Descriptor: "MESH : Hepatocytes" - Searchworks@Jio Institute Digital Library Search Results

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28 results on '"MESH : Hepatocytes"'

1. Genotoxic and enzymatic effects of fluoranthene in microsomes and freshly isolated hepatocytes from sole (Solea solea)

Author: J. Le Goff, Nathalie Wessel, Dominique Ménard, Thierry Burgeot, H. Ollivier, K. Pichavant-Rafini, Farida Akcha, Département Biogéochimie et Ecotoxicologie, Institut Français de Recherche pour l'Exploitation de la Mer ( IFREMER ), Optimisation des régulations physiologiques ( ORPHY (EA 4324) ), Université de Brest ( UBO ) -Institut Brestois du Numérique et des Mathématiques ( IBNM ), Université de Brest ( UBO ) -Université de Brest ( UBO ), Groupe Régional d'Etudes sur le CANcer ( GRECAN ), IFR146-Centre Régional de Lutte contre le Cancer François Baclesse ( CRLC François Baclesse ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Biogéochimie et Ecotoxicologie (IFREMER BE), Institut Français de Recherche pour l'Exploitation de la Mer - Atlantique (IFREMER Atlantique), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Optimisation des régulations physiologiques (ORPHY (EA 4324)), Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Groupe Régional d'Etudes sur le CANcer (GRECAN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), and UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-IFR146
Subjects: MESH: Microsomes, Liver, Health, Toxicology and Mutagenesis, MESH : Hepatocytes, 010501 environmental sciences, medicine.disease_cause, 01 natural sciences, MESH: DNA Breaks, MESH: Hepatocytes, DNA Adducts, chemistry.chemical_compound, MESH: Animals, Cells, Cultured, chemistry.chemical_classification, 0303 health sciences, biology, MESH : Fluorenes, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], MESH: Flatfishes, MESH : DNA Adducts, MESH: Cytochrome P-450 CYP1A1, MESH : Microsomes, Liver, MESH: Water Pollutants, Chemical, Biochemistry, Flatfishes, Microsomes, Liver, cardiovascular system, MESH: DNA Adducts, MESH: Cells, Cultured, MESH : Water Pollutants, Chemical, Aquatic Science, Adduct, 03 medical and health sciences, MESH : Cells, Cultured, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Cytochrome P-450 CYP1A1, medicine, MESH: Fluorenes, Animals, MESH : Flatfishes, 030304 developmental biology, 0105 earth and related environmental sciences, Fluoranthene, Fluorenes, DNA Breaks, Cytochrome P450, In vitro, Enzyme, chemistry, MESH : DNA Breaks, MESH : Cytochrome P-450 CYP1A1, Hepatocytes, biology.protein, Microsome, MESH : Animals, Water Pollutants, Chemical, DNA, Genotoxicity
Abstract: International audience; The fluoranthene (Fluo) is one of the most abundant polycyclic aromatic hydrocarbons (PAHs) in human food and in marine compartments. However, the existing data on its genotoxicity is poor and controversial. The aim of this study was to assess in vitro the potential genotoxicity of Fluo in sole and its possible effect on CYP450 modulation. Freshly isolated hepatocytes were exposed for 24 h to a range of Fluo concentrations from 0.5 to 50 μM in both culture flasks and microplate wells. The ethoxyresorufin-O-deethylase (EROD) activity was measured as an indicator of the activity of the cytochrome P450 1A1 (CYP1A1). The genotoxic effects were evaluated by measuring both DNA strand breaks and DNA adducts by the alkaline comet assay and the postlabeling technique respectively. Calf thymus DNA was also exposed to Fluo in the presence of sole liver microsomes in order to check for Fluo DNA adduct formation. In sole hepatocytes, Fluo was shown to induce a decrease in the EROD activity in a concentration-dependent manner. A significant genotoxic effect was observed in terms of DNA strand breakage from an exposure concentration of 5 μM: despite a concentration-dependent effect was observed, it did not follow a linear dose-response. The response was similar whatever the way of exposure in flasks or in wells. One reproducible adduct was detected in the hepatocytes exposed to the highest concentrations of Fluo. The formation of Fluo adducts was confirmed by the detection of one reproducible adduct following in vitro exposure of calf thymus DNA to 100 and 200 μM of Fluo in the presence of sole microsomes. These results demonstrate the potential of sole hepatocytes to metabolize Fluo in 24 h into reactive species, able to induce genotoxicity by DNA strand breakage and DNA adduct formation. Moreover, a miniaturized cell exposure system was validated for further experiments using fewer amounts of hepatocytes and contaminants, and allowing exposure to PAH metabolites.
Published: 2012
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2. Modulation of the hepatic fatty acid pool in peroxisomal 3-ketoacyl-CoA thiolase B-null mice exposed to the selective PPARalpha agonist Wy14,643

Author: Ronald J.A. Wanders, Marie Claude Clémencet, Valérie Nicolas-Francès, Joseph Gresti, Grégory Chevillard, Stéphane Mandard, Norbert Latruffe, Ségolène Arnauld, Anne Athias, Marco Fidaleo, Mandard, Stéphane, ‘‘Peroxisomes' LSHG-CT-2004-512018 - INCOMING, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Plateforme Lipidomique [Dijon] (LAP), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-IFR100 - Structure fédérative de recherche Santé-STIC-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratory Genetic Metabolic Diseases, Academic Medical Center at the University of Amsterdam, (AMC), Universiteit van Amsterdam (UvA), The European Union project ‘‘Peroxisomes' LSHG-CT-2004-512018, the Regional Council of Burgundy, the INSERM U866 center (Dijon) and the Italian Ministero della Ricerca Scientifica e Tecnologica., European Project, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Genetic Metabolic Diseases, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Plateforme Lipidomique [Dijon] ( LAP ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -IFR100 - Structure fédérative de recherche Santé-STIC-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Laboratory Genetic Metabolic Diseases, Academic Medical Center at the University of Amsterdam, ( AMC ), and Université d'Amsterdam
Subjects: MESH : RNA, Messenger, MESH: Microsomes, Liver, MESH : Pyrimidines, Mono-unsaturated fatty acids n-7 and n-9, MESH : Hepatocytes, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Mice, Knockout, PPARα, Biochemistry, MESH: Acetyl-CoA C-Acetyltransferase, Stearoyl-CoA desaturase-1, MESH: Hepatocytes, Mice, chemistry.chemical_compound, MESH : Lipid Metabolism, Wy14, MESH: Animals, Peroxisomal 3-ketoacyl-CoA thiolase B, Acetyl-CoA C-Acetyltransferase, MESH: PPAR alpha, MESH : Fatty Acids, MESH: Lipid Metabolism, Mice, Knockout, chemistry.chemical_classification, Thiolase, Fatty Acids, General Medicine, Peroxisome, MESH : Stearoyl-CoA Desaturase, MESH: Fatty Acids, MESH : Microsomes, Liver, MESH : Acetyl-CoA C-Acetyltransferase, Microsomes, Liver, Wy14,643, lipids (amino acids, peptides, and proteins), Stearoyl-CoA Desaturase, Polyunsaturated fatty acid, medicine.medical_specialty, MESH : PPAR alpha, MESH : Mice, Inbred C57BL, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biology, MESH: Mice, Inbred C57BL, Internal medicine, MESH : Mice, Peroxisomes, medicine, Animals, Humans, PPAR alpha, RNA, Messenger, MESH: Mice, MESH: RNA, Messenger, SCP2, MESH: Humans, MESH : Humans, Fatty acid, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Stearoyl-CoA, Lipid Metabolism, MESH: Peroxisomes, Sterol regulatory element-binding protein, Mice, Inbred C57BL, Pyrimidines, Endocrinology, chemistry, MESH: Pyrimidines, MESH: Stearoyl-CoA Desaturase, Hepatocytes, MESH : Mice, Knockout, MESH : Animals, MESH : Peroxisomes
Abstract: 10 pages; International audience; The peroxisomal 3-ketoacyl-CoA thiolase B (Thb) gene was previously identified as a direct target gene of PPARalpha, a nuclear hormone receptor activated by hypolipidemic fibrate drugs. To better understand the role of ThB in hepatic lipid metabolism in mice, Sv129 wild-type and Thb null mice were fed or not the selective PPARalpha agonist Wy14,643 (Wy). Here, it is shown that in contrast to some other mouse models deficient for peroxisomal enzymes, the hepatic PPARalpha signaling cascade in Thb null mice was normal under regular conditions. It is of interest that the hypotriglyceridemic action of Wy was reduced in Thb null mice underlining the conclusion that neither thiolase A nor SCPx/SCP2 thiolase can fully substitute for ThB in vivo. Moreover, a significant increased in the expression of lipogenic genes such as Stearoyl CoA Desaturase-1 (SCD1) was observed in Thb null mice fed Wy. Elevation of Scd1 mRNA and protein levels led to higher SCD1 activity, through a molecular mechanism that is probably SREBP1 independent. In agreement with higher SCD1, enrichment of liver mono-unsaturated fatty acids of the n-7 and n-9 series was found in Thb null mice fed Wy. Overall, we show that the reduced peroxisomal beta-oxidation of fat observed in Thb null mice fed Wy is associated with enhanced hepatic lipogenesis, through the combined elevation of microsomal SCD1 protein and activity. Ultimately, not only the amount but also the quality of the hepatic fatty acid pool is modulated upon the deletion of Thb.
Published: 2009
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3. The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions

Author: Maria Mastrogiannaki, Pavle Matak, Carole Peyssonnaux, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bos, Mireille, Institut Cochin (UM3 (UMR 8104 / U1016)), and Institut National de la Santé et de la Recherche Médicale (INSERM) - Université Paris Descartes - Paris 5 (UPD5) - Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, MESH: Inflammation, MESH : Basic Helix-Loop-Helix Transcription Factors, MESH: Anoxia, MESH : Hepatocytes, Review Article, Biochemistry, MESH : Iron, Pathogenesis, MESH: Hepatocytes, Mice, MESH: Enterocytes, 0302 clinical medicine, MESH : Hepcidins, MESH: Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Transcription Factors, Homeostasis, MESH: Animals, MESH: Hepcidins, Hypoxia, Regulation of gene expression, 0303 health sciences, MESH: Iron, MESH : Gene Expression Regulation, MESH: Antimicrobial Cationic Peptides, MESH : Antimicrobial Cationic Peptides, Hematology, MESH : Iron Regulatory Protein 1, MESH : Iron Regulatory Protein 2, MESH: Gene Expression Regulation, MESH : Enterocytes, 3. Good health, Cell biology, MESH : Hemochromatosis, MESH: Homeostasis, MESH : Homeostasis, 030220 oncology & carcinogenesis, Hemochromatosis, medicine.symptom, MESH : Polycythemia, MESH: Hemochromatosis, medicine.medical_specialty, MESH : Anoxia, MESH : Male, Iron, Immunology, Inflammation, Polycythemia, Biology, MESH: Iron Regulatory Protein 1, 03 medical and health sciences, MESH: Iron Regulatory Protein 2, Hepcidins, Hepcidin, Internal medicine, MESH : Mice, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Iron Regulatory Protein 1, Iron Regulatory Protein 2, MESH: Mice, 030304 developmental biology, MESH : Inflammation, MESH: Humans, MESH : Humans, Cell Biology, Hypoxia (medical), medicine.disease, MESH: Male, Gastrointestinal Tract, Enterocytes, Endocrinology, Gene Expression Regulation, Hepatocytes, biology.protein, MESH: Gastrointestinal Tract, MESH : Animals, MESH: Polycythemia, MESH : Gastrointestinal Tract, Antimicrobial Cationic Peptides, Hormone
Abstract: Although earlier, seminal studies demonstrated that the gut per se has the intrinsic ability to regulate the rates of iron absorption, the spotlight in the past decade has been placed on the systemic regulation of iron homeostasis by the hepatic hormone hepcidin and the molecular mechanisms that regulate its expression. Recently, however, attention has returned to the gut based on the finding that hypoxia inducible factor-2 (HIF-2α) regulates the expression of key genes that contribute to iron absorption. Here we review the current understanding of the molecular mechanisms that regulate iron homeostasis in the gut by focusing on the role of HIF-2 under physiological steady-state conditions and in the pathogenesis of iron-related diseases. We also discuss implications for adapting HIF-2–based therapeutic strategies in iron-related pathological conditions.
Published: 2013
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4. Highly efficient SiRNA and gene transfer into hepatocyte-like HepaRG cells and primary human hepatocytes: new means for drug metabolism and toxicity studies

Author: Laurent, Véronique, Glaise, Denise, Nübel, Tobias, Gilot, David, Corlu, Anne, LOYER, Pascal, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078), EFS-Université de Brest ( UBO ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Foie, métabolismes et cancer, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Centre National de la Recherche Scientifique ( CNRS ), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Génétique et Développement de Rennes (IGDR), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Cell Differentiation, MESH : Cell Culture Techniques, Drug-Related Side Effects and Adverse Reactions, Human hepatocytes, MESH: Pharmaceutical Preparations, Cell Culture Techniques, MESH: Stem Cells, MESH : Hepatocytes, Transfection, MESH : RNA, Small Interfering, MESH: Drug Toxicity, MESH : Indicators and Reagents, MESH: Hepatocytes, MESH : Pharmaceutical Preparations, MESH: Cell Proliferation, MESH: RNA, Small Interfering, MESH : Cell Proliferation, Humans, MESH: Electroporation, RNA, Small Interfering, Cell Proliferation, MESH: Cell Culture Techniques, Nucleofection™, Drug metabolism, MESH: Humans, Stem Cells, MESH: Transfection, MESH : Humans, MESH: Indicators and Reagents, MESH : Drug Toxicity, Cell Differentiation, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, In vitro toxicity, Electroporation, Pharmaceutical Preparations, HepaRG cells, Hepatocytes, MESH : Stem Cells, MESH : Electroporation, Indicators and Reagents, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH : Transfection, MESH : Cell Differentiation
Abstract: International audience; The metabolically competent hepatocyte-like human HepaRG cells represent a suitable alternative in vitro cell model to human primary hepatocytes. Here, we describe the culture procedure required to expand progenitor HepaRG cells and to differentiate them into hepatocyte-like cells. Transient transfection of gene and siRNA into cultured cells, using nonviral strategies, is an invaluable technique to decipher gene functions. In this chapter, we detail transfection protocols for efficient transfer of plasmid DNA or siRNAs into proliferating progenitor or quiescent differentiated HepaRG cells as well as into primary hepatocytes.
Published: 2013
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5. Glycogen synthase kinase 3-mediated voltage-dependent anion channel phosphorylation controls outer mitochondrial membrane permeability during lipid accumulation

Author: Guido Kroemer, Cécile Martel, Céline Henry, Catherine Brenner, Elena Fanelli, Maya Allouche, Joël Chopineau, Giuseppe Calamita, Davide Degli Esposti, Antoinette Lemoine, Céline Boursier, Université Joseph Fourier - Grenoble 1 (UJF), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Réponses cellulaires au microenvironnement et cancer, Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Protéines et Nanotechnologies en Sciences Séparatives, Université Paris-Sud - Paris 11 (UP11), Centre Ressources Autisme de Bourgogne (CHU de Dijon) (CRAB), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Nîmes (UNIMES), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), 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)-Centre National de la Recherche Scientifique (CNRS), Apoptose, cancer et immunité (U848), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Pôle de biologie, 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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Microenvironnement et Physiopathologie de la Differenciation, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique [Châtenay-Malabry] (LabEx LERMIT), University of Paris Sud, Institut National pour le Cancer (INCa) [2008-1-PL BIO-04-CNRS ON1], LabEx LERMIT, PRES UniverSud Paris, Association pour la Recherche sur le Cancer, ANR [ANR-08PCVI-0008-01], MIUR [PRIN20089SRS2X_003], Fondazione Cassa di Risparmio di Puglia, Chopineau, Joel, Université Joseph Fourier - Grenoble 1 ( UJF ), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier ( ICGM ICMMM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), University of Bari Aldo Moro ( UNIBA ), Université Paris-Sud - Paris 11 ( UP11 ), Centre Ressources Autisme de Bourgogne (CHU de Dijon) ( CRAB ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université de Nîmes ( UNIMES ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), 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 ) -Centre National de la Recherche Scientifique ( CNRS ), Apoptose, cancer et immunité ( U848 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), PRES UniverSud ( CNRS UMR 8159 ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), University of Bari Aldo Moro (UNIBA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11)
Subjects: Male, MESH : Fatty Liver, MESH : Hepatocytes, Mitochondrion, ACTIVATION, MESH: Hepatocytes, Glycogen Synthase Kinase 3, Mice, MESH : Phosphorylation, 0302 clinical medicine, MESH: Mitochondrial Membranes, MESH : Lipid Metabolism, GSK-3, Voltage-Dependent Anion Channels, MESH : Female, MESH: Animals, Phosphorylation, MESH: Fatty Liver, Cells, Cultured, MESH: Glycogen Synthase Kinase 3, MESH: Lipid Metabolism, 0303 health sciences, INSULIN-RESISTANCE, biology, VDAC, MESH : Voltage-Dependent Anion Channels, NONALCOHOLIC STEATOHEPATITIS, Fatty liver, 3. Good health, Cell biology, APOPTOSIS, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Lipotoxicity, Biochemistry, 030220 oncology & carcinogenesis, MESH: Calcium, Mitochondrial Membranes, Female, MESH: Cells, Cultured, [ SDV.BBM.BP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Voltage-dependent anion channel, MESH : Glycogen Synthase Kinase 3, MESH : Male, bcl-X Protein, INHIBITION, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, MESH : Mice, Inbred C57BL, macromolecular substances, MESH: bcl-X Protein, 03 medical and health sciences, MESH : Mitochondrial Membranes, MESH: Mice, Inbred C57BL, LIVER STEATOSIS, MESH : Mice, MESH : Cells, Cultured, medicine, Animals, Humans, TRANSITION PORE, MODULATION, MESH : Calcium, MESH: Mice, 030304 developmental biology, MESH: Humans, Hepatology, MESH: Phosphorylation, MESH : bcl-X Protein, MESH : Humans, MESH: Voltage-Dependent Anion Channels, Lipid metabolism, Lipid Metabolism, medicine.disease, MESH: Male, Fatty Liver, Mice, Inbred C57BL, CELL-DEATH, Hepatocytes, biology.protein, Calcium, MESH : Animals, Steatosis, MESH: Female
Abstract: International audience; UNLABELLED: Nonalcoholic steatosis is a liver pathology characterized by fat accumulation and severe metabolic alterations involving early mitochondrial impairment and late hepatocyte cell death. However, mitochondrial dysfunction mechanisms remain elusive. Using four models of nonalcoholic steatosis, i.e., livers from patients with fatty liver disease, ob/ob mice, mice fed a high-fat diet, and in vitro models of lipotoxicity, we show that outer mitochondrial membrane permeability is altered and identified a posttranslational modification of voltage-dependent anion channel (VDAC), a membrane channel and NADH oxidase, as a cause of early mitochondrial dysfunction. Thus, in nonalcoholic steatosis VDAC exhibits reduced threonine phosphorylation, which increases the influx of water and calcium into mitochondria, sensitizes the organelle to matrix swelling, depolarization, and cytochrome c release without inducing cell death. This also amplifies VDAC enzymatic and channel activities regulation by calcium and modifies its interaction with proteic partners. Moreover, lipid accumulation triggers a rapid lack of VDAC phosphorylation by glycogen synthase kinase 3 (GSK3). Pharmacological and genetic manipulations proved GSK3 to be responsible for VDAC phosphorylation in normal cells. Notably, VDAC phosphorylation level correlated with steatosis severity in patients. CONCLUSION: VDAC acts as an early sensor of lipid toxicity and its GSK3-mediated phosphorylation status controls outer mitochondrial membrane permeabilization in hepatosteatosis.
Published: 2013
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6. TRAIL but not FasL and TNFα, regulates IL-33 expression in murine hepatocytes during acute hepatitis

Author: Muhammad Imran Arshad, Sabrina Nabti, Annie L'Helgoualc'h, Michel Rauch, Claire Piquet-Pellorce, Christian Trautwein, Frédéric Ezan, Michel Samson, Agnès Lehuen, Francisco Javier Cubero, Catherine Lucas-Clerc, Jean-Philippe Girard, Solène Patrat-Delon, Institut de recherche, santé, environnement et travail ( Irset ), Université d'Angers ( UA ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -École des Hautes Études en Santé Publique [EHESP] ( EHESP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université des Antilles ( UA ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de biochimie générale, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunologie et génétique du diabète de type 1, génétique multifactorielle en endocrinologie pédiatrique ( U986 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Medical Department III, University Hospital Aachen, Institut de pharmacologie et de biologie structurale ( IPBS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et génétique du diabète de type 1, génétique multifactorielle en endocrinologie pédiatrique (U986), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH : RNA, Messenger, medicine.medical_treatment, Gene Expression, Galactosamine, MESH : Hepatocytes, Hepatitis, Animal, MESH : Fas Ligand Protein, Fas ligand, MESH: Antibodies, Monoclonal, TNF-Related Apoptosis-Inducing Ligand, MESH: Hepatocytes, MESH : TNF-Related Apoptosis-Inducing Ligand, Antibodies, Monoclonal, Murine-Derived, Mice, 0302 clinical medicine, MESH : Receptors, Tumor Necrosis Factor, Type I, MESH: Receptors, Tumor Necrosis Factor, Type II, Concanavalin A, MESH: Animals, MESH : Acute Lung Injury, MESH: Galactosamine, MESH : Concanavalin A, Liver injury, MESH: Receptors, Tumor Necrosis Factor, Type I, MESH : Tumor Necrosis Factor-alpha, 0303 health sciences, biology, MESH: Hepatitis, Animal, Antibodies, Monoclonal, Interleukin, MESH : Receptors, Tumor Necrosis Factor, Type II, Natural killer T cell, 3. Good health, Cytokine, Receptors, Tumor Necrosis Factor, Type I, 030220 oncology & carcinogenesis, MESH : Antibodies, Monoclonal, Tumor necrosis factor alpha, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: TNF-Related Apoptosis-Inducing Ligand, Fas Ligand Protein, MESH: Gene Expression, MESH: Interleukins, Acute Lung Injury, Primary Cell Culture, chemical and pharmacologic phenomena, MESH: Concanavalin A, MESH: Primary Cell Culture, 03 medical and health sciences, MESH : Mice, medicine, Animals, Receptors, Tumor Necrosis Factor, Type II, RNA, Messenger, MESH : Perforin, MESH : Primary Cell Culture, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, Hepatitis, Hepatology, MESH : Galactosamine, Perforin, Tumor Necrosis Factor-alpha, Interleukins, MESH: Acute Lung Injury, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Interleukin-33, medicine.disease, MESH : Natural Killer T-Cells, MESH: Fas Ligand Protein, MESH: Perforin, MESH : Gene Expression, MESH: Natural Killer T-Cells, MESH: Tumor Necrosis Factor-alpha, Immunology, Hepatocytes, biology.protein, Cancer research, Natural Killer T-Cells, MESH : Animals, MESH : Interleukins, MESH : Hepatitis, Animal
Abstract: International audience; UNLABELLED: Interleukin (IL)-33, a member of the IL-1 cytokine family, positively correlates with acute hepatitis and chronic liver failure in mice and humans. IL-33 is expressed in hepatocytes and is regulated by natural killer T (NKT) cells during concanavalin A (ConA)-induced acute liver injury. Here, we investigated the molecular mechanisms underlying the expression of IL-33 during acute hepatitis. The expression of IL-33 and its regulation by death receptor pathways was investigated after the induction of ConA-acute hepatitis in wildtype (WT), perforin(-/-) , tumor necrosis factor related apoptosis inducing ligand (TRAIL)(-/-) , and NKT cell-deficient (CD1d(-/-) ) mice. In addition, we used a model of acute liver injury by administering Jo2/Fas-antibody or D-galactosamine-tumor necrosis factor alpha (TNFα) in WT mice. Finally, the effect of TRAIL on IL-33 expression was assessed in primary cultured murine hepatocytes. We show that IL-33 expression in hepatocytes is partially controlled by perforin during acute liver injury, but not by TNFα or Fas ligand (FasL). Interestingly, the expression of IL-33 in hepatocytes is blocked during ConA-acute hepatitis in TRAIL-deficient mice compared to WT mice. In contrast, administration of recombinant murine TRAIL associated with ConA-priming in CD1d-deficient mice or in vitro stimulation of murine hepatocytes by TRAIL but not by TNFα or Jo2 induced IL-33 expression in hepatocytes. The IL-33-deficient mice exhibited more severe ConA liver injury than WT controls, suggesting a protective effect of IL-33 in ConA-hepatitis. CONCLUSION: The expression of IL-33 during acute hepatitis is dependent on TRAIL, but not on FasL or TNFα.
Published: 2012
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7. Immunohistochemical markers on needle biopsies are helpful for the diagnosis of focal nodular hyperplasia and hepatocellular adenoma subtypes

Author: François Paraf, Marie Christine Saint Paul, Saïd Taouji, Jeanne Ramos, Nathalie Sturm, Brigitte Bancel, Valérie Paradis, Dominique Wendum, Emmanuelle Leteurtre, Monique Fabre, Jean-Yves Scoazec, Paulette Bioulac-Sage, Charles Balabaud, Jessica Zucman-Rossi, Gaelle Cubel, Brigitte Le Bail, Sophie Michalak, Catherine Guettier, Jeanne Tran Van Nhieu, Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), equipe 4, Laboratoire Central d'Anatomie et de Cytologie Pathologiques [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Albert Bonniot - Ontogénèse et oncogénèse moléculaires, CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'anatomie et cytologie pathologiques [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Equipe 16, Centre de Recherche en Cancérologie de Lyon (CRCL), Tumorothèque de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Limoges (UNILIM), Hôpital Pasteur [Nice] (CHU), Laboratoire de Pathologie Cellulaire et Tissulaire, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Hôpital Paul Brousse, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse, Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, 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), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [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)-Centre Léon Bérard [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), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse, Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ) -Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ) -Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [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 ) -Centre Léon Bérard [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 ), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Centre de recherche biomédicale Bichat-Beaujon ( CRB3 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Grenoble-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service d'anatomie et cytologie pathologiques, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Université de Limoges ( UNILIM ), Hôpital Pasteur [Nice] ( CHU ), CHU Angers, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Paul Brousse, Genomique Fonctionnelle des Tumeurs Solides, and Université Paris Diderot - Paris 7 ( UPD7 ) -IFR105-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: Core needle, Male, MESH: Biopsy, Large-Core Needle, Pathology, MESH : Liver Neoplasms, MESH: Focal Nodular Hyperplasia, MESH: beta Catenin, MESH : Hepatocytes, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Hepatocytes, MESH: Adenoma, Liver Cell, 0302 clinical medicine, MESH: Liver Neoplasms, MESH : Tumor Markers, Biological, MESH : Female, Hepatocyte Nuclear Factor 1-alpha, MESH : Algorithms, beta Catenin, medicine.diagnostic_test, Liver Neoplasms, Focal nodular hyperplasia, MESH : Adult, MESH : Biopsy, Large-Core Needle, MESH : Diagnosis, Differential, MESH: Predictive Value of Tests, 3. Good health, Focal Nodular Hyperplasia, 030220 oncology & carcinogenesis, Immunohistochemistry, 030211 gastroenterology & hepatology, MESH : Hepatocyte Nuclear Factor 1-alpha, Female, Anatomy, Algorithms, Adult, medicine.medical_specialty, MESH : Male, MESH: Algorithms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pathology and Forensic Medicine, Adenoma, Liver Cell, Diagnosis, Differential, 03 medical and health sciences, MESH : Adenoma, Liver Cell, Glutamate-Ammonia Ligase, Predictive Value of Tests, MESH: Diagnosis, Differential, Biopsy, medicine, Biomarkers, Tumor, Humans, MESH: Glutamate-Ammonia Ligase, MESH : Predictive Value of Tests, MESH: Hepatocyte Nuclear Factor 1-alpha, MESH: Humans, business.industry, Significant difference, MESH : Humans, MESH: Adult, MESH : Glutamate-Ammonia Ligase, Hepatocellular adenoma, medicine.disease, MESH : beta Catenin, MESH: Male, Staining, MESH : Focal Nodular Hyperplasia, MESH: Tumor Markers, Biological, Hepatocytes, Surgery, Biopsy, Large-Core Needle, business, MESH: Female, Immunostaining
Abstract: International audience; Phenotypic identification of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) subtypes using immunohistochemical markers has been developed from their molecular characteristics. Our objective was to evaluate the sensitivity of these markers in the definitive diagnosis of these lesions by core needle biopsies. A total of 239 needle biopsies paired with their surgical resection specimen (group A) or without an associated resection specimen (group B) were reviewed. Using a step-by-step algorithm after standard staining, appropriate immunostaining analyses were performed to determine the certainty of diagnosis of FNH, HNF1α-inactivated HCA, inflammatory HCA, β-catenin-activated HCA, or unclassified HCA. The diagnosis of FNH was certain or probable on routine stains in 53% of needle biopsies of group A, whereas after glutamine synthetase staining, the diagnosis was certain in 86.7% as compared with 100% on the corresponding surgical specimen (P=0.04). In needle biopsies of group A, the diagnosis of HCA was certain on routine stains in 58.6% as compared with 94.3% on surgical specimens. After specific immunostaining, diagnosis was established on biopsies with 74.3% certainty, including all HCA subtypes, with similar distribution in surgical specimens. For each "certain diagnosis" paired diagnostic test (biopsy and surgical specimen), a positive correlation was observed (P
Published: 2012
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8. Live-Cell Imaging Reveals Multiple Interactions between Epstein-Barr Virus Nuclear Antigen 1 and Cellular Chromatin during Interphase and Mitosis

Author: Maïté Coppey-Moisan, Tristan Piolot, Vincent Maréchal, Gabriel Dos Reis, Christophe Klein, Nathalie Jourdan, Marc Tramier, Frédérique Quignon, Aude Jobart-Malfait, Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), 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)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), 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 ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), UPMC, INSERM, Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and De Villemeur, Hervé
Subjects: MESH : Cell Line, viruses, [SDV]Life Sciences [q-bio], Gene Expression, MESH : Hepatocytes, MESH: Hepatocytes, Chromatin bridge, 0302 clinical medicine, MESH : Protein Transport, hemic and lymphatic diseases, MESH : Protein Stability, 0303 health sciences, MESH : Chromatin, MESH : Epstein-Barr Virus Nuclear Antigens, MESH : Interphase, Protein Stability, RNA-Binding Proteins, MESH : Protein Binding, Cell cycle, MESH : Mitosis, Chromatin, Virus-Cell Interactions, Protein Transport, 030220 oncology & carcinogenesis, Premature chromosome condensation, Interphase, MESH: Cell Nucleolus, MESH : Carrier Proteins, MESH: Epstein-Barr Virus Nuclear Antigens, Cell Nucleolus, Plasmids, Protein Binding, MESH: Protein Transport, MESH: Gene Expression, Immunology, Mitosis, MESH: Carrier Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Microbiology, Cell Line, MESH: Chromatin, MESH: Interphase, 03 medical and health sciences, G2 phase, Prophase, MESH: Plasmids, MESH: Protein Stability, Virology, MESH: HMGB2 Protein, HMGB2 Protein, Humans, MESH: Protein Binding, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, MESH: Humans, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH : Humans, MESH: Mitosis, MESH : HMGB2 Protein, Molecular biology, MESH: Cell Line, MESH : Gene Expression, Epstein-Barr Virus Nuclear Antigens, MESH : Plasmids, Insect Science, MESH : Cell Nucleolus, Hepatocytes, Carrier Proteins
Abstract: Epstein-Barr virus (EBV) establishes a life-long latent infection in humans. In proliferating latently infected cells, EBV genomes persist as multiple episomes that undergo one DNA replication event per cell cycle and remain attached to the mitotic chromosomes. EBV nuclear antigen 1 (EBNA-1) binding to the episome and cellular genome is essential to ensure proper episome replication and segregation. However, the nature and regulation of EBNA-1 interaction with chromatin has not been clearly elucidated. This activity has been suggested to involve EBNA-1 binding to DNA, duplex RNA, and/or proteins. EBNA-1 binding protein 2 (EBP2), a nucleolar protein, has been proposed to act as a docking protein for EBNA-1 on mitotic chromosomes. However, there is no direct evidence thus far for EBP2 being associated with EBNA-1 during mitosis. By combining video microscopy and Förster resonance energy transfer (FRET) microscopy, we demonstrate here for the first time that EBNA-1 and EBP2 interact in the nucleoplasm, as well as in the nucleoli during interphase. However, in strong contrast to the current proposed model, we were unable to observe any interaction between EBNA-1 and EBP2 on mitotic chromosomes. We also performed a yeast double-hybrid screening, followed by a FRET analysis, that led us to identify HMGB2 (high-mobility group box 2), a well-known chromatin component, as a new partner for EBNA-1 on chromatin during interphase and mitosis. Although the depletion of HMGB2 partly altered EBNA-1 association with chromatin in HeLa cells during interphase and mitosis, it did not significantly impact the maintenance of EBV episomes in Raji cells.
Published: 2012
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9. Hepatocyte proliferation/growth arrest balance in the liver of mice during E. multilocularis infection: a coordinated 3-stage course

Author: Junhua Wang, Jing Li, Dominique A. Vuitton, Guodong Lü, Georges Mantion, Xiaomei Lu, Renyong Lin, Chuanshan Zhang, Hao Wen, Institut de Recherche en Communications et en Cybernétique de Nantes ( IRCCyN ), Mines Nantes ( Mines Nantes ) -École Centrale de Nantes ( ECN ) -Ecole Polytechnique de l'Université de Nantes ( Polytech Nantes ), Université de Nantes ( UN ) -Université de Nantes ( UN ) -PRES Université Nantes Angers Le Mans ( UNAM ) -Centre National de la Recherche Scientifique ( CNRS ), WHO Collaborating Center on Prevention and Treatment of Human Echinococcosis, Université de Franche-Comté ( UFC ), WHO Collaborating Center on Prevention and Treatment of Human Echinococcosis, SERF Unit, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ), Xinjiang Medical University, Chinese Government, Institut de Recherche en Communications et en Cybernétique de Nantes (IRCCyN), Mines Nantes (Mines Nantes)-École Centrale de Nantes (ECN)-Ecole Polytechnique de l'Université de Nantes (EPUN), Université de Nantes (UN)-Université de Nantes (UN)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)
Subjects: Proteomics, MESH : Hepatocytes, MESH : Echinococcosis, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Hepatocytes, Mice, 0302 clinical medicine, Gene expression, MESH : Cell Proliferation, MESH: Animals, MESH : Antigens, Differentiation, MESH: In Situ Nick-End Labeling, lcsh:Science, MESH: Tumor Suppressor Protein p53, Regulation of gene expression, 0303 health sciences, MESH : Gene Expression Regulation, Intracellular Signaling Peptides and Proteins, 3. Good health, 030220 oncology & carcinogenesis, Disease Progression, Medicine, MESH: Disease Progression, MESH : Carrier Proteins, Cyclin-Dependent Kinase Inhibitor p21, MESH : Cyclin-Dependent Kinase Inhibitor p21, MESH: Enzyme Activation, MESH : Cyclins, Caspase 3, MESH: Carrier Proteins, Gastroenterology and Hepatology, Echinococcus multilocularis, Microbiology, MESH: Cyclin-Dependent Kinase Inhibitor p21, 03 medical and health sciences, MESH: Echinococcosis, Cyclins, In Situ Nick-End Labeling, Biology, MESH: Echinococcus multilocularis, lcsh:R, MESH : Mitogen-Activated Protein Kinases, MESH : Disease Progression, Enzyme Activation, Apoptosis, Immunology, lcsh:Q, Parasitology, Carrier Proteins, MESH: Female, MESH: Liver, Necrosis, lcsh:Medicine, MESH : Models, Biological, MESH : Echinococcus multilocularis, Molecular Cell Biology, MESH: Caspase 3, MESH : Female, MESH : Caspase 3, Mice, Inbred BALB C, Multidisciplinary, biology, Animal Models, MESH: Gene Expression Regulation, medicine.anatomical_structure, Infectious Diseases, Liver, Hepatocyte, MESH: Antigens, Differentiation, MESH : In Situ Nick-End Labeling, Female, medicine.symptom, Mitogen-Activated Protein Kinases, Research Article, Neglected Tropical Diseases, MESH: Mice, Inbred BALB C, [SDV.CAN]Life Sciences [q-bio]/Cancer, Models, Biological, Andrology, Immune system, Model Organisms, Echinococcosis, Proliferating Cell Nuclear Antigen, MESH: Cell Proliferation, MESH : Mice, medicine, Animals, MESH: Mice, MESH : Mice, Inbred BALB C, 030304 developmental biology, Cell Proliferation, MESH: Models, Biological, MESH : Liver, biology.organism_classification, MESH: Cyclins, Antigens, Differentiation, MESH: Mitogen-Activated Protein Kinases, MESH : Tumor Suppressor Protein p53, MESH: Proliferating Cell Nuclear Antigen, Gene Expression Regulation, MESH : Proliferating Cell Nuclear Antigen, Hepatocytes, MESH : Animals, Tumor Suppressor Protein p53, MESH : Enzyme Activation
Abstract: International audience; BACKGROUND: Alveolar echinococcosis (AE) is characterized by the tumor-like growth of Echinococcus (E.) multilocularis. Very little is known on the influence of helminth parasites which develop in the liver on the proliferation/growth arrest metabolic pathways in the hepatocytes of the infected liver over the various stages of infection. METHODOLOGY/PRINCIPAL FINDINGS: Using Western blot analysis, qPCR and immunohistochemistry, we measured the levels of MAPKs activation, Cyclins, PCNA, Gadd45β, Gadd45γ, p53 and p21 expression in the murine AE model, from day 2 to 360 post-infection. Within the early (day 2-60) and middle (day60-180) stages, CyclinB1 and CyclinD1 gene expression increased up to day30 and then returned to control level after day60; Gadd45β, CyclinA and PCNA increased all over the period; ERK1/2 was permanently activated. Meanwhile, p53, p21 and Gadd45γ gene expression, and caspase 3 activation, gradually increased in a time-dependent manner. In the late stage (day180-360), p53, p21 and Gadd45γ gene expression were significantly higher in infected mice; JNK and caspase 3 were activated. TUNEL analysis showed apoptosis of hepatocytes. No significant change in CyclinE, p53 mRNA and p-p38 expression were observed at any time. CONCLUSIONS: Our data support the concept of a sequential activation of metabolic pathways which 1) would first favor parasitic, liver and immune cell proliferation and survival, and thus promote metacestode fertility and tolerance by the host, and 2) would then favor liver damage/apoptosis, impairment in protein synthesis and xenobiotic metabolism, as well as promote immune deficiency, and thus contribute to the dissemination of the protoscoleces after metacestode fertility has been acquired. These findings give a rational explanation to the clinical observations of hepatomegaly and of unexpected survival of AE patients after major hepatic resections, and of chronic liver injury, necrosis and of hepatic failure at an advanced stage and in experimental animals.
Published: 2012
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10. Expression and differential localization of xenobiotic transporters in the rat olfactory neuro-epithelium

Author: Yves Artur, Christine Belloir, Nicolas Thiebaud, Anne-Marie Le Bon, Jean-Marie Heydel, Franck Ménétrier, Anne-Laure Minn, Fabrice Neiers, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Agence Nationale de la Recherche (ANR-05-PNRA-1.E7), Aromalim Burgundy Regional Council (IFR92), French Ministry of Research, Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), and Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS )
Subjects: Male, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, MESH : Multidrug Resistance-Associated Proteins, p glycoprotein, ATP-binding cassette transporter, MESH : Hepatocytes, Receptors, Odorant, MESH : P-Glycoprotein, MESH: Hepatocytes, MESH : Lymphatic Vessels, 0302 clinical medicine, MESH : Protein Transport, ugt2a1, MESH: Smell, MESH: Receptors, Odorant, MESH: Animals, Receptor, xenobiotic metabolizing, mucosa, 0303 health sciences, MESH : Gene Expression Regulation, MESH : Rats, General Neuroscience, MESH : Odors, MESH: Gene Expression Regulation, Smell, Protein Transport, medicine.anatomical_structure, Biochemistry, Liver, transporter, barrier, Efflux, Multidrug Resistance-Associated Proteins, MESH: Multidrug Resistance-Associated Proteins, MESH: Xenobiotics, MESH: Protein Transport, MESH: P-Glycoprotein, MESH: Rats, MESH: Lymphatic Vessels, MESH : Male, odorant clearance, brain, MESH : Xenobiotics, xenobiotic, Biology, system, MESH : Rats, Wistar, Olfactory Receptor Neurons, Xenobiotics, 03 medical and health sciences, bulb, Olfactory Mucosa, multidrug resistance, MESH : Receptors, Odorant, medicine, Animals, ATP Binding Cassette Transporter, Subfamily B, Member 1, Rats, Wistar, detoxification, MESH: Olfactory Mucosa, 030304 developmental biology, Lymphatic Vessels, MESH : Olfactory Mucosa, MESH: Odors, MESH : Liver, Transporter, MESH: Rats, Wistar, MESH: Olfactory Receptor Neurons, Epithelium, MESH: Male, Olfactory bulb, Rats, enzyme, Gene Expression Regulation, Odorants, Hepatocytes, MESH : Smell, MESH : Olfactory Receptor Neurons, MESH : Animals, olfactory epithelium, Olfactory epithelium, perireceptor event, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, Drug metabolism, MESH: Liver
Abstract: International audience; Transporters, such as multidrug resistance P-glycoproteins (MDR), multidrug resistance-related proteins (MRP) and organic anion transporters (OATs), are involved in xenobiotic metabolism, particularly the cellular uptake or efflux of xenobiotics (and endobiotics) or their metabolites. The olfactory epithelium is exposed to both inhaled xenobiotics and those coming from systemic circulation. This tissue has been described as a pathway for xenobiotics to the brain via olfactory perineural space. Thereby, olfactory transporters and xenobiotic metabolizing enzymes, dedicated to the inactivation and the elimination of xenobiotics, have been involved in the toxicological protection of the brain, the olfactory epithelium itself and the whole body. These proteins could also have a role in the preservation of the olfactory sensitivity by inactivation and clearance of the excess of odorant molecules from the perireceptor space. The goal of the present study was to increase our understanding of the expression and the localization of transporters in this tissue. For most of the studied transporters, we observed an opposite mRNA expression pattern (RT-PCR) in the olfactory epithelium compared to the liver, which is considered to be the main metabolic organ. Olfactory epithelium mainly expressed efflux transporters (MRP, MDR). However, a similar pattern was observed between the olfactory epithelium and the olfactory bulb. We also demonstrate distinct cellular immunolocalization of the transporters in the olfactory epithelium. As previously reported, Mrp1 was mainly found in the supranuclear portions of supporting cells. In addition, Mrp3 and Mrp5 proteins, which were detected for the first time in olfactory epithelium, were localized to the olfactory neuron layer, while Mdr1 was localized to the capillary endothelium of lymphatic vessels in the subepithelial region. The pattern of expression and the distinct localization of the olfactory transporters showed in this work may highlight on their specific function in the whole olfactory epithelium.
Published: 2011
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11. Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection

Author: David Durantel, Olivier Hantz, Silke Arzberger, Ulrike Protzer, Fabien Zoulim, Laura Belloni, Massimo Levrero, Michel Strubin, Julie Lucifora, Physiopathologie moléculaire et nouveaux traitements des hépatites virales, Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Technische Universität München [München] ( TUM ), Equipee 16, Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), University of Rome la Sapienza, Departement of internal medicine and laboratory of gene expression, equipe 15, Service d'hépatologie et de gastroentérologie, Hospices Civils de Lyon ( HCL ) -Hôtel-Dieu-Hospices Civils de Lyon ( HCL ) -Hôtel-Dieu-Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Molecular Infectiology - Center for Molecular Medicine Cologne, Institute for Medical Microbiology, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL)-Hôtel-Dieu-Hospices Civils de Lyon (HCL)-Hôtel-Dieu-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL)
Subjects: HBV RNA encapsidation signal epsilon, Transcription, Genetic, viruses, MESH : Hepatitis B virus, MESH : Hepatocytes, medicine.disease_cause, Virus Replication, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Hepatocytes, MESH : Hepatitis B e Antigens, 0302 clinical medicine, Hepatitis B Surface Antigens/metabolism, hbx protein, heparg, hepatitis b virus, natural infection, primary human hepatocytes, Viral Regulatory and Accessory Proteins, Hepatitis B e Antigens, MESH : DNA, Viral, MESH: Hepatitis B e Antigens, DNA, Circular/metabolism, ddc:616, 0303 health sciences, MESH : Trans-Activators, DNA, Viral/metabolism, MESH : Hep G2 Cells, virus diseases, cccDNA, Hep G2 Cells, Hepatitis B, 3. Good health, MESH : Virus Replication, HBx, MESH: Hepatitis B virus, MESH : DNA, Circular, MESH: DNA, Circular, 030211 gastroenterology & hepatology, DNA, Circular, MESH : Transfection, Hepatitis B X-Protein, Hepatitis B virus, MESH: Trans-Activators, MESH: Hep G2 Cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Transfection, Hepatitis B virus PRE beta, 03 medical and health sciences, Hepatitis B virus/genetics/physiology, Antigen, medicine, Humans, Trans-Activators/genetics/physiology, 030304 developmental biology, Hepatitis B Surface Antigens, MESH: Humans, MESH : Hepatitis B Surface Antigens, Hepatology, MESH: Hepatitis B, MESH: Transcription, Genetic, MESH: Transfection, MESH: Virus Replication, MESH : Humans, MESH : Transcription, Genetic, MESH : Hepatitis B, Virology, Molecular biology, digestive system diseases, MESH: DNA, Viral, MESH: Hepatitis B Surface Antigens, Hepatitis B/virology, Viral replication, Hepatitis B e Antigens/metabolism, DNA, Viral, Trans-Activators, Hepatocytes
Abstract: International audience; BACKGROUND & AIMS: The molecular biology of hepatitis B virus (HBV) has been extensively studied but the exact role of the hepatitis B X protein (HBx) in the context of natural HBV infections remains unknown. METHODS: Primary human hepatocytes and differentiated HepaRG cells allowing conditional trans complementation of HBx were infected with wild type (HBV(wt)) or HBx deficient (HBV(x-)) HBV particles and establishment of HBV replication was followed. RESULTS: We observed that cells inoculated with HBx-deficient HBV particles (HBV(x-)) did not lead to productive HBV infection contrary to cells inoculated with wild type HBV particles (HBV(wt)). Although equal amounts of nuclear covalently closed circular HBV-DNA (cccDNA) demonstrated comparable uptake and nuclear import, active transcription was only observed from HBV(wt) genomes. Trans-complementation of HBx was able to rescue transcription from the HBV(x-) genome and led to antigen and virion secretion, even weeks after infection. Constant expression of HBx was necessary to maintain HBV antigen expression and replication. Finally, we demonstrated that HBx is not packaged into virions during assembly but is expressed after infection within the new host cell to allow epigenetic control of HBV transcription from cccDNA. CONCLUSIONS: Our results demonstrate that HBx is required to initiate and maintain HBV replication and highlight HBx as the key regulator during the natural infection process.
Published: 2011
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12. NKT cells are required to induce high IL-33 expression in hepatocytes during ConA-induced acute hepatitis

Author: Michel Rauch, Muhammad Imran Arshad, Michel Samson, Maria Leite-de-Moraes, Valérie Julia, Catherine Lucas-Clerc, Claire Piquet-Pellorce, Annie L'Helgoualc'h, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biochimie générale, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], INSERM, Ministère de l'Education Nationale de la Recherche et de la Technologie, University de Rennes 1, Région Bretagne, National French Society of Gastro-Enterology (SNFGE), Ligue contre le cancer, IFR 140, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140, Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA), Signalisation et Réponses aux Agents Infectieux et Chimiques ( SeRAIC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140, Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ), Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: Male, medicine.medical_treatment, Fluorescent Antibody Technique, MESH : Carbon Tetrachloride, MESH: Flow Cytometry, MESH : Hepatocytes, MESH: Hepatocytes, Mice, 0302 clinical medicine, MESH: Interleukin-1beta, Concanavalin A, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Animals, MESH: Fluorescent Antibody Technique, 0303 health sciences, MESH : Acute Disease, MESH : Reverse Transcriptase Polymerase Chain Reaction, MESH: Hepatitis, Animal, Flow Cytometry, Natural killer T cell, Adoptive Transfer, 3. Good health, NKT cells, Alarmin, CD1D, Acute Disease, MESH: Acute Disease, Tumor necrosis factor alpha, MESH : Antigens, CD1d, MESH: Interleukins, MESH: Gene Expression, Immunology, MESH: Concanavalin A, MESH : Interleukin-1beta, 03 medical and health sciences, Tumor Necrosis Factor-alpha, Interleukins, MESH: Carbon Tetrachloride, Interleukin-33, medicine.disease, MESH: Interleukin-6, MESH : Gene Expression, MESH : Fluorescent Antibody Technique, MESH: Adoptive Transfer, MESH: Antigens, CD1d, MESH: Tumor Necrosis Factor-alpha, Natural Killer T-Cells, MESH : Hepatitis, Animal, MESH: Female, MESH: Liver, Adoptive cell transfer, Interleukin-1beta, Gene Expression, Hepatitis, Animal, MESH: Mice, Knockout, Hepatitis, MESH: Reverse Transcriptase Polymerase Chain Reaction, Immunology and Allergy, MESH : Female, Carbon Tetrachloride, MESH : Concanavalin A, Mice, Knockout, MESH : Tumor Necrosis Factor-alpha, Mice, Inbred BALB C, biology, Reverse Transcriptase Polymerase Chain Reaction, MESH : Adoptive Transfer, Cytokine, Liver, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH : Interleukin-6, MESH : Flow Cytometry, MESH : Male, MESH: Mice, Inbred BALB C, chemical and pharmacologic phenomena, MESH : Mice, medicine, Animals, MESH: Mice, MESH : Mice, Inbred BALB C, 030304 developmental biology, Interleukin-6, MESH : Liver, MESH : Natural Killer T-Cells, Molecular biology, MESH: Male, Interleukin 33, MESH: Natural Killer T-Cells, Hepatocytes, biology.protein, IL-33, MESH : Mice, Knockout, MESH : Animals, Antigens, CD1d, MESH : Interleukins, 030215 immunology
Abstract: International audience; Interleukin-33 (IL-33) is thought to be released during cellular death as an alarming cytokine during the acute phase of disease, but its regulation in vivo is poorly understood. We investigated the expression of IL-33 in two mouse models of acute hepatitis by administering either carbon tetrachloride (CCl(4) ) or concanavalin A (ConA). IL-33 was overexpressed in both models but with a stronger induction in ConA-induced hepatitis. IL-33 was weakly expressed in vascular and sinusoidal endothelial cells from normal liver and was clearly induced in CCl(4) -treated mice. Surprisingly, we found that hepatocytes strongly expressed IL-33 exclusively in the ConA model. CD1d knock-out mice, which are deficient in NKT cells and resistant to ConA-induced hepatitis, no longer expressed IL-33 in hepatocytes following ConA administration. Interestingly, invariant NKT (iNKT) cells adoptively transferred into ConA-treated CD1d KO mouse restored IL-33 expression in hepatocytes. This strongly suggests that NKT cells are responsible for the induction of IL-33 in hepatocytes.
Published: 2011
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13. 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
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14. Invariant natural killer T-cell-deficient mice display increased CCl₄ -induced hepatitis associated with CXCL1 over-expression and neutrophil infiltration

Author: Lisbonne, Mariette, L'Helgoualc'H, Annie, Nauwelaers, Gwendoline, Turlin, Bruno, Lucas, Catherine, Herbelin, André, Piquet-Pellorce, Claire, Samson, Michel, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), departement de pathologie, Laboratoire de biochimie générale, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Cytokines, hématopoïèse et réponse immune (CHRI), 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 de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140, Signalisation et Réponses aux Agents Infectieux et Chimiques ( SeRAIC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140, Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ), Cytokines, hématopoïèse et réponse immune ( CHRI ), 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 de Rennes (UR), and CHU Pontchaillou [Rennes]
Subjects: CXCL1/KC, Neutrophils, Chemokine CXCL1, Receptors, Antigen, T-Cell, alpha-beta, MESH : Carbon Tetrachloride, Apoptosis, MESH : Hepatocytes, Hepatitis, Animal, MESH: Neutrophils, MESH: Mice, Knockout, Hepatitis, MESH : Neutrophils, MESH: Hepatocytes, Mice, Cell Movement, MESH : Cell Movement, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Animals, MESH : Matrix Metalloproteinase 8, Carbon Tetrachloride, MESH: Cell Movement, Cells, Cultured, Mice, Knockout, Alanine, MESH: Receptors, Antigen, T-Cell, alpha-beta, MESH : Acute Disease, Neutrophil, MESH: Hepatitis, Animal, MESH : Chemokine CXCL1, Matrix Metalloproteinase 8, MESH : Receptors, Antigen, T-Cell, alpha-beta, Liver, Acute Disease, MESH: Acute Disease, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Cells, Cultured, MESH: Alanine, MESH : Aspartate Aminotransferases, MESH: Aspartate Aminotransferases, MESH : Mice, MESH : Cells, Cultured, Animals, MESH: Chemokine CXCL1, Aspartate Aminotransferases, MESH: Mice, MESH: Apoptosis, MESH: Carbon Tetrachloride, MESH : Liver, MESH : Natural Killer T-Cells, MESH: Natural Killer T-Cells, MESH: Matrix Metalloproteinase 8, Hepatocytes, Invariant NKT cells, MESH : Mice, Knockout, Natural Killer T-Cells, MESH : Animals, MESH : Alanine, MESH : Hepatitis, Animal, MESH : Apoptosis, MESH: Liver
Abstract: International audience; Invariant natural killer T (iNKT) cells are involved in the intrahepatic immune response and in hepatitis. In particular, iNKT lymphocytes are responsible for hepatocyte death in concanavalin A-induced hepatitis in mice. We examined the role of iNKT cells in acute hepatitis induced by a hepatotoxic agent, carbon tetrachloride (CCl(4) ). WT and iNKT cell-deficient (Jα18(-/-) ) mice were challenged with a single dose of 2.4 g/kg CCl(4) and both hepatic physiopathology and immune responses were studied. Plasma alanine and aspartate amino-transferase levels were significantly higher in Jα18(-/-) mice than in WT mice two days after CCl(4) administration. Chemokine CXCL1/keratinocyte-derived chemokine (KC) and MMP-8 were significantly higher in iNKT cell-deficient mice than in control mice. The more severe liver injury in Jα18(-/-) mice was associated with greater leukocyte infiltrate, which was enriched in neutrophils (CD11b(+) CD11c(-) Gr-1(+) cells), in agreement with CXCL1/KC and MMP-8 levels. Complementary experiments with NK-depleted animals indicate a minor role for NK cells in the liver damage found in iNKT-deficient mice. Thus, unlike for ConA-induced hepatitis, we report that iNKT cells protect the liver against acute hepatitis induced by CCl(4) and limit neutrophil infiltration.
Published: 2011
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15. Increased susceptibility to liver fibrosis with age is correlated with an altered inflammatory response

Author: Meriem Mahrouf-Yorgov, Claudine Cosson, Elsa Abdoun, Bernard Fromenty, Claudia Mitchell, Alexandra Collin de l'Hortet, Hélène Gilgenkrantz, Jacques-Emmanuel Guidotti, Abdelhamid Slama, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie [Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), 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 de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), 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-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Hépatotoxicité et xénobiotiques, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre
Subjects: MESH : Oxidative Stress, MESH: Inflammation, Liver Cirrhosis, Male, Aging, Necrosis, MESH : Carbon Tetrachloride, MESH : Hepatocytes, medicine.disease_cause, Liver disorder, MESH: Hepatocytes, Mice, 0302 clinical medicine, MESH : Chronic Disease, Fibrosis, MESH : Cell Proliferation, MESH: Aging, MESH: Animals, Carbon Tetrachloride, 0303 health sciences, MESH: Oxidative Stress, 3. Good health, medicine.anatomical_structure, Hepatocyte, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 030211 gastroenterology & hepatology, Disease Susceptibility, medicine.symptom, MESH: Liver Cirrhosis, MESH : Male, Hepatitis C virus, MESH: Disease Susceptibility, Context (language use), Inflammation, MESH : Mice, Inbred C57BL, Biology, MESH : Disease Susceptibility, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH: Cell Proliferation, MESH : Mice, medicine, MESH : Liver Cirrhosis, Animals, Humans, MESH: Mice, 030304 developmental biology, Cell Proliferation, MESH: Necrosis, MESH : Inflammation, MESH: Humans, MESH: Carbon Tetrachloride, MESH: Chronic Disease, MESH : Humans, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, MESH : Aging, MESH: Male, MESH : Necrosis, Mice, Inbred C57BL, Oxidative Stress, Immunology, Chronic Disease, Hepatocytes, MESH : Animals, Geriatrics and Gerontology, Oxidative stress
Abstract: International audience; It has been suggested that increasing age is correlated with an acceleration of the progression of liver fibrosis induced by various agents, such as hepatitis C virus or chronic alcohol consumption. However, the cellular and molecular changes underlying this predisposition are not entirely understood. In the context of an aging population, it becomes challenging to decipher the mechanisms responsible for this higher susceptibility of older individuals to this acquired liver disorder. To address this issue, we induced liver fibrosis by carbon tetrachloride (CCl(4)) chronic administration to 8-week- and 15-month-old mice. We confirmed that susceptibility to fibrosis development increased with age and showed that aging did not affect fibrosis resolution capacity. We then focused on the impairment of hepatocyte proliferation, oxidative stress, and inflammation as potential mechanisms accelerating the development of fibrosis in the elderly. We detected no inhibition of hepatocyte proliferation after CCl(4) injury in 15-month-old mice, whereas it was inhibited after a partial hepatectomy. Finally, we observed that, in a context in which liver oxidative stress was not differentially increased in both experimental groups, there was a higher recruitment of inflammatory cells, including mostly macrophages and lymphocytes, oriented toward a T helper 2 (T(H)2) response in older mice. Our data show that in conditions of equivalent levels of oxidative stress and maintained hepatocyte proliferative capacity, an increased inflammatory reaction mainly composed of CD4(+) lymphocytes and macrophages expressing T(H)2 cytokines is the main factor involved in the higher susceptibility to fibrosis with increasing age.
Published: 2011
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16. Overexpression of Bcl-2 in hepatocytes protects against injury but does not attenuate fibrosis in a mouse model of chronic cholestatic liver disease

Author: Bernard Fromenty, Claudia Mitchell, Alicia Mayeuf, Abdellah Mansouri, Marie-Anne Robin, Meriem Mahrouf-Yorgov, Hélène Gilgenkrantz, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hépatotoxicité et xénobiotiques, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de recherche biomédicale Bichat-Beaujon ( CRB3 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Necrosis, MESH : Blotting, Western, MESH : Hepatocytes, MESH: Lipid Peroxidation, MESH : Proto-Oncogene Proteins c-bcl-2, necrosis, MESH: Hepatocytes, Mice, 0302 clinical medicine, Fibrosis, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH : Bile Ducts, MESH: Animals, MESH: In Situ Nick-End Labeling, MESH : Ligation, Liver injury, 0303 health sciences, MESH: Electron Transport Complex I, MESH : Lipid Peroxidation, Reverse Transcriptase Polymerase Chain Reaction, Histological Techniques, MESH : Reverse Transcriptase Polymerase Chain Reaction, apoptosis, Fas receptor, MESH : Mice, Transgenic, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, Caspases, Hepatocyte, MESH : In Situ Nick-End Labeling, MESH : Histological Techniques, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 030211 gastroenterology & hepatology, medicine.symptom, Programmed cell death, medicine.medical_specialty, MESH: Mice, Transgenic, Blotting, Western, Mice, Transgenic, Cholestasis, Intrahepatic, MESH: Histological Techniques, Biology, Pathology and Forensic Medicine, 03 medical and health sciences, Cholestasis, Internal medicine, MESH : Mice, In Situ Nick-End Labeling, medicine, Animals, MESH: Blotting, Western, Bcl-2, Ligation, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: Necrosis, Electron Transport Complex I, MESH: Caspases, MESH: Cholestasis, Intrahepatic, MESH: Apoptosis, MESH : Electron Transport Complex I, fibrosis, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, MESH: Ligation, medicine.disease, oxydative stress, MESH : Necrosis, Endocrinology, MESH: Proto-Oncogene Proteins c-bcl-2, Apoptosis, inflammation, Hepatocytes, MESH : Cholestasis, Intrahepatic, Bile Ducts, Lipid Peroxidation, MESH : Animals, MESH : Caspases, MESH: Bile Ducts, cholestasis, MESH : Apoptosis
Abstract: International audience; The role of hepatocyte apoptosis in the physiopathology of obstructive cholestasis is still controversial. Although some data have strongly suggested that hepatocellular cholestatic injury is due to Fas-mediated hepatocyte apoptosis, some others concluded that necrosis, rather than apoptosis, represents the main type of hepatocyte death in chronic cholestasis. Moreover, it has also been suggested that the reduced liver injury observed in the absence of Fas receptor after bile duct ligation was not due to lower hepatocyte apoptosis but to the indirect role of this receptor in non-hepatocytic cells such as cholangiocytes and inflammatory cells. The aim of this work was therefore to determine whether a protection against cell death limited to hepatocytes could be sufficient to reduce liver injury and delay cholestatic fibrosis. With this purpose, we performed bile duct ligation in transgenic mice overexpressing Bcl-2 in hepatocytes and in wild-type littermates. We found that, compared with necrosis, apoptosis was negligible in this model. Our results also showed that hepatocyte Bcl-2 expression protected hepatocytes against liver injury only in the early steps of the disease. This protection was correlated with reduced mitochondrial dysfunction and lipid peroxidation. However, in contrast to Fas receptor-deficient lpr mice, fibrosis progression was not hampered and liver inflammatory response was not reduced by Bcl-2 overexpression. These results therefore comfort the hypothesis that Fas-mediated apoptotic hepatocyte pathway is not a significant contributing factor to the clinical features observed in cholestasis. Moreover, in the absence of a blunted inflammatory response in transgenic mice, Bcl-2 protection against hepatocyte mitochondrial dysfunction and lipid peroxidation was not sufficient to block fibrosis progression.
Published: 2011
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17. Effects of a high-fat diet on energy metabolism and ROS production in rat liver

Author: Anne Galinier, Hervé Dubouchaud, Nellie Taleux, Karine Couturier, Cécile Cottet-Rousselle, Louis Casteilla, Anne Athias, Xavier Leverve, Guillaume Vial, Bioenergétique fondamentale et appliquée ( LBFA ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Métabolisme, plasticité et mitochondrie, Université Paul Sabatier - Toulouse 3 ( UPS ) -IFR31-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Hamant, Sarah
Subjects: Mitochondrial ROS, Male, Transcription, Genetic, MESH : Reactive Oxygen Species, Mitochondria, Liver, MESH : Hepatocytes, Mitochondrion, Oxidative Phosphorylation, MESH: Hepatocytes, 0302 clinical medicine, MESH: Membrane Potential, Mitochondrial, Citrate synthase, MESH: Animals, Beta oxidation, MESH : Electron Transport, 2. Zero hunger, Membrane Potential, Mitochondrial, 0303 health sciences, MESH : Rats, Adenine nucleotide translocator, MESH: Energy Metabolism, MESH: Reactive Oxygen Species, Lipids, Biochemistry, Liver, MESH: Dietary Fats, Mitochondrial matrix, 030220 oncology & carcinogenesis, Body Composition, MESH : Oxidative Phosphorylation, ATP–ADP translocase, MESH: Mitochondria, Liver, MESH: Rats, MESH : Body Composition, MESH : Male, Oxidative phosphorylation, Biology, MESH : Rats, Wistar, Electron Transport, 03 medical and health sciences, MESH: Oxidative Phosphorylation, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Rats, Wistar, MESH: Electron Transport, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Hepatology, MESH: Transcription, Genetic, MESH : Transcription, Genetic, MESH : Liver, MESH : Lipids, MESH: Body Composition, MESH: Rats, Wistar, MESH: Lipids, Dietary Fats, MESH: Male, Rats, MESH : Energy Metabolism, MESH : Membrane Potential, Mitochondrial, MESH : Mitochondria, Liver, biology.protein, Hepatocytes, MESH : Animals, Energy Metabolism, Reactive Oxygen Species, MESH : Dietary Fats, MESH: Liver
Abstract: International audience; BACKGROUND & AIMS: A high-fat diet affects liver metabolism, leading to steatosis, a complex disorder related to insulin resistance and mitochondrial alterations. Steatosis is still poorly understood since diverse effects have been reported, depending on the different experimental models used. METHODS: We hereby report the effects of an 8 week high-fat diet on liver energy metabolism in a rat model, investigated in both isolated mitochondria and hepatocytes. RESULTS: Liver mass was unchanged but lipid content and composition were markedly affected. State-3 mitochondrial oxidative phosphorylation was inhibited, contrasting with unaffected cytochrome content. Oxidative phosphorylation stoichiometry was unaffected, as were ATPase and adenine nucleotide translocator proteins and mRNAs. Mitochondrial acylcarnitine-related H(2)O(2) production was substantially higher and the mitochondrial quinone pool was smaller and more reduced. Cellular consequences of these mitochondrial alterations were investigated in perifused, freshly isolated hepatocytes. Ketogenesis and fatty acid-dependent respiration were lower, indicating a lower β-oxidation rate contrasting with higher RNA contents of CD36, FABP, CPT-1, and AcylCoA dehydrogenases. Concomitantly, the cellular redox state was more reduced in the mitochondrial matrix but more oxidized in the cytosol: these opposing changes are in agreement with a significantly higher in situ mitochondrial proton motive force. CONCLUSIONS: A high-fat diet results in both a decrease in mitochondrial quinone pool and a profound modification in mitochondrial lipid composition. These changes appear to play a key role in the resulting inhibition of fatty acid oxidation and of mitochondrial oxidative-phosphorylation associated with an increased mitochondrial ROS production. Mitochondrial quinone pool could have prospects as a crucial event, potentially leading to interesting therapeutic perspectives.
Published: 2011
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18. Antiviral activity of Bay 41-4109 on hepatitis B virus in humanized Alb-uPA/SCID mice

Author: Eric Giang, Jacques Belghiti, Serban Morosan, Sophie Berissi, Céline Lamant, Johan Neyts, Eva Wimmer, Gherard Puerstinger, Patrick Soussan, Lucie DaSilva, Olivier Hantz, Marie-Noëlle Brunelle, Laurent Hannoun, Dina Kremsdorf, Hélène Massinet, Nicolas Brezillon, IFR Laennec (IL), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), neuroscience and barin technology, Service de chirurgie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Chirurgie Digestive, Hépato-Bilio-pancréatique et Transplantation Hépatique [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Microbiology and Immunology, Rega Institute for Medical Research, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), equipe 16, Physiopathologie moléculaire et nouveaux traitements des hépatites virales, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Carcinogenèse Hépatique et Virologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), Pathogénèse des Hépatites Virales B et Immunothérapie (UMR_S 812), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR Laennec ( IL ), Institut National de la Recherche Agronomique ( INRA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Beaujon, Service de chirurgie digestive et hépato-bilio-pancréatique [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Catholic University of Leuven ( KU Leuven ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [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 ) -Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Pathogénèse des Hépatites Virales B et Immunothérapie ( UMR_S 812 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université de Lyon-Université de Lyon-IFR62-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Cancérologie de Lyon (CRCL), and Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Mouse, Pyridines, Gastroenterology and hepatology, Biopsy, medicine.medical_treatment, MESH : Immunohistochemistry, MESH : Pyrimidines, MESH : Hepatitis B virus, MESH : Viral Load, Mice, SCID, MESH : Hepatocytes, Liver transplantation, medicine.disease_cause, Hepatitis, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Hepatocytes, Mice, MESH: Biopsy, 0302 clinical medicine, MESH : Albumins, MESH: Animals, MESH : DNA, Viral, MESH: Mice, SCID, 0303 health sciences, Multidisciplinary, MESH: Kinetics, virus diseases, Animal Models, Viral Load, Hepatitis B, Antivirals, Immunohistochemistry, 3. Good health, MESH : Antiviral Agents, Infectious hepatitis, MESH: Hepatitis B virus, Real-time polymerase chain reaction, Liver, Capsid, 030220 oncology & carcinogenesis, Infectious diseases, Medicine, MESH : Kinetics, MESH: Viral Load, Viral load, Research Article, MESH: Antiviral Agents, Hepatitis B virus, MESH : Pyridines, Science, Alpha interferon, Viremia, [SDV.CAN]Life Sciences [q-bio]/Cancer, Viral diseases, Biology, Antiviral Agents, Microbiology, 03 medical and health sciences, Model Organisms, Albumins, Virology, MESH : Mice, medicine, Animals, Humans, MESH: Mice, Liver diseases, 030304 developmental biology, MESH: Humans, MESH: Hepatitis B, MESH : Humans, MESH: Pyridines, MESH : Liver, MESH : Hepatitis B, MESH: Immunohistochemistry, medicine.disease, MESH : Mice, SCID, digestive system diseases, MESH: DNA, Viral, Kinetics, Animal Models of Infection, Pyrimidines, Viral replication, MESH : Biopsy, MESH: Pyrimidines, DNA, Viral, Immunology, Hepatocytes, MESH : Animals, MESH: Albumins, MESH: Liver
Abstract: International audience; Current treatments for HBV chronic carriers using interferon alpha or nucleoside analogues are not effective in all patients and may induce the emergence of HBV resistant strains. Bay 41-4109, a member of the heteroaryldihydropyrimidine family, inhibits HBV replication by destabilizing capsid assembly. The aim of this study was to determine the antiviral effect of Bay 41-4109 in a mouse model with humanized liver and the spread of active HBV. Antiviral assays of Bay 41-4109 on HepG2.2.15 cells constitutively expressing HBV, displayed an IC(50) of about 202 nM with no cell toxicity. Alb-uPA/SCID mice were transplanted with human hepatocytes and infected with HBV. Ten days post-infection, the mice were treated with Bay 41-4109 for five days. During the 30 days of follow-up, the HBV load was evaluated by quantitative PCR. At the end of treatment, decreased HBV viremia of about 1 log(10) copies/ml was observed. By contrast, increased HBV viremia of about 0.5 log(10) copies/ml was measured in the control group. Five days after the end of treatment, a rebound of HBV viremia occurred in the treated group. Furthermore, 15 days after treatment discontinuation, a similar expression of the viral capsid was evidenced in liver biopsies. Our findings demonstrate that Bay 41-4109 displayed antiviral properties against HBV in humanized Alb-uPA/SCID mice and confirm the usefulness of Alb-uPA/SCID mice for the evaluation of pharmaceutical compounds. The administration of Bay 41-4109 may constitute a new strategy for the treatment of patients in escape from standard antiviral therapy.
Published: 2011
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19. What makes cells move: requirements and obstacles for spontaneous cell motility

Author: Urszula Hibner, Fabien Binamé, Géraldine Pawlak, Pierre Roux, Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherches de biochimie macromoléculaire ( CRBM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -IFR122-Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de recherches de biochimie macromoléculaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-IFR122-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Géophysique Interne et Tectonophysique (LGIT), Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Laboratoire Central des Ponts et Chaussées (LCPC)-Institut des Sciences de la Terre (ISTerre), Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-PRES Université de Grenoble-Institut de recherche pour le développement [IRD] : UR219-Institut national des sciences de l'Univers (INSU - CNRS)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-PRES Université de Grenoble-Institut de recherche pour le développement [IRD] : UR219-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR), Association pour la recherche sur le cancer, La Ligue contre le cancer, Agence Nationale de Recherche sur le Sida et les hépatites virales et Institut National du Cancer, Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ), Laboratoire de Géophysique Interne et Tectonophysique ( LGIT ), Observatoire des Sciences de l'Univers de Grenoble ( OSUG ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ) -Laboratoire Central des Ponts et Chaussées ( LCPC ) -Institut des Sciences de la Terre ( ISTerre ), Université Grenoble Alpes ( UGA ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ) -PRES Université de Grenoble-Institut de recherche pour le développement [IRD] : UR219-Institut national des sciences de l'Univers ( INSU - CNRS ) -Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux ( IFSTTAR ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ) -PRES Université de Grenoble-Institut de recherche pour le développement [IRD] : UR219-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux ( IFSTTAR ), Centre de recherche en Biologie Cellulaire (CRBM), and Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)
Subjects: MESH: Signal Transduction, MESH : Hepatocytes, MESH : Models, Biological, Mechanotransduction, Cellular, MESH : Mechanotransduction, Cellular, MESH: Hepatocytes, 0302 clinical medicine, Cell Movement, MESH : Cell Movement, MESH: Animals, Mechanotransduction, MESH: Cell Movement, 0303 health sciences, Amoeboid movement, Systems Biology, Cell Polarity, Cell migration, Molecular machine, Cell biology, 030220 oncology & carcinogenesis, MESH: Systems Biology, MESH : Imaging, Three-Dimensional, MESH: Cell Polarity, MESH : Cell Polarity, Biotechnology, Signal Transduction, Systems biology, Context (language use), MESH: Imaging, Three-Dimensional, Biology, In Vitro Techniques, Models, Biological, MESH: Cell Adhesion, 03 medical and health sciences, Imaging, Three-Dimensional, Cell Adhesion, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDU.STU.GM]Sciences of the Universe [physics]/Earth Sciences/Geomorphology, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH : Systems Biology, MESH : Signal Transduction, MESH: Humans, [ SDU.STU.GM ] Sciences of the Universe [physics]/Earth Sciences/Geomorphology, MESH: Mechanotransduction, Cellular, Mesenchymal stem cell, MESH : Humans, MESH: Models, Biological, Multicellular organism, MESH : Cell Adhesion, Hepatocytes, MESH : Animals
Abstract: International audience; Movement of individual cells and of cellular cohorts, chains or sheets requires physical forces that are established through interactions of cells with their environment. In vivo, migration occurs extensively during embryonic development and in adults during wound healing and tumorigenesis. In order to identify the molecular events involved in cell movement, in vitro systems have been developed. These have contributed to the definition of a number of molecular pathways put into play in the course of migratory behaviours, such as mesenchymal and amoeboid movement. More recently, our knowledge of migratory modes has been enriched by analyses of cells exploring and moving through three-dimensional (3D) matrices. While the cells' morphologies differ in 2D and 3D environments, the basic mechanisms that put a cellular body into motion are remarkably similar. Thus, in both 2D and 3D, the polarity of the migrating cell is initially defined by a specific subcellular localization of signalling molecules and components of molecular machines required for motion. While the polarization can be initiated either in response to extracellular signalling or be a chance occurrence, it is reinforced and sustained by positive feedback loops of signalling molecules. Second, adhesion to a substratum is necessary to generate forces that will propel the cell engaged in either mesenchymal or ameboid migration. For collective cell movement, intercellular coordination constitutes an additional requirement: a cell cohort remains stationary if individual cells pull in opposite directions. Finally, the availability of space to move into is a general requirement to set cells into motion. Lack of free space is probably the main obstacle for migration of most healthy cells in an adult multicellular organism. Thus, the requirements for cell movement are both intrinsic to the cell, involving coordinated signalling and interactions with molecular machines, and extrinsic, imposed by the physicochemical nature of the environment. In particular, the geometry and stiffness of the support act on a range of signalling pathways that induce specific cell migratory responses. These issues are discussed in the present review in the context of published work and our own data on collective migration of hepatocyte cohorts.
Published: 2010
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20. General review on in vitro hepatocyte models and their applications

Author: Christiane, Guguen-Guillouzo, Andre, Guillouzo, Régulations des équilibres fonctionnels du foie normal et pathologique, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Détoxication et réparation tissulaire, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Xenobiotics, MESH : Cell Culture Techniques, proliferation, Cell Culture Techniques, MESH : Xenobiotics, transporters, MESH : Hepatocytes, MESH : Models, Biological, cryopreservation, Models, Biological, Toxicogenetics, bile metabolism, Xenobiotics, MESH: Hepatocytes, stem cells, culture conditions, Animals, Humans, MESH: Animals, MESH: Cell Culture Techniques, MESH: Humans, liver cell lines, MESH : Humans, MESH: Models, Biological, MESH : Toxicogenetics, MESH: Toxicogenetics, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, differentiation, HepaRG cells, Hepatocytes, xenebiotic metabolism, hapatotoxicity, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH : Animals
Abstract: International audience; In vitro hepatocyte models represent very useful systems in both fundamental research and various application areas. Primary hepatocytes appear as the closest model for the liver in vivo. However, they are phenotypically unstable, have a limited life span and in addition, exhibit large interdonor variability when of human origin. Hepatoma cell lines appear as an alternative but only the HepaRG cell line exhibits various functions, including major cytochrome P450 activities, at levels close to those found in primary hepatocytes. In vitro hepatocyte models have brought a substantial contribution to the understanding of the biochemistry, physiology, and cell biology of the normal and diseased liver and in various application domains such as xenobiotic metabolism and toxicity, virology, parasitology, and more generally cell therapies. In the future, new well-differentiated hepatocyte cell lines derived from tumors or from either embryonic or adult stem cells might be expected and although hepatocytes will continue to be used in various fields, these in vitro liver models should allow marked advances, especially in cell-based therapies and predictive and mechanistic hepatotoxicity of new drugs and other chemicals. All models will benefit from new developments in throughput screening based on cell chips coupled with high-content imaging and in toxicogenomics technologies.
Published: 2010
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21. Impact of visceral adipose tissue on liver metabolism and insulin resistance. Part II: Visceral adipose tissue production and liver metabolism

Author: J. Girard, Max Lafontan, Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de médecine moléculaire de Rangueil ( I2MR ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Simon, Marie Francoise, Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH : Fatty Liver, Endocrinology, Diabetes and Metabolism, Adipose tissue, White adipose tissue, MESH : Hepatocytes, MESH: Hepatocytes, chemistry.chemical_compound, Endocrinology, MESH : Diabetes Mellitus, Type 2, Nonalcoholic fatty liver disease, MESH : Cardiovascular Diseases, MESH: Fatty Liver, MESH : Viscera, Fatty liver, General Medicine, MESH : Triglycerides, MESH: Viscera, MESH: Glucose, MESH: Insulin Resistance, Adipose Tissue, Liver, Cardiovascular Diseases, MESH : Insulin Resistance, MESH: Adipose Tissue, MESH: Diabetes Mellitus, Type 2, MESH: Triglycerides, medicine.medical_specialty, Adipose tissue macrophages, Biology, Carbohydrate metabolism, MESH : Adipose Tissue, Insulin resistance, Internal medicine, Internal Medicine, medicine, Humans, Triglycerides, MESH: Humans, Triglyceride, MESH : Glucose, MESH : Humans, MESH: Cardiovascular Diseases, MESH : Liver, medicine.disease, Fatty Liver, Viscera, Glucose, Diabetes Mellitus, Type 2, chemistry, Hepatocytes, Insulin Resistance, MESH: Liver
Abstract: International audience; Excess visceral adipose tissue is associated with anomalies of blood glucose homoeostasis, elevation of plasma triglycerides and low levels of high-density lipoprotein cholesterol that contribute to the development of type-2 diabetes and cardiovascular syndromes. Visceral adipose tissue releases a large amount of free fatty acids and hormones/cytokines in the portal vein that are delivered to the liver. The secreted products interact with hepatocytes and various immune cells in the liver. Altered liver metabolism and determinants of insulin resistance associated with visceral adipose tissue distribution are discussed, as well as, determinants of an insulin-resistant state promoted by the increased free fatty acids and cytokines delivered by visceral adipose tissue to the liver.
Published: 2008
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22. Expression of major histocompatibility complex class I chain-related molecule A, NKG2D, and transforming growth factor-beta in the liver of humans with alveolar echinococcosis: new actors in the tolerance to parasites?

Author: Solange Bresson-Hadni, Sophie Hue, Sophie Caillat-Zucman, Shaoling Zhang, Damien Sène, Dominique A. Vuitton, Bernadette Kantelip, Alfred Penfornis, Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( EA 3920) (PCVP / CARDIO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Diabétologie - Endocrinologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), WHO Collaborating Center on Prevention and Treatment of Human Echinococcosis, Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Service d'Anatomie pathologique [CHRU Besançon], Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), WHO Collaborating Center on Prevention and Treatment of Human Echinococcosis, SERF Unit, Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( PCVP / CARDIO ), Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Service de diabétologie - endocrinologie, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Université de Franche-Comté ( UFC ), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), Laboratoire d'anatomie pathologique [Besancon], Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz-Université de Franche-Comté ( UFC ), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Laboratoire Chrono-environnement - CNRS - UFC (UMR 6249) (LCE), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz-Université de Franche-Comté (UFC), and Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)
Subjects: MESH : Host-Parasite Interactions, Genes, MHC Class I, MESH : Hepatocytes, MESH : Echinococcus multilocularis, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Histocompatibility Antigens Class I, MESH: Hepatocytes, 0302 clinical medicine, Transforming Growth Factor beta, MESH : Receptors, Immunologic, Immunology and Allergy, MESH: Animals, Receptors, Immunologic, [ SDV.MP.MYC ] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, 0303 health sciences, MESH: Echinococcosis, Hepatic, MESH: Genes, MHC Class I, 3. Good health, Infectious Diseases, medicine.anatomical_structure, Liver, NK Cell Lectin-Like Receptor Subfamily K, Receptors, Natural Killer Cell, MESH: NK Cell Lectin-Like Receptor Subfamily K, MESH : Histocompatibility Antigens Class I, Echinococcosis, Hepatic, T cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Major histocompatibility complex, MESH: Host-Parasite Interactions, MESH : Genes, MHC Class I, Natural killer cell, Host-Parasite Interactions, MESH: Receptors, Natural Killer Cell, 03 medical and health sciences, MESH : Receptors, Natural Killer Cell, MHC class I, medicine, MESH : NK Cell Lectin-Like Receptor Subfamily K, Animals, Humans, MESH: Receptors, Immunologic, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH: Echinococcus multilocularis, MESH: Humans, Histocompatibility Antigens Class I, MESH : Humans, MESH : Liver, NKG2D, Molecular biology, stomatognathic diseases, MESH : Transforming Growth Factor beta, Giant cell, Immunology, biology.protein, Hepatocytes, Echinococcus multilocularis, MESH : Animals, MESH : Echinococcosis, Hepatic, CD8, 030215 immunology, Transforming growth factor, MESH: Liver
Abstract: International audience; BACKGROUND: Echinococcus multilocularis growth and persistent granuloma, which lead to the development of the severe parasitic disease alveolar echinococcosis (AE), might be caused by abnormal expression of stress-induced proteins, with subsequent abnormalities in T cell activation. Similar to its involvement in tumors, the NKG2D-major histocompatability complex class I chain-related molecules A and B (MICA/B) signaling system could be involved in host-parasite interactions; however, its involvement in helminthic diseases has never been studied. METHODS: We studied MICA/B, NKG2D, and transforming growth factor-beta (TGF-beta) expression on liver sections and measured levels of soluble MICA in serum samples obtained from patients with progressive AE. Livers from healthy and cirrhotic subjects were studied as controls. RESULTS: Expression of MICA/B proteins was strongly enhanced in the hepatocytes and endothelial and bile duct cells; in the CD68+ cells of the periparasitic infiltrate, especially epithelioid and giant cells; and, also, in the metacestode germinal layer. Strong expression of MICA/B in the liver contrasted with low numbers of NK cells and lack of expression of NKG2D on the numerous CD8+ T lymphocytes of the periparasitic infiltrate, as well as with the absence of soluble MICA in serum. TGF-beta was strongly expressed by most of the infiltrating lymphocytes. CONCLUSIONS: Sustained expression of MICA/B molecules and TGF-beta might lead to modulation of NKG2D with subsequent inhibition of NKG2D-dependent cytotoxicity. Abnormalities of this signaling system could contribute to parasitic evasion of the host's immunity.
Published: 2008
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23. Transforming growth factor beta controls the directional migration of hepatocyte cohorts by modulating their adhesion to fibronectin

Author: Urszula Hibner, Fabien Binamé, Patrice Lassus, Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Génétique Moléculaire de Montpellier (IGMM), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: rac1 GTP-Binding Protein, MESH : Cell Line, MESH : Protein Subunits, Apoptosis, Cell Communication, Integrin alpha5, MESH : Hepatocytes, Epithelium, Mesoderm, MESH: Hepatocytes, Mice, 0302 clinical medicine, Cell Movement, Transforming Growth Factor beta, MESH: Fibronectins, MESH : Cell Movement, MESH : Fibronectins, MESH: Animals, MESH: Cell Movement, MESH: Mesoderm, 0303 health sciences, MESH : Gene Expression Regulation, MESH: Cell Surface Extensions, MESH : Mesoderm, Articles, Adhesion, MESH: Protein Subunits, MESH: Gene Expression Regulation, Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Hepatocyte, MESH: Integrin alpha5, MESH : Cell Communication, MESH : Cell Membrane, MESH : Cell Surface Extensions, Biology, Cell Line, MESH: Cell Adhesion, MESH: Gene Expression Profiling, 03 medical and health sciences, MESH : rac1 GTP-Binding Protein, MESH : Integrin alpha5, MESH: Cell Communication, MESH : Mice, Cell Adhesion, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH: Humans, MESH: rac1 GTP-Binding Protein, Gene Expression Profiling, MESH: Apoptosis, MESH : Gene Expression Profiling, Cell Membrane, MESH : Humans, Cell Biology, MESH : Epithelium, Fibronectins, MESH: Cell Line, Fibronectin, Protein Subunits, MESH: Epithelium, MESH : Cell Adhesion, MESH : Transforming Growth Factor beta, Gene Expression Regulation, Hepatocytes, biology.protein, Cell Surface Extensions, MESH : Animals, MESH : Apoptosis, MESH: Cell Membrane, Transforming growth factor
Abstract: International audience; Transforming growth factor beta (TGF-beta) has a strong impact on liver development and physiopathology, exercised through its pleiotropic effects on growth, differentiation, survival, and migration. When exposed to TGF-beta, the mhAT3F cells, immortalized, highly differentiated hepatocytes, maintained their epithelial morphology and underwent dramatic alterations of adhesion, leading to partial or complete detachment from a culture plate, followed by readhesion and spreading. These alterations of adhesive behavior were caused by sequential changes in expression of the alpha5beta1 integrin and of its ligand, the fibronectin. The altered specificity of anchorage to the extracellular matrix gave rise to changes in cells' collective motility: cohorts adhering to fibronectin maintained a persistent, directional motility, with ezrin-rich pathfinder cells protruding from the tips of the cohorts. The absence of adhesion to fibronectin prevented the appearance of polarized pathfinders and lead to random, oscillatory motility. Our data suggest a novel role for TGF-beta in the control of collective migration of epithelial cohorts.
Published: 2008
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24. NOD2: a potential target for regulating liver injury

Author: Jean-Pierre Hugot, Philippe Mathurin, Sylvie Hudault, Sébastien Dharancy, Laurent Dubuquoy, Mathias Chamaillard, Filomena Conti, Pierre Desreumaux, Irene Garcia, Alexandre Louvet, Dominique Berrebi, Emilie Gantier, Philippe J. Sansonetti, Dana J. Philpott, Fabrice Chareyre, Mathilde Body-Malapel, Gilles Pagès, Marco Giovannini, Stephen E. Girardin, Physiopathologie des Maladies Inflammatoires de l'Intestin, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Université de Lille, Droit et Santé, Hôpital Duriez, Service des Maladies de l'Appareil digestif et de la Nutrition, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Anatomie et de Cytologie Pathologiques, Hôpital Robert Debré, Inflammation intestinale pathologique de l'enfant, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Immunology, University of Toronto, 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), Institut de signalisation, biologie du développement et cancer (ISBDC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Department of Laboratory Medicine and Pathobiology (LMP), Université de Genève = University of Geneva (UNIGE), Pathogenes et Fonctions des Cellules Epitheliales Polarisees, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biologie Cellulaire, Université Paris Descartes - Paris 5 (UPD5), Pathogénie Microbienne Moléculaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France - Chaire Microbiologie et Maladies infectieuses, Collège de France (CdF (institution)), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Genomique Fonctionnelle des Tumeurs Solides, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -IFR105-Université Paris Diderot - Paris 7 ( UPD7 ), Institut de signalisation, biologie du développement et cancer ( ISBDC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Laboratory Medicine and Pathobiology ( LMP ), Department of Pathology and Immunology, Univ. Geneva, University of Geneva [Switzerland], Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], and Chaire Microbiologie et Maladies infectieuses
Subjects: MESH : RNA, Messenger, MESH: Spleen, Lymphocyte, Nod2 Signaling Adaptor Protein, RNA, Messenger/metabolism, MESH: Adjuvants, Immunologic, Apoptosis, MESH : Hepatocytes, ddc:616.07, MESH : Nod2 Signaling Adaptor Protein, Interferon-gamma/analysis/pharmacology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Hepatocytes, Mice, 0302 clinical medicine, Concanavalin A, MESH: Up-Regulation, MESH: Nod2 Signaling Adaptor Protein, MESH: Animals, MESH : Up-Regulation, MESH : Acetylmuramyl-Alanyl-Isoglutamine, Cells, Cultured, Liver injury, 0303 health sciences, Leukocytes, Mononuclear/drug effects/*immunology, MESH: Hepatitis, Animal, MESH : Interferon Type II, MESH: Case-Control Studies, 3. Good health, Up-Regulation, Acetylmuramyl-Alanyl-Isoglutamine/pharmacology, 030220 oncology & carcinogenesis, Hepatocytes/drug effects/metabolism/physiology, Muramyl dipeptide, MESH: Cells, Cultured, MESH : Case-Control Studies, Liver/*injuries, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Concanavalin A, Nod2 Signaling Adaptor Protein/analysis/*deficiency/genetics/*metabolism, Pathology and Forensic Medicine, Interferon-gamma, 03 medical and health sciences, Adjuvants, Immunologic, Humans, RNA, Messenger, Molecular Biology, MESH: Humans, Tumor Necrosis Factor-alpha, MESH : Humans, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, digestive system diseases, Immunity, Innate, MESH : Leukocytes, Mononuclear, Mice, Inbred C57BL, chemistry, MESH: Tumor Necrosis Factor-alpha, Case-Control Studies, Immunology, Hepatitis, Animal/chemically induced/*immunology/metabolism/pathology, Leukocytes, Mononuclear, MESH : Hepatitis, Animal, MESH : Apoptosis, MESH: Liver, MESH : Immunity, Natural, Cell Separation, Hepatitis, Animal, MESH: Mice, Knockout, chemistry.chemical_compound, Adjuvants, Immunologic/pharmacology, NOD2, MESH : Concanavalin A, Tumor Necrosis Factor-alpha/analysis/pharmacology, MESH : Tumor Necrosis Factor-alpha, Mice, Knockout, MESH: Kinetics, Concanavalin A/toxicity, MESH: Leukocytes, Mononuclear, medicine.anatomical_structure, Liver, medicine.symptom, MESH : Kinetics, Acetylmuramyl-Alanyl-Isoglutamine, Cell Separation/methods, MESH : Spleen, MESH: Interferon Type II, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemical and pharmacologic phenomena, MESH : Mice, Inbred C57BL, Biology, MESH: Cell Separation, Immune system, MESH: Mice, Inbred C57BL, MESH : Mice, MESH : Cells, Cultured, medicine, Animals, Spleen/cytology/drug effects, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, MESH: Immunity, Natural, Hepatitis, Innate immune system, MESH: Apoptosis, MESH : Liver, Cell Biology, Kinetics, MESH: Acetylmuramyl-Alanyl-Isoglutamine, MESH : Cell Separation, Hepatocytes, MESH : Adjuvants, Immunologic, MESH : Mice, Knockout, MESH : Animals, Spleen
Abstract: The recent discovery of bacterial receptors such as NOD2 that contribute to crosstalk between innate and adaptive immune systems in the digestive tract constitutes an important challenge in our understanding of liver injury mechanisms. The present study focuses on NOD2 functions during liver injury. NOD2, TNF-alpha and IFN-gamma mRNA were quantified using real-time PCR in liver samples from patients and mice with liver injury. We evaluated the susceptibility of concanavalin A (ConA) challenge in NOD2-deficient mice (Nod2-/-) compared to wild-type littermates. We tested the effect of muramyl dipeptide (MDP), the specific activator of NOD2, on ConA-induced liver injury in C57BL/6 mice. We studied the cellular distribution and the role of NOD2 in immune cells and hepatocytes. We demonstrated that NOD2, TNF-alpha and IFN-gamma were upregulated during liver injury in mice and humans. Nod2-/- mice were resistant to ConA-induced hepatitis compared to their wild-type littermates, through reduced IFN-gamma production by immune cells. Conversely, administration of MDP exacerbated ConA-induced liver injury. MDP was a strong inducer of IFN-gamma in freshly isolated human PBMC, splenocytes and hepatocytes. Our study supports the hypothesis that NOD2 contributes to liver injury via a regulatory mechanism affecting immune cells infiltrating the liver and hepatocytes. Taken together, our results indicate that NOD2 may represent a new therapeutic target in liver diseases.
Published: 2008
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25. Loss of Trim24 (Tif1alpha) gene function confers oncogenic activity to retinoic acid receptor alpha

Author: Johan Tisserand, Daniel Metzger, Pierre Chambon, Benjamin Herquel, Florence Cammas, Marius Teletin, Mihaela Ignat, Christelle Thibault, Konstantin Khetchoumian, Thierry Lerouge, Manuel Mark, Jessica Zucman-Rossi, Régine Losson, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Labex Immuno-oncology, 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)-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)-PRES Sorbonne Paris Cité-Faculté de Médecine, Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Institut de génétique et biologie moléculaire et cellulaire ( IGBMC ), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), 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 ) -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 ) -PRES Sorbonne Paris Cité-Faculté de Médecine, and 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)-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)-PRES Sorbonne Paris Cité-Faculté de Médecine
Subjects: MESH : Liver Neoplasms, MESH : Transcription Factors, Receptors, Retinoic Acid, Retinoic acid, Retinoic acid receptor beta, MESH : Hepatocytes, MESH: Hepatocytes, Mice, chemistry.chemical_compound, 0302 clinical medicine, MESH: Liver Neoplasms, MESH : Cell Proliferation, Genes, Tumor Suppressor, MESH: Animals, MESH: Carcinoma, Hepatocellular, 0303 health sciences, Retinoic Acid Receptor alpha, Liver Neoplasms, Nuclear Proteins, MESH: Transcription Factors, MESH : Receptors, Retinoic Acid, 030220 oncology & carcinogenesis, MESH : Carcinoma, Hepatocellular, Carcinoma, Hepatocellular, MESH : Genes, Tumor Suppressor, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biology, Retinoic acid-inducible orphan G protein-coupled receptor, 03 medical and health sciences, MESH: Cell Proliferation, MESH : Mice, Genetics, Animals, MESH: Mice, Cell Proliferation, 030304 developmental biology, MESH: Receptors, Retinoic Acid, Retinoid X receptor alpha, MESH : Nuclear Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Retinoic acid receptor gamma, MESH: Genes, Tumor Suppressor, Retinoid X receptor gamma, Retinoic acid receptor, chemistry, Retinoic acid receptor alpha, Hepatocytes, Cancer research, MESH : Animals, MESH: Nuclear Proteins, Transcription Factors
Abstract: Hepatocellular carcinoma (HCC) is a major cause of death worldwide. Here, we provide evidence that the ligand-dependent nuclear receptor co-regulator Trim24 (also known as Tif1alpha) functions in mice as a liver-specific tumor suppressor. In Trim24-null mice, hepatocytes fail to execute proper cell cycle withdrawal during the neonatal-to-adult transition and continue to cycle in adult livers, becoming prone to a continuum of cellular alterations that progress toward metastatic HCC. Using pharmacological approaches, we show that inhibition of retinoic acid signaling markedly reduces hepatocyte proliferation in Trim24-/- mice. We further show that deletion of a single retinoic acid receptor alpha (Rara) allele in a Trim24-null background suppresses HCC development and restores wild-type expression of retinoic acid-responsive genes in the liver, thus demonstrating that in this genetic background Rara expresses an oncogenic activity correlating with a dysregulation of the retinoic acid signaling pathway. Our results not only provide genetic evidence that Trim24 and Rara co-regulate hepatocarcinogenesis in an antagonistic manner but also suggest that aberrant activation of Rara is deleterious to liver homeostasis.
Published: 2007
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26. Glycogen synthase 2 is a novel target gene of peroxisome proliferator-activated receptors

Author: Mandard, Stéphane, Stienstra, Rinke, Escher, Pascal, Tan, Nguan Soon, Kim, Insook, Gonzalez, Frank, Wahli, Walter, Desvergne, Béatrice, Müller, Michael, Kersten, Sander, Nutrition, Metabolism and Genomics group and Nutrigenomics Consortium ( NMG ), Wageningen University and Research Centre [Wageningen] ( WUR ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Institute of Physiology, University of Basel ( Unibas ), Center for Integrative Genomics - Institute of Bioinformatics, Génopode ( CIG ), University of Lausanne, Laboratory of Metabolism, National Cancer Institute ( NIH ), This study was supported by the Netherlands Organization for Scientific Research (NWO), with additional support from the Dutch Diabetes Foundation, the Royal Netherlands Academy of Art and Sciences (KNAW), Wageningen Center for Food Sciences, the Center for Human Nutrigenomics, the Swiss National Science Foundation and the Human Frontier Science Program., Nutrition, Metabolism and Genomics group and Nutrigenomics Consortium (NMG), Wageningen University and Research [Wageningen] (WUR), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), University of Basel (Unibas), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), National Cancer Institute [Bethesda] (NCI-NIH), and National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH)
Subjects: MESH: DNA Primers, MESH: Rats, glycogen synthase 2, MESH: Peroxisome Proliferator-Activated Receptors, MESH : Hepatocytes, PPRE, liver, MESH: Mice, Knockout, PPAR, MESH: Chromatin, MESH : Gene Expression Regulation, Enzymologic, MESH: Hepatocytes, MESH: RNA, MESH : Mice, MESH : RNA, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, HNF4α, MESH : Polymerase Chain Reaction, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Glycogen Synthase, MESH : Chromatin, MESH : Rats, MESH: Transcription, Genetic, MESH: Gene Expression Regulation, Enzymologic, MESH : Transcription, Genetic, MESH: Polymerase Chain Reaction, MESH : Peroxisome Proliferator-Activated Receptors, adipose tissue, gene transcription, MESH : Mice, Knockout, MESH : DNA Primers, MESH : Animals, microarray, MESH : Glycogen Synthase
Abstract: International audience; Glycogen synthase 2 (Gys-2) is the ratelimiting enzyme in the storage of glycogen in liver and adipose tissue, yet little is known about regulation of Gys-2 transcription. The peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in the regulation of lipid and glucose metabolism and might be hypothesized to govern glycogen synthesis as well. Here, we show that Gys-2 is a direct target gene of PPARalpha, PPARbeta/delta and PPARgamma. Expression of Gys-2 is significantly reduced in adipose tissue of PPARalpha-/-, PPARbeta/delta-/- and PPARgamma+/- mice. Furthermore, synthetic PPARbeta/delta, and gamma agonists markedly up-regulate Gys-2 mRNA and protein expression in mouse 3T3-L1 adipocytes. In liver, PPARalpha deletion leads to decreased glycogen levels in the refed state, which is paralleled by decreased expression of Gys-2 in fasted and refed state. Two putative PPAR response elements (PPREs) were identified in the mouse Gys-2 gene: one in the upstream promoter (DR-1prom) and one in intron 1 (DR-1int). It is shown that DR-1int is the response element for PPARs, while DR-1prom is the response element for Hepatic Nuclear Factor 4 alpha (HNF4alpha). In adipose tissue, which does not express HNF4alpha, DR-1prom is occupied by PPARbeta/delta and PPARgamma, yet binding does not translate into transcriptional activation of Gys-2. Overall, we conclude that mouse Gys-2 is a novel PPAR target gene and that transactivation by PPARs and HNF4alpha is mediated by two distinct response elements.
Published: 2007
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27. Transdifferentiation of hepatocyte-like cells from the human hepatoma HepaRG cell line through bipotent progenitor

Author: Philippe Gripon, Bruno Turlin, Anne Corlu, Dina Kremsdorf, Serban Morosan, Bernard Drenou, Delphine Garnier, Virginie Cerec, Christiane Guguen-Guillouzo, Denise Glaise, Régulations des équilibres fonctionnels du foie normal et pathologique, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathogénèse des Hépatites Virales B et Immunothérapie (UMR_S 812), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Haematology Department, Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA)-Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140, Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Pathogénèse des Hépatites Virales B et Immunothérapie ( UMR_S 812 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Emile Muller [Mulhouse] ( CH E.Muller Mulhouse ), Groupe Hospitalier de Territoire Haute Alsace ( GHTHA ) -Groupe Hospitalier de Territoire Haute Alsace ( GHTHA ), Signalisation et Réponses aux Agents Infectieux et Chimiques ( SeRAIC ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140, Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: MESH: Cell Death, Pathology, MESH : Liver Neoplasms, Cell Transplantation, Cellular differentiation, Gene Expression, MESH : Hepatocytes, Mice, SCID, MESH: Hepatocytes, Mice, 0302 clinical medicine, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Liver Neoplasms, MESH : Cell Proliferation, MESH : Female, MESH: Animals, MESH: Mice, SCID, MESH: Carcinoma, Hepatocellular, 0303 health sciences, Cell Death, Transdifferentiation, Liver Neoplasms, Cell Differentiation, Cell biology, MESH: Cell Transplantation, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Liver, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Female, MESH : Cell Differentiation, MESH : Carcinoma, Hepatocellular, MESH: Cell Differentiation, medicine.medical_specialty, MESH: Gene Expression, MESH: Cell Line, Tumor, Carcinoma, Hepatocellular, MESH : Cell Lineage, Biology, Cholangiocyte, 03 medical and health sciences, MESH : Neoplastic Stem Cells, MESH: Cell Proliferation, Cell Line, Tumor, MESH : Mice, Reversible differentiation, medicine, Animals, Humans, Cell Lineage, Progenitor cell, MESH: Mice, 030304 developmental biology, Progenitor, Cell Proliferation, MESH: Humans, Hepatology, MESH : Cell Line, Tumor, MESH : Humans, MESH: Biological Markers, MESH : Liver, MESH: Cell Lineage, MESH: Neoplastic Stem Cells, MESH : Mice, SCID, MESH : Cell Transplantation, Transplantation, MESH : Biological Markers, MESH : Gene Expression, Cell culture, MESH : Cell Death, Hepatocytes, MESH : Animals, MESH: Female, Biomarkers, MESH: Liver
Abstract: International audience; Hepatic tumors, exhibiting mature hepatocytes and undifferentiated cells merging with cholangiocyte and hepatocyte phenotypes, are frequently described. The mechanisms by which they occur remain unclear. We report differentiation and transdifferentiation behaviors of human HepaRG cells isolated from a differentiated tumor developed consecutively to chronic HCV infection. We demonstrate that, in vitro, proliferating HepaRG cells differentiate toward hepatocyte-like and biliary-like cells at confluence. If hepatocyte-like cells are selectively isolated and cultured at high cell density, they proliferate and preserve their differentiation status. However, when plated at low density, they transdifferentiate into hepatocytic and biliary lineages through a bipotent progenitor. In accordance, transplantation of either undifferentiated or differentiated HepaRG cells in uPA/SCID mouse damaged liver gives rise mainly to functional human hepatocytes infiltrating mouse parenchyma. Analysis of the differentiation/transdifferentiation process reveals that: (1) the reversible differentiation fate of HepaRG cells is related to the absence of p21(CIP1) and p53 accumulation in differentiated cells; (2) HepaRG bipotent progenitors express the main markers of in vivo hepatic progenitors, and that cell differentiation process is linked to loss of their expression; (3) early and transient changes of beta-catenin localization and HNF3beta expression are correlated to Notch3 upregulation during hepatobiliary commitment of HepaRG cells. CONCLUSION: Our results demonstrate the great plasticity of transformed hepatic progenitor cells and suggest that the transdifferentiation process could supply the pool of hepatic progenitor cells. Moreover, they highlight possible mechanisms by which transdifferentiation and proliferation of unipotent hepatocytes might cooperate in the development of mixed and differentiated tumors.
Published: 2007
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28. Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes

Author: Dalila Azzout-Marniche, Marc Foretz, Fabienne Foufelle, Pascal Ferré, Colette Guichard, Dominique Bécard, Physiologie de la Nutrition et du Comportement Alimentaire (PNCA), AgroParisTech-Institut National de la Recherche Agronomique (INRA), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut Cochin (IC UM3 (UMR 8104 / U1016)), 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)-Centre National de la Recherche Scientifique (CNRS), 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), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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), Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Physiologie de la Nutrition et du Comportement Alimentaire ( PNCA ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) ( EMD ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), 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 ) -Centre National de la Recherche Scientifique ( CNRS ), 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 ), and Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE)
Subjects: MESH: Protein Precursors, Transcription, Genetic, medicine.medical_treatment, MESH : Hepatocytes, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biochemistry, MESH: CCAAT-Enhancer-Binding Proteins, MESH: Hepatocytes, 0302 clinical medicine, Insulin receptor substrate, Insulin, MESH: Animals, Enzyme Inhibitors, MESH : Immunoblotting, Cells, Cultured, Protein Synthesis Inhibitors, 0303 health sciences, MESH : Cell Nucleus, MESH : Glucokinase, MESH: Immunoblotting, food and beverages, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], MESH: Glucokinase, 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, 3. Good health, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 030220 oncology & carcinogenesis, MESH : DNA-Binding Proteins, Sterol Regulatory Element Binding Protein 1, MESH: Cells, Cultured, MESH: Cell Nucleus, MESH: Enzyme Activation, MESH : Cell Membrane, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Insulin, digestive system, 03 medical and health sciences, MESH: Sterol Regulatory Element Binding Protein 1, MESH : Sterol Regulatory Element Binding Protein 1, MESH: Blotting, Northern, Protein Precursors, Molecular Biology, Dose-Response Relationship, Drug, Glucokinase, Endoplasmic reticulum, Cell Membrane, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Sterol regulatory element-binding protein, Enzyme Activation, MESH: Phosphatidylinositol 3-Kinases, CCAAT-Enhancer-Binding Proteins, MESH: Female, Transcription Factors, MESH: Signal Transduction, Time Factors, MESH : Transcription Factors, MESH : Insulin, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, MESH : Dose-Response Relationship, Drug, Endoplasmic Reticulum, MESH: Dose-Response Relationship, Drug, Phosphatidylinositol 3-Kinases, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], polycyclic compounds, MESH : Female, Cycloheximide, MESH: Cycloheximide, MESH : Protein Precursors, MESH : Endoplasmic Reticulum, MESH : Rats, [ SDV.MHEP.PHY ] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], MESH : Blotting, Northern, DNA-Binding Proteins, Fatty acid synthase, MESH : CCAAT-Enhancer-Binding Proteins, MESH: Enzyme Inhibitors, Female, lipids (amino acids, peptides, and proteins), MESH : Time Factors, Research Article, Signal Transduction, MESH: Rats, Immunoblotting, Biology, [ 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], MESH: Endoplasmic Reticulum, MESH : Cycloheximide, MESH : Cells, Cultured, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, MESH : Protein Synthesis Inhibitors, Transcription factor, 030304 developmental biology, MESH : Signal Transduction, Cell Nucleus, MESH : Enzyme Inhibitors, MESH: Protein Synthesis Inhibitors, MESH: Transcription, Genetic, MESH: Time Factors, [ SDV.BC.BC ] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], MESH : Transcription, Genetic, MESH : Phosphatidylinositol 3-Kinases, Cell Biology, Blotting, Northern, Rats, biology.protein, Hepatocytes, MESH : Animals, MESH : Enzyme Activation, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, MESH: DNA-Binding Proteins, MESH: Cell Membrane
Abstract: International audience; The transcription factor sterol regulatory-element-binding protein-1c (SREBP-1c) plays a major role in the effect of insulin on the transcription of hepatic genes such as glucokinase and fatty acid synthase. We show here in cultured rat hepatocytes that insulin, through activation of the phosphatidylinositol 3-kinase pathway increases the abundance of the precursor form of SREBP-1c in endoplasmic reticulum. This precursor form is then rapidly cleaved, possibly irrespective of the continuous presence of insulin, leading to an increased content of the nuclear mature form of SREBP-1c. Nevertheless, the increased amount of the mature form of SREBP-1c in the nucleus is not a prerequisite for the rapid effect of insulin on the transcription of genes such as glucokinase, suggesting that additional actions of the hormone are involved, such as the activation of the nuclear form of SREBP-1c or of an unidentified SREBP-1c partner.
Published: 2000

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28 results on '"MESH : Hepatocytes"'

1. Genotoxic and enzymatic effects of fluoranthene in microsomes and freshly isolated hepatocytes from sole (Solea solea)

2. Modulation of the hepatic fatty acid pool in peroxisomal 3-ketoacyl-CoA thiolase B-null mice exposed to the selective PPARalpha agonist Wy14,643

3. The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions

4. Highly efficient SiRNA and gene transfer into hepatocyte-like HepaRG cells and primary human hepatocytes: new means for drug metabolism and toxicity studies

5. Glycogen synthase kinase 3-mediated voltage-dependent anion channel phosphorylation controls outer mitochondrial membrane permeability during lipid accumulation

6. TRAIL but not FasL and TNFα, regulates IL-33 expression in murine hepatocytes during acute hepatitis

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9. Hepatocyte proliferation/growth arrest balance in the liver of mice during E. multilocularis infection: a coordinated 3-stage course

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11. Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection

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14. Invariant natural killer T-cell-deficient mice display increased CCl₄ -induced hepatitis associated with CXCL1 over-expression and neutrophil infiltration

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19. What makes cells move: requirements and obstacles for spontaneous cell motility

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21. Impact of visceral adipose tissue on liver metabolism and insulin resistance. Part II: Visceral adipose tissue production and liver metabolism

22. Expression of major histocompatibility complex class I chain-related molecule A, NKG2D, and transforming growth factor-beta in the liver of humans with alveolar echinococcosis: new actors in the tolerance to parasites?

23. Transforming growth factor beta controls the directional migration of hepatocyte cohorts by modulating their adhesion to fibronectin

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26. Glycogen synthase 2 is a novel target gene of peroxisome proliferator-activated receptors

27. Transdifferentiation of hepatocyte-like cells from the human hepatoma HepaRG cell line through bipotent progenitor

28. Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes

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28 results on '"MESH : Hepatocytes"'

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