affiliation: Viral Hepatitis Laboratory, Centre for Human Virology, University of Birmingham, UK.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Farquhar
authors.affiliation: Viral Hepatitis Laboratory, Centre for Human Virology, University of Birmingham, UK.
authors.forename: Isla S
authors.initials: IS
authors.lastname: Humphreys
authors.affiliation: The Babraham Institute, Cambridge, UK.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Rudge
authors.affiliation: Viral Hepatitis Laboratory, Centre for Human Virology, University of Birmingham, UK.
authors.forename: Garrick K
authors.initials: GK
authors.lastname: Wilson
authors.affiliation: Viral Hepatitis Laboratory, Centre for Human Virology, University of Birmingham, UK.
authors.forename: Bishnupriya
authors.initials: B
authors.lastname: Bhattacharya
authors.affiliation: The Babraham Institute, Cambridge, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Ciaccia
authors.affiliation: Viral Hepatitis Laboratory, Centre for Human Virology, University of Birmingham, UK.
authors.forename: Ke
authors.initials: K
authors.lastname: Hu
authors.affiliation: The Babraham Institute, Cambridge, UK.
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: INSERM U1110, University of Strasbourg, 3 Rue Koeberlé, F-67000 Strasbourg, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mailly
authors.affiliation: NIHR Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Reynolds
authors.affiliation: Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Ashcroft
authors.affiliation: Viral Hepatitis Laboratory, Centre for Human Virology, University of Birmingham, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Balfe
authors.affiliation: INSERM U1110, University of Strasbourg, 3 Rue Koeberlé, F-67000 Strasbourg, France.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Roessler
authors.affiliation: The Babraham Institute, Cambridge, UK.
authors.forename: Michael J O
authors.initials: MJO
authors.lastname: Wakelam
authors.affiliation: Viral Hepatitis Laboratory, Centre for Human Virology, University of Birmingham, UK. Electronic address: jane.mckeating@ndm.ox.ac.uk.
authors.forename: Jane A
authors.initials: JA
authors.lastname: McKeating
mesh_terms: D000818:Animals; D002460:Cell Line; D016174:Hepacivirus / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000150:complications; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D008113:Liver Neoplasms / Q000209:etiology; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D049368:Receptors, Lysophosphatidic Acid / Q000502:physiology*; D015398:Signal Transduction; D014779:Virus Replication; D000099189:Lysophospholipase D
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010727:Phosphoric Diester Hydrolases; D012333:RNA, Messenger; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D; C497442:HIF1A protein, human
keywords: Autotaxin; Hepatitis C virus; Hypoxia; Hypoxia-Inducible Factor 1, alpha subunit; Lipid signalling; Lysophosphatidic acid