Metformin lowers glucose 6-phosphate in hepatocytes by activation of glycolysis downstream of glucose phosphorylation
| Autor: | Ahmed Alshawi, Loranne Agius, Marc Foretz, Benoit Viollet, Silvia Marin, Natasha S. Adam-Primus, Shruti S. Chachra, Ziad H. Al-Oanzi, Tabassum Moonira, Marta Cascante, Catherine Arden, Brian E. Ford |
|---|---|
| Přispěvatelé: | Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP) |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Phosphofructokinase-1 Hypoglucemic agents AMP-Activated Protein Kinases MESH: Metformin MESH: Mice Knockout Biochemistry MESH: Hepatocytes chemistry.chemical_compound Mice Adenosine Triphosphate MESH: Adenosine Triphosphate Malalties cròniques MESH: Animals Glycolysis MESH: AMP-Activated Protein Kinases Phosphorylation Antidiabètics Mice Knockout Chemistry MESH: Gluconeogenesis MESH: Glycerolphosphate Dehydrogenase [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism glycolysis MESH: Glucose-6-Phosphate Metformin 3. Good health MESH: Glucose phosphofructokinase MESH: Glycolysis Dihydroxyacetone medicine.drug Phosphofructokinase medicine.medical_specialty MESH: Rats Allosteric regulation Glucose-6-Phosphate Glycerolphosphate Dehydrogenase liver 03 medical and health sciences MESH: Phosphofructokinase-1 MESH: Mice Inbred C57BL Internal medicine Rotenone medicine hepatocyte Animals [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] Rats Wistar MESH: Mice Molecular Biology glucose 6-phosphate MESH: Dihydroxyacetone MESH: Phosphorylation 030102 biochemistry & molecular biology Gluconeogenesis [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology Fructose MESH: Rats Wistar Cell Biology Metabolism MESH: Male Rats Mice Inbred C57BL 030104 developmental biology Endocrinology Glucose Glucose 6-phosphate Chronic diseases Hepatocytes MESH: Rotenone |
| Zdroj: | The Journal of Biological Chemistry Dipòsit Digital de la UB Universidad de Barcelona Journal of Biological Chemistry Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2020, 295 (10), pp.3330-3346. ⟨10.1074/jbc.ra120.012533⟩ |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | International audience; The chronic effects of metformin on liver gluconeogenesisinvolve repression of theG6pcgene, which is regulated by thecarbohydrate-response element–binding protein throughraised cellular intermediates of glucose metabolism. In thisstudy we determined the candidate mechanisms by which met-formin lowers glucose 6-phosphate (G6P) in mouse and rathepatocytes challenged with high glucose or gluconeogenic pre-cursors. Cell metformin loads in the therapeutic range loweredcell G6P but not ATP and decreasedG6pcmRNA at high glu-cose. The G6P lowering by metformin was mimicked by a com-plex 1 inhibitor (rotenone) and an uncoupler (dinitrophenol)and by overexpression of mGPDH, which lowers glycerol3-phosphate and G6P and also mimics theG6pcrepression bymetformin. In contrast, direct allosteric activators of AMPK(A-769662, 991, and C-13) had opposite effects from metforminon glycolysis, gluconeogenesis, and cell G6P. The G6P loweringby metformin, which also occurs in hepatocytes from AMPKknockout mice, is best explained by allosteric regulation ofphosphofructokinase-1 and/or fructose bisphosphatase-1, assupported by increased metabolism of [3-3H]glucose relative to[2-3H]glucose; by an increase in the lactate m2/m1 isotopologratio from [1,2-13C2]glucose; by lowering of glycerol 3-phos-phate an allosteric inhibitor of phosphofructokinase-1; and bymarked G6P elevation by selective inhibition of phosphofruc-tokinase-1; but not by a more reduced cytoplasmic NADH/NADredox state. We conclude that therapeutically relevant doses of metformin lower G6P in hepatocytes challenged with high glu-cose by stimulation of glycolysis by an AMP-activated proteinkinase–independent mechanism through changes in allostericeffectors of phosphofructokinase-1 and fructose bisphospha-tase-1, including AMP, Pi, and glycerol 3-phosphate |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|