Hepatocyte glutathione peroxidase-1 deficiency improves hepatic glucose metabolism and decreases steatohepatitis in mice

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dc.contributor.author Merry, Troy en
dc.contributor.author Tran, M en
dc.contributor.author Dodd, GT en
dc.contributor.author Mangiafico, SP en
dc.contributor.author Wiede, F en
dc.contributor.author Kaur, S en
dc.contributor.author McLean, CL en
dc.contributor.author Andrikopoulos, S en
dc.contributor.author Tiganis, T en
dc.date.accessioned 2017-05-04T04:17:44Z en
dc.date.issued 2016-12 en
dc.identifier.citation Diabetologia 59(12):2632-2644 Dec 2016 en
dc.identifier.issn 0012-186X en
dc.identifier.uri http://hdl.handle.net/2292/32769 en
dc.description.abstract Aims/hypothesis: 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 H2O2 to liver pathophysiology. Methods: Glutathione peroxidase (GPX) 1 is an antioxidant enzyme that is abundant in the liver and converts H2O2 to water. We generated Gpx1lox/lox mice 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. Results: Chow-fed Alb-Cre;Gpx1lox/lox mice 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/lox mice, associated with increased H2O2 production 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/lox mice 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/lox mice fed a CDAA diet that promotes non-alcoholic steatohepatitis exhibited decreased hepatic lymphocytic infiltrates, inflammation and liver fibrosis. Conclusions/interpretation: Increased hepatocyte-derived H2O2 enhances hepatic insulin signalling, improves glucose control and protects mice from the development of non-alcoholic steatohepatitis. en
dc.publisher Springer Verlag en
dc.relation.ispartofseries Diabetologia en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.title Hepatocyte glutathione peroxidase-1 deficiency improves hepatic glucose metabolism and decreases steatohepatitis in mice en
dc.type Journal Article en
dc.identifier.doi 10.1007/s00125-016-4084-3 en
pubs.issue 12 en
pubs.begin-page 2632 en
pubs.volume 59 en
dc.rights.holder Copyright: Springer Verlag en
dc.identifier.pmid 27628106 en
pubs.end-page 2644 en
pubs.publication-status Published en
dc.rights.accessrights http://purl.org/eprint/accessRights/RestrictedAccess en
pubs.subtype Article en
pubs.elements-id 542362 en
pubs.org-id Medical and Health Sciences en
pubs.org-id Medical Sciences en
pubs.org-id Nutrition en
dc.identifier.eissn 1432-0428 en
pubs.record-created-at-source-date 2017-05-04 en
pubs.online-publication-date 2016-09-15 en
pubs.dimensions-id 27628106 en

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