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11 results on '"MESH: Lipogenesis"'

1. Induction of vesicular steatosis by amiodarone and tetracycline is associated with up-regulation of lipogenic genes in heparg cells

Author

Sébastien Anthérieu, Alexandra Rogue, Marie-Anne Robin, Bernard Fromenty, André Guillouzo, 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 ), 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
Amiodarone, MESH: Tetracycline, MESH: Down-Regulation, chemistry.chemical_compound, 0302 clinical medicine, MESH: Liver Neoplasms, Lipid droplet, MESH: Up-Regulation, MESH: Carcinoma, Hepatocellular, MESH: Fatty Liver, MESH: Lipid Metabolism, Liver injury, 0303 health sciences, biology, Liver Neoplasms, MESH: Fatty Acid Synthetase Complex, Type I, 3. Good health, Up-Regulation, Fatty Acid Synthase, Type I, Fatty acid synthase, 030220 oncology & carcinogenesis, Lipogenesis, MESH: Membrane Proteins, Stearoyl-CoA Desaturase, MESH: Triglycerides, medicine.medical_specialty, MESH: Cell Line, Tumor, Carcinoma, Hepatocellular, Perilipin 2, Down-Regulation, MESH: Carrier Proteins, Perilipin-4, MESH: Phosphoproteins, Perilipin-2, 03 medical and health sciences, Internal medicine, Cell Line, Tumor, medicine, Oil Red O, Humans, Triglycerides, 030304 developmental biology, MESH: Lipogenesis, Phospholipidosis, MESH: Humans, Hepatology, MESH: Amiodarone, MESH: Oleic Acid, Membrane Proteins, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Tetracycline, medicine.disease, Lipid Metabolism, Phosphoproteins, Fatty Liver, Endocrinology, chemistry, MESH: Stearoyl-CoA Desaturase, biology.protein, Steatosis, Carrier Proteins, Oleic Acid
Abstract

International audience; Drug-induced liver injury occurs in general after several weeks and is often unpredictable. It is characterized by a large spectrum of lesions that includes steatosis and phospholipidosis. Many drugs such as amiodarone and tetracycline have been reported to cause phospholipidosis and/or steatosis. In this study, acute and chronic hepatic effects of these two drugs were investigated using well-differentiated human hepatoma HepaRG cells. Accumulation of typical lipid droplets, labeled with Oil Red O, was observed in hepatocyte-like HepaRG cells after repeat exposure to either drug. Amiodarone caused the formation of additional intracytoplasmic vesicles that did not stain in all HepaRG cells. At the electron microscopic level, these vesicles appeared as typical lamellar bodies and were associated with an increase of phosphatidylethanolamine and phosphatidylcholine. A dose-dependent induction of triglycerides (TG) was observed after repeat exposure to either amiodarone or tetracycline. Several genes known to be related to lipogenesis were induced after treatment by these two drugs. By contrast, opposite deregulation of some of these genes (FASN, SCD1, and THSRP) was observed in fat HepaRG cells induced by oleic acid overload, supporting the conclusion that different mechanisms were involved in the induction of steatosis by drugs and oleic acid. Moreover, several genes related to lipid droplet formation (ADFP, PLIN4) were up-regulated after exposure to both drugs and oleic acid. CONCLUSION: Our results show that amiodarone causes phospholipidosis after short-term treatment and, like tetracycline, induces vesicular steatosis after repeat exposure in HepaRG cells. These data represent the first demonstration that drugs can induce vesicular steatosis in vitro and show a direct relationship between TG accumulation and enhanced expression of lipogenic genes.

Published
2011
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2. Rexinoid Bexarotene Modulates Triglyceride but not Cholesterol Metabolism via Gene-Specific Permissivity of the RXR/LXR Heterodimer in the Liver

Author

Anne Tailleux, Barbara Gross, Fanny Lalloyer, Emmanuelle Vallez, Sophie Lestavel, Thomas Åskov Pedersen, Bart Staels, Saïd Yous, Catherine Fievet, Jan-Ake Gustafsson, Susanne Mandrup, Récepteurs nucléaires, lipoprotéines et athérosclérose, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Department of Biochemistry and Molecular Biology, University of Southern Denmark (SDU), Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Université de Lille, Droit et Santé, Department of Biosciences and Nutrition, Karolinska Institut, Karolinska Institutet [Stockholm], Department of Biology and Biochemistry, University of Houston, and Derudas, Marie-Hélène

Subjects
Receptors, Cytoplasmic and Nuclear, murine model, Mice, MESH: Cholesterol, 0302 clinical medicine, Homeostasis, MESH: Animals, Retinoid, Receptor, Liver X Receptors, Bexarotene, 0303 health sciences, Orphan Nuclear Receptors, MESH: Tetrahydronaphthalenes, 3. Good health, DNA-Binding Proteins, Cholesterol, Liver, MESH: Homeostasis, 030220 oncology & carcinogenesis, Lipogenesis, MESH: Retinoid X Receptors, Female, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, Dimerization, medicine.drug, MESH: Triglycerides, medicine.medical_specialty, Tetrahydronaphthalenes, rexinoid, medicine.drug_class, hypertriglyceridemia, ChIP, MESH: Receptors, Cytoplasmic and Nuclear, Retinoid X receptor, Biology, digestive system, Article, Liver-X-Receptor, 03 medical and health sciences, Retinoid-X-Receptor, MESH: Mice, Inbred C57BL, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Liver X receptor, MESH: Mice, Triglycerides, 030304 developmental biology, MESH: Lipogenesis, Hypertriglyceridemia, medicine.disease, Mice, Inbred C57BL, Retinoid X Receptors, Endocrinology, MESH: Dimerization, Cancer research, MESH: Female, Chromatin immunoprecipitation, MESH: DNA-Binding Proteins, MESH: Liver
Abstract

Objective— Bexarotene (Targretin) is a clinically used antitumoral agent which exerts its action through binding to and activation of the retinoid-X-receptor (RXR). The most frequent side-effect of bexarotene administration is an increase in plasma triglycerides, an independent risk factor of cardiovascular disease. The molecular mechanism behind this hypertriglyceridemia remains poorly understood. Methods and Results— Using wild-type and LXRα/β-deficient mice, we show here that bexarotene induces hypertriglyceridemia and activates hepatic LXR-target genes of lipogenesis in an LXR-dependent manner, hence exerting a permissive effect on RXR/LXR heterodimers. Interestingly, RNA analysis and Chromatin Immunoprecipitation assays performed in the liver reveal that the in vivo permissive effect of bexarotene on the RXR/LXR heterodimer is restricted to lipogenic genes without modulation of genes controlling cholesterol homeostasis. Conclusion— These findings demonstrate that the hypertriglyceridemic action of bexarotene occurs via the RXR/LXR heterodimer and show that RXR heterodimers can act with a selective permissivity on target genes of specific metabolic pathways in the liver.

Published
2009
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3. PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells

Author

Thierry Umbdenstock, Alexandra Rogue, Catherine de la Moureyre-Spire, Sébastien Anthérieu, Aurore Vluggens, Richard J. Weaver, Nancy Claude, André Guillouzo, 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 ), Biologie Servier, Technologie Servier, Institut de Recherches Servier, This work was supported by the International Research Servier Group (IRIS) and the European Community (Contracts Predict-IV-202222 and MIP-DILI-115336). The MIP-DILI project has received support from the Innovative Medicines Initiative Joint Undertaking, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/20072013) and EFPIA companies' in kind contribution. http://www.imi.europa.eu/., 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 Cadieu, Muriel

Subjects
MESH: Oxidation-Reduction, Peroxisome Proliferator-Activated Receptors, Drug Evaluation, Preclinical, Receptors, Cytoplasmic and Nuclear, Peroxisome proliferator-activated receptor, MESH: Peroxisome Proliferator-Activated Receptors, Fatty Acids, Nonesterified, Toxicology, PPAR agonist, Muraglitazar, chemistry.chemical_compound, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, MESH: PPAR alpha, Oxazoles, MESH: Fatty Liver, Liver X Receptors, MESH: Lipid Metabolism, chemistry.chemical_classification, 0303 health sciences, MESH: Fatty Acids, Nonesterified, Lipotropic Agents, Fatty liver, MESH: Oxazoles, Orphan Nuclear Receptors, MESH: Gene Expression Regulation, MESH: Glycine, 3. Good health, Liver, MESH: Orphan Nuclear Receptors, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 030220 oncology & carcinogenesis, Lipogenesis, MESH: Drug Evaluation, Preclinical, Oxidation-Reduction, medicine.drug, MESH: Triglycerides, medicine.medical_specialty, Tesaglitazar, Glycine, Biology, MESH: Receptors, Cytoplasmic and Nuclear, MESH: Lipotropic Agents, Cell Line, 03 medical and health sciences, Internal medicine, medicine, Humans, PPAR alpha, Constitutive Androstane Receptor, Triglycerides, 030304 developmental biology, Pharmacology, MESH: Lipogenesis, MESH: Humans, MESH: Oleic Acid, Troglitazone, Lipid Metabolism, medicine.disease, MESH: Cell Line, Fatty Liver, PPAR gamma, Endocrinology, Gene Expression Regulation, chemistry, MESH: PPAR gamma, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Steatosis, Oleic Acid, MESH: Liver
Abstract

International audience; Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various PPAR agonists, i.e. fenofibrate, bezafibrate, troglitazone, rosiglitazone, muraglitazar and tesaglitazar on oleic acid-induced steatotic HepaRG cells were investigated after a single 24-hour or 2-week repeat treatment. Lipid vesicles stained by Oil-Red O and triglycerides accumulation caused by oleic acid overload, were decreased, by up to 50%, while fatty acid oxidation was induced after 2-week co-treatment with PPAR agonists. The greatest effects on reduction of steatosis were obtained with the dual PPARα/γ agonist muraglitazar. Such improvement of steatosis was associated with up-regulation of genes related to fatty acid oxidation activity and down-regulation of many genes involved in lipogenesis. Moreover, modulation of expression of some nuclear receptor genes, such as FXR, LXRα and CAR, which are potent actors in the control of lipogenesis, was observed and might explain repression of de novo lipogenesis. CONCLUSION: Altogether, our in vitro data on steatotic HepaRG cells treated with PPAR agonists correlated well with clinical investigations, bringing a proof of concept that drug-induced reversal of steatosis in human can be evaluated in in vitro before conducting long-term and costly in vivo studies in animals and patients.

Published
2014
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4. A systems biology approach to the hepatic role of the oxysterol receptor LXR in the regulation of lipogenesis highlights a cross-talk with PPARα

Author

Stefania Murzilli, Frédéric Lasserre, Jean-Marc A. Lobaccaro, Normand Podechard, Arnaud Polizzi, Justine Bertrand-Michel, Thierry Pineau, Chiara Di Lisio, Alexandra Montagner, Pascal G.P. Martin, Nicolas Loiseau, Hervé Guillou, Simon Ducheix, Simona D'Amore, Aurélien Pommier, ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT), Stress, membrane, signalisation, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de recherche en santé, environnement et travail (Irset), 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 )-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 ), Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Laboratory of Lipid Metabolism and Cancer, Consorzio Mario NegriSud, MetaToul Lipidomics, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Physiopathologie Toulouse Purpan (CPTP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INRA-FORMAS France-Sweden cooperative program, Region Midi-Pyrenees, ANR project (Crisalis), Ministere de l'Enseignement Superieur et de la Recherche, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-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 )-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 ), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Institut National de la Recherche Agronomique (INRA), Plateau MetaToul-LIPIDOMIQUE = MetaToul-Lipidomics, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Clermont Université-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Recherche Agronomique (INRA), Plateau MetaToul-LIPIDOMIQUE, Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaToul, Plateau de lipidomique, Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Le Corre, Morgane, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de recherche en santé, environnement et travail (Irset), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaboHUB-MetaToul, Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)

Subjects
Male, Steatosis, Hydrocarbons, Fluorinated, MESH: Sulfonamides, Peroxisome proliferator-activated receptor, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Protein Isoforms, Ligands, Biochemistry, PPARα, Mice, 0302 clinical medicine, Cytochrome P-450 Enzyme System, Fenofibrate, MESH: Ligands, Protein Isoforms, MESH: Animals, MESH: PPAR alpha, Beta oxidation, Liver X Receptors, Oligonucleotide Array Sequence Analysis, chemistry.chemical_classification, 0303 health sciences, Sulfonamides, Systems Biology, Fatty Acids, General Medicine, Orphan Nuclear Receptors, MESH: Fatty Acids, Liver, MESH: Orphan Nuclear Receptors, 030220 oncology & carcinogenesis, MESH: Systems Biology, Lipogenesis, MESH: Cytochrome P-450 Enzyme System, lipids (amino acids, peptides, and proteins), LXR, Transcriptional Activation, medicine.medical_specialty, Oxysterol, MESH: Mice, Transgenic, MESH: Receptor Cross-Talk, Mice, Transgenic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Retinoid X receptor, 03 medical and health sciences, Internal medicine, medicine, Animals, PPAR alpha, Cytochrome P450 Family 4, Liver X receptor, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, 030304 developmental biology, MESH: Lipogenesis, [SDV.GEN]Life Sciences [q-bio]/Genetics, Fatty acid, Receptor Cross-Talk, MESH: Fenofibrate, MESH: Male, MESH: Hydrocarbons, Fluorinated, Endocrinology, Nuclear receptor, chemistry, MESH: Oligonucleotide Array Sequence Analysis, MESH: Transcriptional Activation, MESH: Liver
Abstract

International audience; The Liver X Receptors (LXRs) α and β and the Peroxisome Proliferator-Activated Receptor α (PPARα) are transcription factors that belong to class II nuclear receptors. They drive the expression of genes involved in hepatic lipid homeostasis and therefore are important targets for the prevention and treatment of nonalcoholic fatty liver disease (NAFLD). LXRs and PPARα are regulated by endogenous ligands, oxysterols and fatty acid derived molecules, respectively. In the liver, pharmacological activation of LXRs leads to the over-expression of genes involved in de novo lipogenesis, while PPARα is critical for fatty acid catabolism in nutrient deprivation. Even if these two nuclear receptors seemed to play opposite parts, recent studies have highlighted that PPARα also influence the expression of genes involved in fatty acids synthesis. In this study, we used pharmacological approaches and genetically engineered mice to investigate the cross-talk between LXRs and PPARα in the regulation of genes responsible for lipogenesis. We first investigated the effect of T0901317 and fenofibrate, two synthetic agonists of LXRs and PPARα, respectively. As expected, T0901317 and fenofibrate induce expression of genes involved LXR-dependent and PPARα-dependent lipogenic responses. Considering such overlapping effect, we then tested whether LXR agonist may influence PPARα driven response and vice versa. We show that the lack of PPARα does not influence the effects of T0901317 on lipogenic genes expression. However, PPARα deficiency prevents the up-regulation of genes involved in ω-hydroxylation that are induced by the LXR agonist. In addition, over-expression of lipogenic genes in response to fenofibrate is decreased in LXR knockout mice as well as the expression of PPARα target genes involved in fatty acid oxidation. Altogether, our work provides in vivo evidence for a central interconnection between nuclear receptors that drive hepatic lipid metabolism in response to oxysterol and fatty acids.

Published
2013
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5. Pentoxifylline aggravates fatty liver in obese and diabetic ob/ob mice by increasing intestinal glucose absorption and activating hepatic lipogenesis

Author

Massart, Julie, Robin, Marie-Anne, Noury, Fanny, Fautrel, Alain, Lettéron, P., Bado, A., Eliat, Pierre-Antoine, Fromenty, Bernard, 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 ), Laboratoire Traitement du Signal et de l'Image (LTSI), 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), Hépatotoxicité et xénobiotiques, Détoxication et réparation Tissulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-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)-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 )-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), Plate-forme Rennaise d'Imagerie et Spectroscopie Structurale et Métabolique (PRISM), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Recherche Agronomique (INRA), INSERM (Institut Nationale de la Santé et de la Recherche Médicale), 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 Recherche Agronomique (INRA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), 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 ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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 )-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 National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Blood Glucose, Male, MESH: Inflammation, obesity, Mice, Obese, methylxanthine, Mice, Adipocytes, MESH: Obesity, MESH: Animals, glucose, MESH: Mice, Obese, MESH: Fatty Liver, MESH: Pentoxifylline, Glucose Transporter Type 2, MESH: Oxidative Stress, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Nuclear Proteins, MESH: Transcription Factors, Research Papers, Lipids, MESH: Glucose, Jejunum, Liver, MESH: Glycolysis, MESH: Sodium-Glucose Transporter 1, Sterol Regulatory Element Binding Protein 1, Glycolysis, drug-induced liver injury, MESH: Diabetes Mellitus, Type 2, MESH: Triglycerides, MESH: Cell Line, Tumor, ChREBP, MESH: Intestinal Absorption, MESH: Glucose Tolerance Test, MESH: Sterol Regulatory Element Binding Protein 1, Sodium-Glucose Transporter 1, MESH: Mice, Inbred C57BL, MESH: Transaminases, Cell Line, Tumor, Animals, Humans, MESH: Mice, Transaminases, Triglycerides, MESH: Adipocytes, fatty liver, Inflammation, MESH: Lipogenesis, MESH: Humans, Lipogenesis, MESH: Biological Markers, Glucose Tolerance Test, MESH: Lipids, MESH: Male, Mice, Inbred C57BL, Oxidative Stress, pentoxifylline, Diabetes Mellitus, Type 2, Intestinal Absorption, MESH: Jejunum, MESH: Blood Glucose, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Glucose Transporter Type 2, MESH: Nuclear Proteins, Biomarkers, Transcription Factors, MESH: Liver
Abstract

International audience; BACKGROUND AND PURPOSE: Pentoxifylline is in clinical trials for non-alcoholic fatty liver disease and diabetic nephropathy. Metabolic and hepatic effects of pentoxifylline were assessed in a murine model of obesity and type 2 diabetes. EXPERIMENTAL APPROACH: Pentoxifylline (100 mg*kg(-1) *day(-1)) was administered for 4 days or 3 weeks in lean and obese/diabetic ob/ob mice. Plasma lipids, glucose, other metabolites and relevant enzymes were measured by standard assays. Hepatic lipids in vivo were assessed with magnetic resonance spectroscopy and by histology. Hepatic extracts were also analysed with RT-PCR and Western blotting. KEY RESULTS: Four days of pentoxifylline treatment slightly increased liver lipids in ob/ob mice. After 3 weeks, pentoxifylline exacerbated fatty liver and plasma transaminases in ob/ob mice but did not induce liver steatosis in lean mice. Plasma glucose was highest in fed, but not fasted, ob/ob mice treated with pentoxifylline. During the first 10 min of an oral glucose tolerance test, blood glucose increased more rapidly in pentoxifylline-treated mice. Jejunal expression of glucose transporter 2 isoform was increased in pentoxifylline-treated obese mice. Hepatic activity of carbohydrate response element binding protein (ChREBP) increased after pentoxifylline in ob/ob, but not lean, mice. Hepatic expression of lipogenic enzymes was highest in pentoxifylline-treated ob/ob mice. However, pentoxifylline reduced markers of oxidative stress and inflammation in ob/ob liver. CONCLUSION AND IMPLICATIONS: Pentoxifylline exacerbated fatty liver in ob/ob mice through enhanced intestinal glucose absorption, increased postprandial glycaemia and activation of hepatic lipogenesis. Long-term treatment with pentoxifylline could worsen fatty liver in some patients with pre-existing hyperglycaemia.

Published
2012
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6. CYP4F3B expression is associated with differentiation of HepaRG human hepatocytes and unaffected by fatty acid overload

Author

Virginie Cerec, Emmanuelle Plée-Gautier, Anne Corlu, Stéphanie Madec, Joseph Antoun, Christiane Guguen-Guillouzo, Denise Glaise, Jean-Pierre Salaün, Laboratoire des Sciences de l'Environnement Marin (LEMAR) (LEMAR), Institut Universitaire Européen de la Mer (IUEM), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Centre National de la Recherche Scientifique (CNRS)-Université de Brest (UBO), Végétaux marins et biomolécules, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-GOEMAR-Centre National de la Recherche Scientifique (CNRS), 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 ), Conseil Régional de Bretagne [Grants PRIR-A3CBL9, 560408], European Community 6th Framework Program [Grant COMICS, project 037575], Institut National de la Santé et Recherche Médicale, Centre National de Recherche Scientifique et Technique, Institut de Recherche pour le Développement (IRD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Brest (UBO)-Institut Universitaire Européen de la Mer (IUEM), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), 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: Microsomes, Liver, CYP4F3, Pharmaceutical Science, MESH: Protein Isoforms, MESH: Hepatocytes, MESH: Fatty Acid Synthetase Complex, 0302 clinical medicine, Cytochrome P-450 Enzyme System, Protein Isoforms, MESH: PPAR alpha, MESH: Lipid Metabolism, chemistry.chemical_classification, Hepatocyte differentiation, 0303 health sciences, MESH: Alternative Splicing, MESH: Gene Expression Regulation, Enzymologic, Fatty Acids, Cell Differentiation, MESH: Fatty Acids, Fatty acid synthase, MESH: Docosahexaenoic Acids, Biochemistry, Liver, Docosahexaenoic acid, 030220 oncology & carcinogenesis, Lipogenesis, MESH: Cytochrome P-450 Enzyme System, Microsomes, Liver, Sterol Regulatory Element Binding Protein 1, Polyunsaturated fatty acid, MESH: Cell Differentiation, Docosahexaenoic Acids, MESH: Hydroxylation, Biology, Hydroxylation, Gene Expression Regulation, Enzymologic, Cell Line, 03 medical and health sciences, MESH: Sterol Regulatory Element Binding Protein 1, Humans, PPAR alpha, Cytochrome P450 Family 4, 030304 developmental biology, Pharmacology, MESH: Lipogenesis, MESH: Humans, Fatty acid, Lipid metabolism, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Lipid Metabolism, MESH: Cell Line, PPAR gamma, Alternative Splicing, chemistry, MESH: PPAR gamma, biology.protein, Hepatocytes, Fatty Acid Synthases, MESH: Liver
Abstract

International audience; Fatty acid microsomal ω-oxidation involves cytochrome P450 enzymes. Some of them belonging to the CYP4F3 family are mainly expressed in the liver, making this organ a major player in energy homeostasis and lipid metabolism. To study this important regulation pathway, we used HepaRG cells, which gradually undergo a complete differentiation process. Even at the early stage of the differentiation process, CYP4F3B generated by alternative splicing of the CYP4F3 gene represented the prevalent isoform in HepaRG cells as in the liver. Its increasing expression associated with hepatocyte differentiation status suggested a hepatic-specific control of this isoform. As in liver microsomes, the catalytic hydroxylation of the CYP4F3B substrate [1-¹⁴C]Z9(10)-epoxystearic acid led to major production of 18-hydroxy-9(10)-epoxystearic acid. When treated with saturated, monounsaturated, or polyunsaturated fatty acids, CYP4F3B and CYP4A11 expression remained unchanged whereas CYP4F2 and CYP4F12 expression was transiently up-regulated. A 24-h exposure of differentiated HepaRG cells to various polyunsaturated fatty acids and derivatives induced microvesicular steatosis; down-regulation of lipid metabolism gene regulators such as sterol regulatory element-binding protein-1c, fatty acid synthase, peroxisome proliferator-activated receptor γ (PPARγ), PPARα, and decreased expression of glucose-dependent metabolism genes, which could limit de novo lipogenesis. Docosahexaenoic acid seemed to be the most effective compound. These results suggest that a PPARα-independent pathway could participate to limit lipogenesis and emphasize the role of hepatocytes in the fatty acid ω-hydroxylation pathway. They also give insights on the use of HepaRG hepatocytes to open new avenues of investigations on factors mediating the lipid metabolic pathway and finding new hypolipidemic molecules.

Published
2011
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7. Kruppel-like factor KLF10 is a link between the circadian clock and metabolism in liver

Author

Thomas C. Spelsberg, Franck Delaunay, Aline Gréchez-Cassiau, Sophie Brangolo, Malayannan Subramaniam, Catherine Fievet, Fabienne Guillaumond, Brigitta Peteri-Brunbäck, Michèle Teboul, Bart Staels, Institut de signalisation, biologie du développement et cancer (ISBDC), 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), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de physiologie des membranes cellulaires (LPMC), Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-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 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), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
Male, Circadian clock, Response element, Transcriptome, Mice, 0302 clinical medicine, MESH: Animals, Promoter Regions, Genetic, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Regulation of gene expression, 0303 health sciences, Genome, Fasting, Articles, MESH: Gene Expression Regulation, Circadian Rhythm, CLOCK, MESH: Glucose, Liver, Knockout mouse, Metabolome, MESH: Feeding Behavior, Female, MESH: Kruppel-Like Transcription Factors, MESH: Metabolome, medicine.medical_specialty, MESH: Biological Clocks, Kruppel-Like Transcription Factors, MESH: Fasting, Protein Serine-Threonine Kinases, Biology, MESH: Protein-Serine-Threonine Kinases, Cell Line, 03 medical and health sciences, MESH: Gene Expression Profiling, Biological Clocks, Internal medicine, MESH: Promoter Regions, Genetic, medicine, Animals, Humans, MESH: Genome, RNA, Messenger, Circadian rhythm, MESH: Circadian Rhythm, Molecular Biology, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, MESH: Lipogenesis, MESH: Humans, Gene Expression Profiling, Lipogenesis, Feeding Behavior, Cell Biology, MESH: Male, MESH: Cell Line, Gene expression profiling, Glucose, Endocrinology, Gene Expression Regulation, MESH: Female, 030217 neurology & neurosurgery, MESH: Liver
Abstract

International audience; The circadian timing system coordinates many aspects of mammalian physiology and behavior in synchrony with the external light/dark cycle. These rhythms are driven by endogenous molecular clocks present in most body cells. Many clock outputs are transcriptional regulators, suggesting that clock genes primarily control physiology through indirect pathways. Here, we show that Krüppel-like factor 10 (KLF10) displays a robust circadian expression pattern in wild-type mouse liver but not in clock-deficient Bmal1 knockout mice. Consistently, the Klf10 promoter recruited the BMAL1 core clock protein and was transactivated by the CLOCK-BMAL1 heterodimer through a conserved E-box response element. Profiling the liver transcriptome from Klf10(-/-) mice identified 158 regulated genes with significant enrichment for transcripts involved in lipid and carbohydrate metabolism. Importantly, approximately 56% of these metabolic genes are clock controlled. Male Klf10(-/-) mice displayed postprandial and fasting hyperglycemia, a phenotype accompanied by a significant time-of-day-dependent upregulation of the gluconeogenic gene Pepck and increased hepatic glucose production. Consistently, functional data showed that the proximal Pepck promoter is repressed directly by KLF10. Klf10(-/-) females were normoglycemic but displayed higher plasma triglycerides. Correspondingly, rhythmic gene expression of components of the lipogenic pathway, including Srebp1c, Fas, and Elovl6, was altered in females. Collectively, these data establish KLF10 as a required circadian transcriptional regulator that links the molecular clock to energy metabolism in the liver.

Published
2010
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8. Abrogation of de novo lipogenesis by stearoyl-CoA desaturase 1 inhibition interferes with oncogenic signaling and blocks prostate cancer progression in mice. : Lipid synthesis and cancer

Author

Fritz, Vanessa, Benfodda, Zohra, Rodier, Geneviève, Henriquet, Corinne, Iborra, François, Avancès, Christophe, Allory, Yves, De La Taille, Alexandre, Culine, Stéphane, Blancou, Hubert, Cristol, Jean Paul, Michel, Françoise, Sardet, Claude, Fajas, Lluis, Institut de recherche en cancérologie de Montpellier ( IRCM ), Université Montpellier 1 ( UM1 ) -CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Université de Nîmes ( UNIMES ), Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Biochimie, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Lapeyronie, Prévention des Malnutritions et des Pathologies Associées, Institut Universitaire de Recherche Clinique, Service d'Urologie, Centre Hospitalier Régional Universitaire de Nîmes ( CHRU Nîmes ) -Hôpital Universitaire Carémeau [Nîmes], Service d'urologie, Polyclinique Kennedy, Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] ( IBMM ), Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Association pour la Recherche contre le Cancer, Fondation pour la Recherche Médicale (FRM), and Institut National du Cancer (INCA)., Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Nîmes (UNIMES), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Signal Transduction, MESH: Xenograft Model Antitumor Assays, MESH: Cell Line, Tumor, MESH : Male, small molecule, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Xenograft Model Antitumor Assays, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Cell Proliferation, MESH : Fibroblasts, MESH : Mice, MESH : Cell Proliferation, MESH: Animals, MESH: Cell Line, Transformed, MESH: Tumor Suppressor Protein p53, MESH: Mice, MESH: Lipogenesis, MESH : Signal Transduction, MESH : Cell Survival, MESH : Enzyme Inhibitors, MESH: Humans, MESH : Cell Line, Tumor, AKT, monounsaturated fatty acids, MESH : Humans, MESH : Cell Line, Transformed, MESH : Disease Progression, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH : Fatty Acids, Monounsaturated, MESH: Male, MESH : Lipogenesis, MESH : Stearoyl-CoA Desaturase, MESH: Fatty Acids, Monounsaturated, MESH : Tumor Suppressor Protein p53, Metabolism, MESH: Cell Survival, MESH: Enzyme Inhibitors, MESH: Fibroblasts, MESH: Prostatic Neoplasms, MESH: Stearoyl-CoA Desaturase, MESH: Disease Progression, lipids (amino acids, peptides, and proteins), MESH : Animals, desaturase, MESH : Prostatic Neoplasms
Abstract

International audience; Increased de novo fatty acid (FA) synthesis is one hallmark of tumor cells, including prostate cancer. We present here our most recent results showing that lipid composition in human prostate cancer is characterized by an increased ratio of monounsaturated FA to saturated FA, compared with normal prostate, and evidence the overexpression of the lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1) in human prostate cancer. As a new therapeutic strategy, we show that pharmacologic inhibition of SCD1 activity impairs lipid synthesis and results in decreased proliferation of both androgen-sensitive and androgen-resistant prostate cancer cells, abrogates the growth of prostate tumor xenografts in nude mice, and confers therapeutic benefit on animal survival. We show that these changes in lipid synthesis are translated into the inhibition of the AKT pathway and that the decrease in concentration of phosphatidylinositol-3,4,5-trisphosphate might at least partially mediate this effect. Inhibition of SCD1 also promotes the activation of AMP-activated kinase and glycogen synthase kinase 3alpha/beta, the latter on being consistent with a decrease in beta-catenin activity and mRNA levels of various beta-catenin growth-promoting transcriptional targets. Furthermore, we show that SCD1 activity is required for cell transformation by Ras oncogene. Together, our data support for the first time the concept of targeting the lipogenic enzyme SCD1 as a new promising therapeutic approach to block oncogenesis and prostate cancer progression.

Published
2010
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9. Postprandial Nutrient Partitioning but Not Energy Expenditure Is Modified in Growing Rats during Adaptation to a High-Protein Diet

Author

Daniel Tomé, Claire Gaudichon, Patrick C. Even, Gilles Fromentin, Dalila Azzout-Marniche, Magdalena Stepien, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Physiologie de la Nutrition et du Comportement Alimentaire (PNCA), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, and AgroParisTech-Institut National de la Recherche Agronomique (INRA)

Subjects
Male, MESH: Dietary Carbohydrates, MESH: Oxidation-Reduction, 030309 nutrition & dietetics, MESH: Dietary Proteins, Medicine (miscellaneous), High-protein diet, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Protein oxidation, medicine.disease_cause, Lipid peroxidation, chemistry.chemical_compound, 0302 clinical medicine, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Ingestion, Urea, MESH: Obesity, MESH: Animals, Adiposity, 2. Zero hunger, 0303 health sciences, Nutrition and Dietetics, MESH: Energy Metabolism, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Postprandial Period, MESH: Body Temperature Regulation, Postprandial, MESH: Dietary Fats, Lipogenesis, MESH: Postprandial Period, Dietary Proteins, MESH: Calorimetry, Indirect, Oxidation-Reduction, Body Temperature Regulation, medicine.medical_specialty, MESH: Rats, 030209 endocrinology & metabolism, Biology, 03 medical and health sciences, Lipid oxidation, Internal medicine, medicine, Dietary Carbohydrates, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Obesity, Rats, Wistar, MESH: Urea, MESH: Adiposity, MESH: Lipogenesis, Calorimetry, Indirect, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, MESH: Rats, Wistar, Carbohydrate, Dietary Fats, MESH: Male, Rats, Endocrinology, chemistry, Energy Metabolism, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

International audience; It has been suggested that high-protein (HP) diets may favor weight management by lowering energy intake and reducing body fat. Whether these effects result from changes in energy metabolism remains unclear. We measured the adaptation of energy metabolism components during 2 wk of HP feeding. Fifty male Wistar rats were switched from a control diet to an HP diet (14 and 55% of protein, respectively) for 1, 3, 6, or 14 d. Energy expenditure (EE) and substrate oxidation were measured by indirect calorimetry in feed-deprived rats and after consumption of a test meal. EE components, including the thermic effect of feeding and activity, were not modified during adaptation to an HP diet. Nutrient oxidation in feed-deprived rats was not affected by HP feeding, except for an early increase in protein oxidation. After 1 d, the postprandial inhibition of lipid oxidation (Lox) was blunted, carbohydrate (CHO) oxidation decreased by one-half, and urea clearance decreased by 66%. Thereafter, CHO oxidation gradually rose, resulting in a null CHO balance. Lox and urea clearance recovered after 3 d of adaptation to an HP diet, while protein oxidation reached a plateau. The postprandial oxidation of CHO counterbalanced the amount of ingested CHO as soon as 3 d, leading to a null postprandial CHO balance. We conclude that the inhibition of de novo lipogenesis from dietary CHO, but not EE and Lox, may participate in limiting the adiposity induced by HP feeding. The transient changes occurring during the period of adaptation to the diet highlight that the duration of the diet is critical in HP diet studies.

Published
2010
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10. In vivo evidence for a role of adipose tissue SR-BI in the nutritional and hormonal regulation of adiposity and cholesterol homeostasis

Author

Georges Dagher, Alexandre Bobard, Florence Massiera, Laurent Yvan-Charvet, Xavier Rousset, Pascal Ferré, Michèle Teboul, Gérard Ailhaud, Pascale Bossard, Annie Quignard-Boulangé, Pathologies nutritionnelles et métaboliques : obésité et diabète, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-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), Metabolisme et Differenciation Intestinale, Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
Male, Time Factors, Transcription, Genetic, medicine.medical_treatment, Angiotensinogen, Adipose tissue, Receptors, Cytoplasmic and Nuclear, White adipose tissue, 030204 cardiovascular system & hematology, MESH: Eating, Eating, Mice, 0302 clinical medicine, MESH: Cholesterol, Adipocytes, Homeostasis, Insulin, MESH: Animals, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Adiposity, Liver X Receptors, Epididymis, 0303 health sciences, Angiotensin II, Scavenger Receptors, Class B, Orphan Nuclear Receptors, DNA-Binding Proteins, Protein Transport, Cholesterol, Adipose Tissue, MESH: Homeostasis, Lipogenesis, MESH: ATP-Binding Cassette Transporters, lipids (amino acids, peptides, and proteins), MESH: Angiotensin II, MESH: Cholesterol, HDL, Cardiology and Cardiovascular Medicine, Sterol Regulatory Element Binding Protein 1, MESH: Adipose Tissue, ATP Binding Cassette Transporter 1, MESH: Triglycerides, medicine.medical_specialty, MESH: Protein Transport, MESH: Mice, Transgenic, Adipose tissue macrophages, MESH: Epididymis, MESH: Angiotensinogen, Mice, Transgenic, MESH: Insulin, Biology, MESH: Receptors, Cytoplasmic and Nuclear, 03 medical and health sciences, MESH: Sterol Regulatory Element Binding Protein 1, Internal medicine, 3T3-L1 Cells, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Liver X receptor, MESH: Mice, Triglycerides, MESH: Adipocytes, 030304 developmental biology, MESH: RNA, Messenger, MESH: Adiposity, MESH: Lipogenesis, MESH: Transcription, Genetic, Cell Membrane, Cholesterol, HDL, MESH: Time Factors, MESH: 3T3-L1 Cells, MESH: Male, MESH: Scavenger Receptors, Class B, Endocrinology, ATP-Binding Cassette Transporters, MESH: DNA-Binding Proteins, Lipoprotein, MESH: Cell Membrane
Abstract

Objectives— This study examines the role of insulin and angiotensin II in high-density lipoprotein (HDL) metabolism by focusing on the regulation and function of scavenger receptor type-BI (SR-BI) in adipose tissue. Methods and Results— Insulin or angiotensin II injection in wild-type mice induced a decrease in circulating HDL and it was associated with the translocation of SR-BI from intracellular sites to the plasma membrane of adipose tissue. Refeeding upregulated adipose HDL selective cholesteryl esters uptake and SR-BI proteins through transcriptional and posttranscriptional mechanisms. This occurred along with a decrease in serum HDL and an increase in adipose cholesterol content. Similar results were obtained with transgenic mice overexpressing locally angiotensinogen in adipose tissue. In adipose 3T3-L1 cell line, HDL induced lipogenesis by increasing liver X receptor binding activity. This mechanism was dependent of insulin and angiotensin II. Conclusions— Our results raise the possibility that adipose tissue SR-BI translocation might be a link between adipose tissue lipid storage and HDL clearance.

Published
2007
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11. HNF1alpha inactivation promotes lipogenesis in human hepatocellular adenoma independently of SREBP-1 and carbohydrate-response element-binding protein (ChREBP) activation

Author

Sandrine Imbeaud, Justine Bertrand-Michel, Sandra Rebouissou, Charles Auffray, Charles Balabaud, François Tercé, Paulette Bioulac-Sage, Virginie Boulanger, Jessica Zucman-Rossi, 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), Labex Immuno-oncology, Centre de Recherche des Cordeliers (CRC), 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)-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)-PRES Sorbonne Paris Cité-Faculté de Médecine, Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateau MetaToul-LIPIDOMIQUE = MetaToul-Lipidomics, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, This work was supported by the Inserm (Réseau de Recherche clinique et en santé des populations), ARC n°5188, SNFGE and the Fondation de France. SR is supported by a Ligue Nationale Contre le Cancer doctoral fellowship., Zucman-Rossi, Jessica, 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 Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaboHUB-MetaToul, Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), 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), MetaToul Lipidomics, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 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 ), 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, Génétique moléculaire de la neurotransmission et des processus neurodégénératifs ( LGMNPN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateau de lipidomique, Hôpital Purpan [Toulouse], and CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Claude de Preval

Subjects
Male, Biochemistry, 0302 clinical medicine, MESH: Liver Neoplasms, Glycolysis, MESH : Glycolysis, Oligonucleotide Array Sequence Analysis, chemistry.chemical_classification, 0303 health sciences, MESH: Middle Aged, Fatty Acids, Liver Neoplasms, MESH: SREBP-1, MESH: Transcription Factors, Gene Expression Regulation, Neoplastic, MESH : Oligonucleotide Array Sequence Analysis, MESH: Promoter Regions (Genetics), 030220 oncology & carcinogenesis, MESH : Hepatocyte Nuclear Factor 1-alpha, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Sterol Regulatory Element Binding Protein 1, MESH: Citric Acid, MESH : Gene Expression Regulation, Neoplastic, Adenoma, Liver Cell, 03 medical and health sciences, MESH: Gene Expression Profiling, MESH: Sterol Regulatory Element Binding Protein 1, MESH : steatosis, MESH : Adenoma, Liver Cell, MESH : Sterol Regulatory Element Binding Protein 1, MESH : Adolescent, Humans, MESH : Middle Aged, MESH: Hepatocyte Nuclear Factor 1-alpha, Molecular Biology, Fatty acid synthesis, MESH: Lipogenesis, MESH: Adolescent, MESH: Humans, MESH : Gene Expression Profiling, MESH : Humans, Fatty acid, MESH : HNF1α, MESH: Adult, medicine.disease, MESH : Promoter Regions (Genetics), Sterol regulatory element-binding protein, chemistry, MESH: Tumor Markers, Biological, MESH : Response Elements, MESH: Female, Transcription Factors, MESH: Liver, MESH: Signal Transduction, MESH : Liver Neoplasms, MESH : Fatty Liver, MESH : Transcription Factors, chemistry.chemical_compound, MESH: Adenoma, Liver Cell, MESH : Tumor Markers, Biological, MESH : Female, Hepatocyte Nuclear Factor 1-alpha, Promoter Regions, Genetic, MESH : Fatty Acids, MESH: Fatty Liver, MESH: Gluconeogenesis, MESH: Gene Expression Regulation, Neoplastic, Middle Aged, MESH : Adult, MESH: Fatty Acids, Liver, Lipogenesis, MESH: Glycolysis, Female, MESH: Response Elements, MESH : SREBP-1, Signal Transduction, Adult, Adolescent, MESH : Male, MESH : Gluconeogenesis, MESH : Citric Acid, Biology, Response Elements, Citric Acid, MESH: steatosis, Biomarkers, Tumor, medicine, MESH : hepatocellular adenoma, Carbohydrate-responsive element-binding protein, Transcription factor, 030304 developmental biology, MESH : Signal Transduction, Gene Expression Profiling, MESH: hepatocellular adenoma, Gluconeogenesis, MESH : Liver, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, MESH: HNF1α, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Male, MESH : Lipogenesis, Fatty Liver, MESH: Oligonucleotide Array Sequence Analysis, Steatosis
Abstract

International audience; Biallelic inactivating mutations of the transcription factor 1 gene (TCF1), encoding hepatocyte nuclear factor 1alpha (HNF1alpha) were identified in 50% of hepatocellular adenomas (HCA) phenotypically characterized by a striking steatosis. To understand the molecular basis of this aberrant lipid storage, we performed a microarray transcriptome analysis validated by quantitative reverse transcription-PCR, Western blotting, and lipid profiling. In mutated HCA, we showed a repression of gluconeogenesis coordinated with an activation of glycolysis, citrate shuttle, and fatty acid synthesis predicting elevated rates of lipogenesis. Moreover, the strong down-regulation of liver fatty acid-binding protein suggests that impaired fatty acid trafficking may also contribute to the fatty phenotype. In addition, transcriptional profile analysis of the observed deregulated genes in non-HNF1alpha-mutated HCA as well as in non-tumor livers allowed us to define a specific signature of the HNF1alpha-mutated HCA. In these tumors, lipid composition was dramatically modified according to the transcriptional deregulations identified in the fatty acid synthetic pathway. Surprisingly, lipogenesis activation did not operate through sterol regulatory element-binding protein-1 (SREBP-1) and carbohydrate-response element-binding protein (ChREBP) that were repressed. We conclude that steatosis in HNF1alpha-mutated HCA results mainly from an aberrant promotion of lipogenesis that is linked to HNF1alpha inactivation and that is independent of both SREBP-1 and ChREBP activation. Finally, our findings have potential clinical implications since lipogenesis can be efficiently inhibited by targeted therapies.

Published
2007
Full Text
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