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5 results on '"MESH : Adenoviridae"'

1. Coagulation factor X mediates adenovirus type 5 liver gene transfer in non-human primates (Microcebus murinus)

Author

Nadine Mestre-Francés, Angela C. Bradshaw, Daniel Henaff, Andrew H. Baker, Raul Alba, Jean-Michel Verdier, British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université Montpellier 2 - Sciences et Techniques (UM2)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the European Commission FP7 BRAINCAV programme., European Project: 222992,EC:FP7:HEALTH,FP7-HEALTH-2007-B,BRAINCAV(2008), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Mécanismes moléculaires dans les démences neurodégénératives ( MMDN ), École pratique des hautes études ( EPHE ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université de Montpellier ( UM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ), European Project : 222992,EC:FP7:HEALTH,FP7-HEALTH-2007-B,BRAINCAV ( 2008 ), Université Montpellier 2 - Sciences et Techniques (UM2)-École pratique des hautes études (EPHE), Verdier, Jean-Michel, and NONHUMAN ADENOVIRUS VECTORS FOR GENE TRANSFER TO THE BRAIN - BRAINCAV - - EC:FP7:HEALTH2008-10-01 - 2013-03-31 - 222992 - VALID

Subjects
Liver cytology, MESH: Spleen, MESH : Immunohistochemistry, viruses, MESH: Factor X, MESH : Hepatocytes, MESH: Gene Targeting, medicine.disease_cause, MESH: Hepatocytes, chemistry.chemical_compound, Transduction (genetics), 0302 clinical medicine, MESH: Genetic Vectors, MESH: Animals, 0303 health sciences, biology, Factor X, Gene Transfer Techniques, Gene targeting, MESH : Protein Binding, MESH: Adenoviridae, Immunohistochemistry, MESH : Genetic Vectors, 3. Good health, MESH : Factor X, medicine.anatomical_structure, Liver, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030220 oncology & carcinogenesis, Hepatocyte, Gene Targeting, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Molecular Medicine, MESH: Cheirogaleidae, MESH: Genome, Viral, Cheirogaleidae, MESH : Gene Therapy, MESH : Genome, Viral, MESH : Heparan Sulfate Proteoglycans, Protein Binding, MESH : Spleen, Microcebus murinus, MESH : Cell Membrane, Genetic Vectors, Spleen, MESH: Gene Transfer Techniques, Genome, Viral, Article, Adenoviridae, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, MESH: Protein Binding, Animals, MESH : Adenoviridae, MESH : Gene Transfer Techniques, Molecular Biology, 030304 developmental biology, MESH : Cheirogaleidae, Cell Membrane, MESH : Liver, MESH: Immunohistochemistry, Genetic Therapy, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Molecular biology, chemistry, MESH: Heparan Sulfate Proteoglycans, Hepatocytes, MESH : Animals, MESH: Gene Therapy, MESH : Gene Targeting, Heparan Sulfate Proteoglycans, MESH: Liver, MESH: Cell Membrane
Abstract

International audience; Coagulation factor X (FX)-binding ablated adenovirus type 5 (Ad5) vectors have been genetically engineered to ablate the interaction with FX, resulting in substantially reduced hepatocyte transduction following intravenous administration in rodents. Here, we quantify viral genomes and gene transfer mediated by Ad5 and FX-binding-ablated Ad5 vectors in non-human primates. Ad5 vectors accumulated in and mediated gene transfer predominantly to the liver, whereas FX-binding-ablated vectors primarily targeted the spleen but showed negligible liver gene transfer. In addition, we show that Ad5 binding to hepatocytes may be due to the presence of heparan sulfate proteoglycans (HSPGs) on the cell membrane. Therefore, the Ad5-FX-HSPG pathway mediating liver gene transfer in rodents is also the mechanism underlying Ad5 hepatocyte transduction in Microcebus murinus.

Published
2011

2. Adenovirus 5-fiber 35 chimeric vector mediates efficient apical correction of the cystic fibrosis transmembrane conductance regulator defect in cystic fibrosis primary airway epithelia

Author

Nagy A. Habib, Philip H. Karp, Frédéric Becq, Gaëlle Gonzalez, Pierre Boulanger, Joseph Zabner, Patricia Melin, Caroline Norez, Maria K. Magnusson, Petra Henning, Leif Lindholm, Saw-See Hong, Ophélia Granio, Katherine J. D. A. Excoffon, Virologie et Pathologie Humaine (VirPath), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Medicine, University of Iowa [Iowa City], Department of Microbiology and Immunology, University of Gothenburg (GU), Got-a-Gene AB, Got-A-Gene AB, Institut de physiologie et biologie cellulaires (IPBC), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Department of Surgical Oncology and Technology [London], Imperial College London, French Cystic Fibrosis Foundation, VLM, CNRS, University of Lyon I, Hospices Civils de Lyon, Virologie et Pathologie Humaine ( VirPath ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), University of Iowa [Iowa], University of Gothenburg ( GU ), Institut de physiologie et biologie cellulaires ( IPBC ), Université de Poitiers-Centre National de la Recherche Scientifique ( CNRS ), and École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
Integrins, MESH : RNA, Messenger, MESH : Respiratory Mucosa, MESH : Blotting, Western, MESH : Green Fluorescent Proteins, Cystic fibrosis, 0302 clinical medicine, MESH : Chlorides, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Cells, Cultured, MESH: Capsid Proteins, 0303 health sciences, Adenoviridae/*genetics, Gene Transfer Techniques, MESH : Reverse Transcriptase Polymerase Chain Reaction, MESH: Adenoviridae, MESH: Integrins, Endocytosis, MESH : Genetic Vectors, 3. Good health, Cell biology, 030220 oncology & carcinogenesis, Chloride channel, MESH : Transgenes, MESH : Integrins, MESH : Gene Therapy, MESH: Cells, Cultured, MESH : Endocytosis, Blotting, Western, MESH: Gene Transfer Techniques, Adenoviridae, 03 medical and health sciences, MESH: Green Fluorescent Proteins, MESH : Cystic Fibrosis, Genetics, Humans, MESH: Blotting, Western, RNA, Messenger, MESH : Gene Transfer Techniques, MESH: Chlorides, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, MESH: Humans, MESH : Cystic Fibrosis Transmembrane Conductance Regulator, MESH : Humans, MESH: Adult, medicine.disease, Virology, respiratory tract diseases, Mutation, Capsid Proteins, [ SDV.MHEP.PSR ] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Cystic Fibrosis, Genetic enhancement, MESH : Capsid Proteins, Cystic Fibrosis Transmembrane Conductance Regulator, medicine.disease_cause, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Transduction (genetics), MESH: Genetic Vectors, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Respiratory Mucosa, Transgenes, MESH: Cystic Fibrosis Transmembrane Conductance Regulator, biology, Reverse Transcriptase Polymerase Chain Reaction, MESH : Adult, respiratory system, Cystic fibrosis transmembrane conductance regulator, MESH: Endocytosis, Molecular Medicine, MESH : Mutation, MESH: Genome, Viral, MESH : Genome, Viral, Adult, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Mutation, MESH: Cystic Fibrosis, Genetic Vectors, Green Fluorescent Proteins, MESH: Transgenes, Genome, Viral, Respiratory Mucosa, Chlorides, MESH : Cells, Cultured, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Adenoviridae, 030304 developmental biology, MESH: RNA, Messenger, [ SDV.SP.PHARMA ] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Genetic Therapy, biology.organism_classification, Mastadenovirus, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Gene Therapy, Ex vivo
Abstract

IF : 4,104; International audience; In vivo gene transfer to the human respiratory tract by adenovirus serotype 5 (Ad5) vectors has revealed their limitations related to inefficient gene transfer, host antiviral response, and innate adenoviral toxicity. In the present work, we compared the cytotoxicity and efficiency of Ad5 and a chimeric Ad5F35 vector with respect to CFTR gene transfer to cystic fibrosis (CF) and non-CF human airway epithelial cells. We found that high doses of Ad5 vector had an adverse effect on the function of exogenous and endogenous CFTR. Results obtained with Ad5 capsid mutants suggested that the RGD motifs on the penton base capsomers were responsible for the negative effect on CFTR function. This negative interference did not result from a lower level of biosynthesis and/or altered cellular trafficking of the CFTR protein, but rather from an indirect mechanism of functional blockage of CFTR, related to the RGD integrin-mediated endocytic pathway of Ad5. No negative interference with CFTR was observed for Ad5F35, an Ad5-based vector pseudotyped with fibers from Ad35, a serotype that uses another cell entry pathway. In vitro, Ad5F35 vector expressing the GFP-tagged CFTR (Ad5F35-GFP-CFTR) showed a 30-fold higher efficiency of transduction and chloride channel correction in CFTR-deficient cells, compared with Ad5GFP-CFTR. Ex vivo, Ad5F35-GFP-CFTR had the capacity to transduce efficiently reconstituted airway epithelia from patients with CF (CF-HAE) via the apical surface, restored chloride channel function at relatively low vector doses, and showed relatively stable expression of GFP-CFTR for several weeks.

Published
2010

3. Interactions between human plasma components and a xenogenic adenovirus vector: reduced immunogenicity during gene transfer

Author

Marie-Christine Guérin, Matthieu Perreau, Eric J. Kremer, Christian Drouet, Centre de recherche d'histoire quantitative ( CRHQ ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), GREPI, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications [Grenoble] ( TIMC-IMAG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut polytechnique de Grenoble - Grenoble Institute of Technology ( Grenoble INP ) -IMAG-Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Automatic mesh generation and advanced methods ( Gamma3 ), Institut Charles Delaunay ( ICD ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Technologie de Troyes ( UTT ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Technologie de Troyes ( UTT ) -Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National de Recherche en Informatique et en Automatique ( Inria ), Centre de recherche d'histoire quantitative (CRHQ), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Institut de Génétique Moléculaire de Montpellier (IGMM), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)

Subjects
MESH: Signal Transduction, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Genetic enhancement, Ribosome Inactivating Proteins, MESH : Ribosome Inactivating Proteins, MESH: Cross Reactions, 0302 clinical medicine, MESH: Genetic Vectors, MESH: Immunogenetics, Transduction, Genetic, Drug Discovery, MESH: Blood Proteins, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Vector (molecular biology), [INFO.INFO-BT]Computer Science [cs]/Biotechnology, MESH: Ribosome Inactivating Proteins, MESH: Immunoglobulin G, 0303 health sciences, biology, Immunogenicity, MESH : Cross Reactions, MESH: Adenoviridae, Blood Proteins, MESH: Plant Lectins, Acquired immune system, MESH: Transduction, Genetic, MESH : Plant Lectins, MESH: Antibody Formation, MESH : Genetic Vectors, 3. Good health, 030220 oncology & carcinogenesis, cardiovascular system, Molecular Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, Plant Lectins, [ INFO.INFO-BT ] Computer Science [cs]/Biotechnology, Signal Transduction, MESH : Blood Proteins, MESH : Immunoglobulin G, Transgene, Genetic Vectors, MESH : Transduction, Genetic, Cross Reactions, MESH : Antibody Formation, Viral vector, Adenoviridae, 03 medical and health sciences, Genetics, Immunogenetics, Humans, MESH : Adenoviridae, Molecular Biology, 030304 developmental biology, Pharmacology, MESH : Signal Transduction, MESH : Immunogenetics, MESH: Humans, MESH : Humans, [ SDV.BIO ] Life Sciences [q-bio]/Biotechnology, Virology, Complement system, Immunoglobulin G, Antibody Formation, biology.protein
Abstract

International audience; By the time we are adolescents most of us have been in contact with several of the >50 human adenovirus (HAd) serotypes. These common subclinical infections lead to an efficient anti-adenovirus cross-reacting adaptive immunity. During gene therapy, the ubiquitous anti-adenovirus humoral response and complement activation will modify and dictate vector biodistribution, as well as the response to the virion and transgene(s). In this study, we assayed the interactions of a xenogenic adenovirus derived from canine serotype 2 (CAV-2) with naturally occurring human antibodies (Abs) and the complement system. In our cohort, we found class G immunoglobulins (Igs) that recognized the intact CAV-2 virion and the external virion proteins. However, the majority of donors had low or no neutralizing Abs, class A, or class M Igs. Purified anti-HAd serotype 5 Abs also recognized CAV-2 virion proteins. In addition, in spite of the presence of anti-CAV-2 IgGs, CAV-2 poorly activated the classical and alternative complement cascades. This atypical response was due to a block upstream of the component 3 (C3) convertase and interplay between the component 1 (C1) inhibitor, the C1q-C1r2-C1s2 complex and CAV-2. Our data demonstrate that some xenogenic adenovirus vectors, like CAV-2, could lead to notably different outcomes following systemic delivery.

Published
2007

4. Controlling TRAIL-mediated caspase-3 activation

Author

Delphine Merino, Olivier Micheau, Mort cellulaire et cancer, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Micheau, Olivier

Subjects
Cancer Research, T-Lymphocytes, MESH: Membrane Glycoproteins, Apoptosis, MESH : Membrane Glycoproteins, Jurkat cells, MESH : Proto-Oncogene Proteins c-bcl-2, TNF-Related Apoptosis-Inducing Ligand, MESH : TNF-Related Apoptosis-Inducing Ligand, 0302 clinical medicine, MESH: Caspase 3, MESH : Caspase 3, Caspase, bcl-2-Associated X Protein, MESH : Tumor Necrosis Factor-alpha, 0303 health sciences, Leukemia, Membrane Glycoproteins, biology, Caspase 3, MESH: Mitochondrial Proteins, MESH: Adenoviridae, Hematology, Mitochondria, 3. Good health, Cell biology, bcl-2 Homologous Antagonist-Killer Protein, Proto-Oncogene Proteins c-bcl-2, Oncology, Caspases, 030220 oncology & carcinogenesis, MESH : Proto-Oncogene Proteins, MESH : Mitochondria, MESH: Membrane Proteins, biological phenomena, cell phenomena, and immunity, MESH : Apoptosis Regulatory Proteins, MESH: TNF-Related Apoptosis-Inducing Ligand, Bcl-2 Homologous Antagonist-Killer Protein, Programmed cell death, MESH: Enzyme Activation, MESH: Mitochondria, Adenoviridae, Mitochondrial Proteins, 03 medical and health sciences, Bcl-2-associated X protein, Proto-Oncogene Proteins, MESH: Leukemia, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, MESH: bcl-2-Associated X Protein, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Adenoviridae, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH : Mitochondrial Proteins, 030304 developmental biology, Death domain, MESH : T-Lymphocytes, MESH: Caspases, MESH: Humans, Tumor Necrosis Factor-alpha, MESH : bcl-2-Associated X Protein, MESH: Apoptosis Regulatory Proteins, MESH: Apoptosis, MESH : Humans, MESH : Leukemia, Membrane Proteins, MESH : bcl-2 Homologous Antagonist-Killer Protein, Enzyme Activation, MESH: Proto-Oncogene Proteins, MESH: T-Lymphocytes, MESH: Proto-Oncogene Proteins c-bcl-2, MESH : Membrane Proteins, MESH: Tumor Necrosis Factor-alpha, biology.protein, MESH : Caspases, Apoptosis Regulatory Proteins, MESH : Enzyme Activation, MESH: bcl-2 Homologous Antagonist-Killer Protein, MESH : Apoptosis
Abstract

This commentary is addressed at the paper by Dr Jie and his co-workers in the current issue of Leukemia (‘Differential involvement of Bax and Bak in TRAIL-mediated apoptosis of leukemic T cells’). In this paper, the authors show the preferential use of Bax over Bak for the induction of mitochondrial apoptotic events in leukemic cell exposed to TRAIL 1. These findings are consistent with previous studies involving Bax in TRAIL-mediated apoptosis in the colon carcinoma cell line HCT116 2–4. The redundant function of Bak and Bax was initially demonstrated in lymphocytes subjected to various apoptotic stimuli 5–8. Hence, simultaneous Bax and Bak gene inactivation results in a profound effect on the control of lymphocyte survival upon growth factor or glucose deprivation 9. Whereas, Bak inactivation, alone, appears to have no effect, Bax inactivation, however, slightly affected lymphocyte survival 9. These data could therefore suggest that Bax and Bak may not be so redundant after all. Accordingly, the use of Jurkat clones deficient for both Bak and Bax by Jie and collaborators, revealed that Bax and Bak could exhibit differential functions, at least in the studied cell type system, as only Bax re-expression could restore caspase-3 processing and sensitization to TRAIL-induced cell death 1. Loss of function mutations of Bax are often found both in colon carcinomas 10 and in leukemias 11,12. Therefore, since both death domain containing receptors and chemotherapeutic agents may require Bax for the triggering of the apoptotic process 2,13, this information may be important for future cancer therapeutic approaches using TRAIL or TRAIL receptor agonists either alone or in combination with chemotherapeutic agents.

Published
2004

5. Adenovirus-mediated overexpression of sterol regulatory element binding protein-1c mimics insulin effects on hepatic gene expression and glucose homeostasis in diabetic mice

Author

Isabelle Hainault, Dalila Azzout-Marniche, Pascal Ferré, Lydia Bertry-Coussot, Dominique Bécard, Fabienne Foufelle, Physiologie de la Nutrition et du Comportement Alimentaire ( PNCA ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Physiologie de la Nutrition et du Comportement Alimentaire (PNCA), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Azzout-Marniche, Dalila, AgroParisTech-Institut National de la Recherche Agronomique (INRA), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE)

Subjects
Male, MESH : RNA, Messenger, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], MESH: CCAAT-Enhancer-Binding Proteins, MESH: Recombinant Proteins, Mice, 0302 clinical medicine, Homeostasis, Insulin, Glucose homeostasis, MESH: Animals, 0303 health sciences, MESH: Mice, Inbred CBA, Glycogen, Gene Transfer Techniques, MESH: Adenoviridae, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], MESH: Transcription Factors, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH : Genetic Vectors, 3. Good health, MESH : DNA-Binding Proteins, MESH : Diabetes Mellitus, Experimental, Sterol Regulatory Element Binding Protein 1, medicine.medical_specialty, MESH: Gene Expression, MESH: Gene Transfer Techniques, MESH: Insulin, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Adenoviridae, MESH: Sterol Regulatory Element Binding Protein 1, 03 medical and health sciences, MESH : Sterol Regulatory Element Binding Protein 1, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], RNA, Messenger, MESH : Gene Transfer Techniques, MESH : Injections, Intraperitoneal, MESH : Glucose, Glucokinase, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH : Gene Expression, Glucose, Endocrinology, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], chemistry, CCAAT-Enhancer-Binding Proteins, Mice, Inbred CBA, MESH: Liver, Transcription Factors, MESH : Transcription Factors, MESH : Insulin, MESH : Mice, Inbred CBA, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Gene Expression, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, chemistry.chemical_compound, MESH: Genetic Vectors, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Diabetes Mellitus, Experimental, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Recombinant Proteins, MESH: Glucose, DNA-Binding Proteins, Liver, MESH : CCAAT-Enhancer-Binding Proteins, MESH: Homeostasis, MESH : Homeostasis, Phosphoenolpyruvate carboxykinase, MESH: Injections, Intraperitoneal, Injections, Intraperitoneal, MESH : Recombinant Proteins, MESH : Male, Genetic Vectors, 030209 endocrinology & metabolism, Biology, Diabetes Mellitus, Experimental, [ SDV.BC.IC ] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [ SDV.BBM.MN ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Diabetes mellitus, Internal medicine, MESH : Mice, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Internal Medicine, medicine, Animals, MESH : Adenoviridae, MESH: Mice, Transcription factor, MESH: RNA, Messenger, 030304 developmental biology, [ SDV.BC.BC ] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], MESH : Liver, Metabolism, MESH: Male, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, MESH : Animals, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, MESH: DNA-Binding Proteins
Abstract

International audience; In vitro, the transcription factor sterol regulatory element binding protein-1c (SREBP-1c) mimics the positive effects of insulin on hepatic genes involved in glucose utilization, such as glucokinase (GK) and enzymes of the lipogenic pathway, suggesting that it is a key factor in the control of hepatic glucose metabolism. Decreased glucose utilization and increased glucose production by the liver play an important role in the development of the hyperglycemia in diabetic states. We thus reasoned that if SREBP-1c is indeed a mediator of hepatic insulin action, a hepatic targeted overexpression of SREBP-1c should greatly improve glucose homeostasis in diabetic mice. This was achieved by injecting streptozotocin-induced diabetic mice with a recombinant adenovirus containing the cDNA of the mature, transcriptionally active form of SREBP-1c. We show here that overexpressing SREBP-1c specifically in the liver of diabetic mice induces GK and lipogenic enzyme gene expression and represses the expression of phosphoenolpyruvate carboxykinase, a key enzyme of the gluconeogenic pathway. This in turn increases glycogen and triglyceride hepatic content and leads to a marked decrease in hyperglycemia in diabetic mice. We conclude that SREBP-1c has a major role in vivo in the long-term control of glucose homeostasis by insulin.

Published
2001

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