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2 results on '"Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]"'

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

Author

Fadila Benhamed, Jean Rosenbaum, Joaquim Javary, Nicolas Saucisse, Pierre Costet, Marcio Do Cruzeiro, Corinne Buré, Capucine Heraud, Catherine Postic, Samira Benhamouche-Trouillet, Pierre Dubus, Rémi Pierre, Nestor Pallares-Lupon, Daniela Cota, Nathalie Allain-Courtois, Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM, Neurocentre Magendie, U1215, Physiopathologie de la Plasticité Neuronale, F-33000 Bordeaux, France, Université de Bordeaux (UB), Chimie et Biologie des Membranes et des Nanoobjets (CBMN), École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), ANR-10-EQPX-0008,OPTOPATH,Innovations instrumentales et procédurales en psychopathologie expérimentale chez le rongeur(2010), ANR-15-CE14-0026,Hepatokind,FGF21 contrôle homéostasie glucidique via les facteurs de transcription ChREBP et PPARa(2015), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Recombinaison Homologue, Transfert d'Embryons et Cryoconservation [Institut Cochin] (PRHTEC), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Mechanistic Target of Rapamycin Complex 2, mTORC1, Mechanistic Target of Rapamycin Complex 1, Biology, Diet, High-Fat, mTORC2, 03 medical and health sciences, Insulin resistance, Internal medicine, Glucose Intolerance, medicine, RUVBL2, Animals, ComputingMilieux_MISCELLANEOUS, PI3K/AKT/mTOR pathway, Adenosine Triphosphatases, Mice, Knockout, Lipogenesis, Body Weight, Fatty liver, DNA Helicases, Gastroenterology, [CHIM.MATE]Chemical Sciences/Material chemistry, Lipid Metabolism, medicine.disease, Fatty Liver, Disease Models, Animal, Glucose, 030104 developmental biology, Endocrinology, Liver, Hepatocytes, ATPases Associated with Diverse Cellular Activities, Insulin Resistance, Energy Metabolism, Homeostasis, Signal Transduction
Abstract

ObjectiveThe AAA+ ATPase 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 resultsWe generated an inducible liver-specific Reptin knockout (RepinLKO) 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 ATPase 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.ConclusionWe show here that the AAA +ATPase 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.

Published
2017
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2. Adeno-associated virus in the liver: natural history and consequences in tumour development

Author

Paulette Bioulac-Sage, Catherine Guettier, Sandrine Imbeaud, Valérie Paradis, Alexis Laurent, Théo Z. Hirsch, Julien Calderaro, Shalini Datta, Iadh Mami, Quentin Bayard, Jean-Frédéric Blanc, Guillaume Morcrette, Laurence Chiche, Camille Peneau, Stefano Caruso, Eric Letouzé, Tiziana La Bella, Jean-Charles Nault, Giuliana Amaddeo, Laurent Possenti, Jessica Zucman-Rossi, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pathologie [CHU Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Service d’Anatomopathologie [Le Kremlin-Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service d'Anatomopathologie [Clichy, France], Service d'hépato-gastro-entérologie [APHP Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de chirurgie digestive, Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Département de chirurgie digestive, Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Zucman-Rossi, Jessica, and Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Hôpital Henri Mondor-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, viruses, medicine.disease_cause, AAV13, Cohort Studies, 0302 clinical medicine, Child, Adeno-associated virus, Aged, 80 and over, 0303 health sciences, education.field_of_study, Liver Neoplasms, Gastroenterology, DNA virus, hepatocellular carcinoma, Dependovirus, Middle Aged, 3. Good health, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Helper virus, AAV2, Child, Preschool, Female, Adult, Carcinoma, Hepatocellular, Adolescent, Population, hepatocellular adenoma, Biology, telomerase, Virus, Insertional mutagenesis, Parvoviridae Infections, 03 medical and health sciences, Young Adult, cyclin, medicine, Humans, education, 030304 developmental biology, Aged, Infant, Newborn, Infant, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Virology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Adeno Associated Virus, Case-Control Studies, DNA, Viral, insertional mutagenesis, Carcinogenesis
Abstract

ObjectiveAdeno-associated virus (AAV) is a defective mono-stranded DNA virus, endemic in human population (35%–80%). Recurrent clonal AAV2 insertions are associated with the pathogenesis of rare human hepatocellular carcinoma (HCC) developed on normal liver. This study aimed to characterise the natural history of AAV infection in the liver and its consequence in tumour development.DesignViral DNA was quantified in tumour and non-tumour liver tissues of 1461 patients. Presence of episomal form and viral mRNA expression were analysed using a DNAse/TaqMan-based assay and quantitative RT-PCR. In silico analyses using viral capture data explored viral variants and new clonal insertions.ResultsAAV DNA was detected in 21% of the patients, including 8% of the tumour tissues, equally distributed in two major viral subtypes: one similar to AAV2, the other hybrid between AAV2 and AAV13 sequences. Episomal viral forms were found in 4% of the non-tumour tissues, frequently associated with viral RNA expression and human herpesvirus type 6, the candidate natural AAV helper virus. In 30 HCC, clonal AAV insertions were recurrently identified in CCNA2, CCNE1, TERT, TNFSF10, KMT2B and GLI1/INHBE. AAV insertion triggered oncogenic overexpression through multiple mechanisms that differ according to the localisation of the integration site.ConclusionWe provided an integrated analysis of the wild-type AAV infection in the liver with the identification of viral genotypes, molecular forms, helper virus relationship and viral integrations. Clonal AAV insertions were positive selected during HCC development on non-cirrhotic liver challenging the notion of AAV as a non-pathogenic virus.

Published
2019
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