title: Hepatocyte glutathione peroxidase-1 deficiency improves hepatic glucose metabolism and decreases steatohepatitis in mice.
abstract: In obesity oxidative stress is thought to contribute to the development of insulin resistance, non-alcoholic fatty liver disease and the progression to non-alcoholic steatohepatitis. Our aim was to examine the precise contributions of hepatocyte-derived H2O2to liver pathophysiology.
  
  
  
  Glutathione peroxidase (GPX) 1 is an antioxidant enzyme that is abundant in the liver and converts H2O2to water. We generated Gpx1lox/loxmice to conditionally delete Gpx1 in hepatocytes (Alb-Cre;Gpx1lox/lox) and characterised mice fed chow, high-fat or choline-deficient amino-acid-defined (CDAA) diets.
  
  
  
  Chow-fed Alb-Cre;Gpx1lox/loxmice did not exhibit any alterations in body composition or energy expenditure, but had improved insulin sensitivity and reduced fasting blood glucose. This was accompanied by decreased gluconeogenic and increased glycolytic gene expression as well as increased hepatic glycogen. Hepatic insulin receptor Y1163/Y1163 phosphorylation and Akt Ser-473 phosphorylation were increased in fasted chow-fed Alb-Cre;Gpx1lox/loxmice, associated with increased H2O2production and insulin signalling in isolated hepatocytes. The enhanced insulin signalling was accompanied by the increased oxidation of hepatic protein tyrosine phosphatases previously implicated in the attenuation of insulin signalling. High-fat-fed Alb-Cre;Gpx1lox/loxmice did not exhibit alterations in weight gain or hepatosteatosis, but exhibited decreased hepatic inflammation, decreased gluconeogenic gene expression and increased insulin signalling in the liver. Alb-Cre;Gpx1lox/loxmice fed a CDAA diet that promotes non-alcoholic steatohepatitis exhibited decreased hepatic lymphocytic infiltrates, inflammation and liver fibrosis.
  
  
  
  Increased hepatocyte-derived H2O2enhances hepatic insulin signalling, improves glucose control and protects mice from the development of non-alcoholic steatohepatitis.
authors.affiliation: Metabolic Disease and Obesity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia.|Faculty of Medical and Health Sciences, The University of Auckland, Aukland, New Zealand.
authors.forename: Troy L
authors.initials: TL
authors.lastname: Merry
authors.affiliation: Metabolic Disease and Obesity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Tran
authors.affiliation: Metabolic Disease and Obesity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia.
authors.forename: Garron T
authors.initials: GT
authors.lastname: Dodd
authors.affiliation: Department of Medicine (Austin Hospital), The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Salvatore P
authors.initials: SP
authors.lastname: Mangiafico
authors.affiliation: Metabolic Disease and Obesity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia.
authors.forename: Florian
authors.initials: F
authors.lastname: Wiede
authors.affiliation: Metabolic Disease and Obesity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia.
authors.forename: Supreet
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Department of Anatomical Pathology, Alfred Hospital, Prahran, VIC, Australia.
authors.forename: Catriona L
authors.initials: CL
authors.lastname: McLean
authors.affiliation: Department of Medicine (Austin Hospital), The University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Sofianos
authors.initials: S
authors.lastname: Andrikopoulos
authors.affiliation: Metabolic Disease and Obesity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia. Tony.Tiganis@monash.edu.
authors.forename: Tony
authors.initials: T
authors.lastname: Tiganis
mesh_terms: D000483:Alleles; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000172:deficiency* / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000201:enzymology* / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
chemical_list: D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D017027:Protein Tyrosine Phosphatases; D005947:Glucose; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse
keywords: Fibrosis; Glutathione peroxidase-1; Hepatocyte; Inflammation; Insulin resistance; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; Protein tyrosine phosphatase; Reactive oxygen species; Type 2 diabetes