Regulation of Glyceraldehyde 3-Phosphate Dehydrogenase Expression by Metformin in HepG2 Cells
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概要
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Biguanides are known to have a serious side effect, lactic acidosis. We previously reported that buformin suppressed the expression of glyceraldehyde 3-phosphate dehydrogenase (GAPD) and suggested that this decrease was one of the causes of lactic acidosis. In this study, we examined the signaling pathway and regulatory factors for the expression of the GAPD gene triggered by metformin in HepG2 cells. The mRNA and protein expression of GAPD, detected by real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, respectively, decreased upon treatment of the cells with 10 mM metformin for 24 h. Under the conditions, metformin induced phosphorylation of AMP-activated protein kinase (AMPK). The expression of GAPD mRNA decreased on treatment with an activator for AMPK, 5-amino-imidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). Inhibitors for signal transducers, Compound C, H-89, and MDL-12,330A, restored the level of GAPD mRNA. A luciferase reporter plasmid containing bp −1795 to +57 of the 5′-flanking region of the GAPD gene was constructed for a reporter gene assay. The luciferase activity in transfectants decreased on incubation with metformin. A mutant reporter plasmid with an altered cAMP-response element (CRE) counteracted the metformin-mediated repression of GAPD transcription. These results suggest that signal transducers, adenylate cyclase (AC), protein kinase A (PKA), and AMPK, are involved in the signaling pathway triggered by metformin and CRE-binding protein is one of the transcription factors for the GAPD gene down-regulated by metformin.
著者
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HIRANO Kazuyuki
Laboratory of Pharmaceutics, Gifu Pharmaceutical University
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IGUCHI Kazuhiro
岐阜薬科大学薬剤学教室
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Iguchi Kazuhiro
Laboratory Of Pharmaceutics Gifu Pharmaceutical University
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USUI Shigeyuki
Laboratory of Pharmaceutics, Gifu Pharmaceutical University
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Hirano Kazuyuki
Laboratory Of Pharmaceutics Gifu Pharmaceutical University
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KUBOTA Masafumi
Laboratory of Pharmaceutics, Gifu Pharmaceutical University
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Usui Shigeyuki
Laboratory Of Pharmaceutics Gifu Pharmaceutical University
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Yokoyama Yuichi
Laboratory of Pharmaceutics, Department of Medical Pharmaceutics, Gifu Pharmaceutical University
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Kiho Tadashi
Laboratory of Pharmaceutics, Department of Medical Pharmaceutics, Gifu Pharmaceutical University
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Hirano Kazuyuki
Laboratory of Pharmaceutics, Department of Medical Pharmaceutics, Gifu Pharmaceutical University
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Usui Shigeyuki
Laboratory of Pharmaceutics, Department of Medical Pharmaceutics, Gifu Pharmaceutical University
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Kubota Masafumi
Laboratory of Pharmaceutics, Department of Medical Pharmaceutics, Gifu Pharmaceutical University
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Iguchi Kazuhiro
Laboratory of Pharmaceutics, Department of Medical Pharmaceutics, Gifu Pharmaceutical University
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