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Liver Reptin/RUVBL2 controls glucose and lipid metabolism with opposite actions on mTORC1 and mTORC2 signalling

dc.rights.licenseopenen_US
hal.structure.identifierBordeaux Research In Translational Oncology [Bordeaux] [BaRITOn]
dc.contributor.authorJAVARY, Joaquim
hal.structure.identifierBordeaux Research In Translational Oncology [Bordeaux] [BaRITOn]
dc.contributor.authorALLAIN-COURTOIS, Nathalie
dc.contributor.authorSAUCISSE, Nicolas
hal.structure.identifierUniversité de Bordeaux [UB]
dc.contributor.authorCOSTET, Pierre
hal.structure.identifierBordeaux Research In Translational Oncology [Bordeaux] [BaRITOn]
dc.contributor.authorHERAUD, Capucine
dc.contributor.authorBENHAMED, Fadila
dc.contributor.authorPIERRE, Remi
hal.structure.identifierChimie et Biologie des Membranes et des Nanoobjets [CBMN]
dc.contributor.authorBURE, Corinne
hal.structure.identifierBordeaux Research In Translational Oncology [Bordeaux] [BaRITOn]
dc.contributor.authorPALLARES-LUPON, Nestor
dc.contributor.authorDO CRUZEIRO, Marcio
dc.contributor.authorPOSTIC, Catherine
dc.contributor.authorCOTA, Daniela
hal.structure.identifierBordeaux Research In Translational Oncology [Bordeaux] [BaRITOn]
dc.contributor.authorDUBUS, Pierre
hal.structure.identifierBordeaux Research In Translational Oncology [Bordeaux] [BaRITOn]
dc.contributor.authorROSENBAUM, Jean
hal.structure.identifierBordeaux Research In Translational Oncology [Bordeaux] [BaRITOn]
dc.contributor.authorBENHAMOUCHE-TROUILLET, Samira
dc.date.accessioned2020-04-07T13:19:33Z
dc.date.available2020-04-07T13:19:33Z
dc.date.issued2018
dc.identifier.issn0017-5749en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/4149
dc.description.abstractEnObjective The AAA+ AT Pase Reptin is overexpressed in hepatocellular carcinoma and preclinical studies indicate that it could be a relevant therapeutic target. However, its physiological and pathophysiological roles in vivo remain unknown. This study aimed to determine the role of Reptin in mammalian adult liver. Design and results We generated an inducible liver-specific Reptin knockout (Repin(LKO)) mouse model. Following Reptin invalidation, mice displayed decreased body and fat mass, hypoglycaemia and hypolipidaemia. This was associated with decreased hepatic mTOR protein abundance. Further experiments in primary hepatocytes demonstrated that Reptin maintains mTOR protein level through its AT Pase activity. Unexpectedly, loss or inhibition of Reptin induced an opposite effect on mTORC1 and mTORC2 signalling, with: (1) strong inhibition of hepatic mTORC1 activity, likely responsible for the reduction of hepatocytes cell size, for decreased de novo lipogenesis and cholesterol transcriptional programmes and (2) enhancement of mTORC2 activity associated with inhibition of the gluconeogenesis transcriptional programme and hepatic glucose production. Consequently, the role of hepatic Reptin in the pathogenesis of insulin resistance (IR) and non-alcoholic fatty liver disease consecutive to a high-fat diet was investigated. We found that Reptin deletion completely rescued pathological phenotypes associated with IR, including glucose intolerance, hyperglycaemia, hyperlipidaemia and hepatic steatosis. Conclusion We show here that the AAA+ AT Pase Reptin is a regulator of mTOR signalling in the liver and global glucido-lipidic homeostasis. Inhibition of hepatic Reptin expression or activity represents a new therapeutic perspective for metabolic syndrome.
dc.description.sponsorshipInnovations instrumentales et procédurales en psychopathologie expérimentale chez le rongeur - ANR-10-EQPX-0008en_US
dc.description.sponsorshipFGF21 contrôle homéostasie glucidique via les facteurs de transcription ChREBP et PPARa - ANR-15-CE14-0026en_US
dc.language.isoENen_US
dc.title.enLiver Reptin/RUVBL2 controls glucose and lipid metabolism with opposite actions on mTORC1 and mTORC2 signalling
dc.typeArticle de revueen_US
dc.identifier.doi10.1136/gutjnl-2017-314208en_US
dc.subject.halChimie/Matériauxen_US
bordeaux.journalGuten_US
bordeaux.page2192-2203en_US
bordeaux.volume67en_US
bordeaux.hal.laboratoriesInstitut de Chimie & de Biologie des Membranes & des Nano-objets (CBMN) - UMR 5248
bordeaux.issue12en_US
bordeaux.institutionBordeaux INPen_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-02535305
hal.version1
hal.date.transferred2020-04-07T13:19:39Z
hal.exporttrue
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