Impact of perturbed pyruvate metabolism on adipocyte triglyceride accumulation |
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| Authors: | Yaguang Si Hai Shi Kyongbum Lee |
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| Institution: | 1. Department of Biology, Tufts University, Medford, MA 02155, USA;2. Department of Chemical and Biological Engineering, Tufts University, 4 Colby Street, Room 142, MA 02155, Medford, MA 02155, USA;1. Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;2. Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA;3. Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA;4. Howard Hughes Medical Institute, Boston, MA 02115, USA;5. Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA;6. Merck & Co., Inc., Kenilworth, NJ 07033, USA;7. Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA;1. Metabolic Unit, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, 1081 HV Amsterdam, the Netherlands;2. Department of Clinical Genetics, VU University Medical Center, 1081 HV Amsterdam, the Netherlands;3. Génétique CHU Angers, 49000 Angers, France;4. Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation and Weill Cornell Medical College, P.O. Box 3050, Doha-Qatar;5. Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children’s Hospital, 69120 Heidelberg, Germany;6. Inherited Metabolic Diseases, Hôpital Necker–Enfants Malades, Université Paris Descartes Sorbonne Paris cité, 75015 Paris, France;7. Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC 27710, USA;8. Neonatal Unit, Vestfold Hospital Trust, 3103 Tønsberg, Norway;9. Department of Molecular Paediatrics, Dr von Hauner Children’s Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany;10. Division of Pediatric Endocrinology, Diabetology and Metabolism and University Institute of Clinical Chemistry, Inselspital, University Hospital, University of Bern, 3010 Bern, Switzerland;11. Unità Operativa Semplice Malattie Metaboliche Rare, Department of Pediatrics, Fondazione “MBBM,” Azienda Ospedaliera San Gerardo, 20900 Monza, Italy;12. Laboratoire de Biochimie, CHU de Caen, 14033 Caen, France;13. Department of Pediatrics and Neuropediatrics, Klinik am Bürgerpark, 27574 Bremerhaven, Germany;14. Pediatric Metabolic Medicine, Department of Pediatrics, University Children’s Hospital, 20246 Hamburg, Germany;15. Department of Neonatology, Klinikum Stuttgart, Olgahospital, 70176 Stuttgart, Germany;16. Laboratory of Physiological Chemistry, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium;17. Department of Child Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, 1081 HV Amsterdam, the Netherlands;1. College of Chinese Medicinal Materials, Jilin Agriculture University, Changchun, China;2. Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China;1. Department of Immunology, IIS-Fundacion Jimenez Diaz, UAM, REDinREN, Madrid, Spain;2. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands;3. Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, SESCAM, Toledo, Spain;4. Department of Cardiac Surgery, Hospital Virgen de la Salud, SESCAM, Toledo, Spain;5. Department of Cardiology, Hospital Virgen de la Salud, SESCAM, Toledo, Spain;6. Department of Biochemistry and Molecular Biology I, Universidad Complutense, Madrid, Spain |
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| Abstract: | This study aimed to test the hypothesis that adipocyte TG accumulation could be altered by specifically perturbing pyruvate metabolism. We treated cultured 3T3-L1 adipocytes with chemical inhibitors of lactate dehydrogenase (LDH) and pyruvate carboxylase (PC), and characterized their global effects on intermediary metabolism using metabolic flux and isotopomer analysis. Inhibiting the enzymes over several days did not alter the adipocyte differentiation program as assessed by the expression levels of peroxisome proliferator-activated receptor-γ and glycerol-3-phosphate dehydrogenase. The main metabolic effects were to up-regulate intracellular lipolysis and decrease TG accumulation. Inhibiting PC also up-regulated glycolysis. Flux estimates indicated that the reduction in TG was due to decreased de novo fatty acid synthesis. Exogenous addition of free fatty acids dose-dependently increased the cellular TG level in the inhibitor-treated adipocytes, but not in untreated control cells. The results of this study support our hypothesis regarding the critical role of pyruvate reactions in TG synthesis. |
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