| Silencing of the mitochondrial NADH shuttle component aspartate-glutamate carrier AGC1/Aralar1 in INS-1E cells and rat islets. | |
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MedLine Citation:
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PMID: 19764902 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Transfer of reducing equivalents between cytosolic compartments and the mitochondrial matrix is mediated by NADH shuttles. Among these, the malate-aspartate shuttle has been proposed to play a major role in beta-cells for the control of glucose-stimulated insulin secretion. AGC1 or Aralar1 (aspartate-glutamate carrier 1) is a key component of the malate-aspartate shuttle. Overexpression of AGC1 increases the capacity of the malate-aspartate shuttle, resulting in enhanced metabolism-secretion coupling, both in INS-1E cells and rat islets. In the present study, knockdown of AGC1 was achieved in the same beta-cell models, using adenovirus-mediated delivery of shRNA (small-hairpin RNA). Compared with control INS-1E cells, down-regulation of AGC1 blunted NADH formation (-57%; P<0.05), increased lactate production (+16%; P<0.001) and inhibited glucose oxidation (-22%; P<0.01). This correlated with a reduced secretory response at 15 mM glucose (-25%; P<0.05), while insulin release was unchanged at intermediate 7.5 mM and basal 2.5 mM glucose. In isolated rat islets, efficient AGC1 knockdown did not alter insulin exocytosis evoked by 16.7 mM glucose. However, 4 mM amino-oxyacetate, commonly used to block transaminases of the malate-aspartate shuttle, inhibited glucose-stimulated insulin secretion to similar extents in INS-1E cells (-66%; P<0.01) and rat islets (-56%; P<0.01). These results show that down-regulation of the key component of the malate-aspartate shuttle AGC1 reduced glucose-induced oxidative metabolism and insulin secretion in INS-1E cells, whereas similar AGC1 knockdown in rat islets did not affect their secretory response. |
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Authors:
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Marina Casimir; Blanca Rubi; Francesca Frigerio; Gaelle Chaffard; Pierre Maechler |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-12-10 |
Journal Detail:
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Title: The Biochemical journal Volume: 424 ISSN: 1470-8728 ISO Abbreviation: Biochem. J. Publication Date: 2009 Dec |
Date Detail:
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Created Date: 2009-11-25 Completed Date: 2010-01-14 Revised Date: 2011-11-09 |
Medline Journal Info:
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Nlm Unique ID: 2984726R Medline TA: Biochem J Country: England |
Other Details:
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Languages: eng Pagination: 459-66 Citation Subset: IM |
Affiliation:
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Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenosine Triphosphate
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metabolism Aminooxyacetic Acid / pharmacology Animals Calcium / metabolism Cell Line, Tumor Enzyme Inhibitors / pharmacology Glucose / metabolism, pharmacology Glutamic Acid / metabolism Insulin / secretion Islets of Langerhans / cytology, drug effects, metabolism* Lactates / metabolism Membrane Potential, Mitochondrial / drug effects Membrane Transport Proteins / genetics, metabolism* Mitochondria / metabolism, physiology Mitochondrial Proteins / genetics, metabolism* RNA Interference* Rats |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Lactates; 0/Membrane Transport Proteins; 0/Mitochondrial Proteins; 0/Slc25a12 protein, rat; 11061-68-0/Insulin; 50-99-7/Glucose; 56-65-5/Adenosine Triphosphate; 56-86-0/Glutamic Acid; 645-88-5/Aminooxyacetic Acid; 7440-70-2/Calcium |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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