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Dominant-negative suppression of HNF-1alpha function results in defective insulin gene transcription and impaired metabolism-secretion coupling in a pancreatic beta-cell line

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Published in EMBO Journal. 1998, vol. 17, no. 22, p. 6701-13
Abstract Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) have been linked to subtype 3 of maturity-onset diabetes of the young (MODY3), which is characterized by a primary defect in insulin secretion. The role of HNF-1alpha in the regulation of pancreatic beta-cell function was investigated. Gene manipulation allowed graded overexpression of HNF-1alpha and controlled dominant-negative suppression of HNF-1alpha function in insulinoma INS-1 cells. We show that HNF-1alpha is essential for insulin gene transcription, as demonstrated by a pronounced decrease in insulin mRNA expression and in insulin promoter activity under dominant-negative conditions. The expression of genes involved in glucose transport and metabolism including glucose transporter-2 and L-type pyruvate kinase is also regulated by HNF-1alpha. Loss of HNF-1alpha function leads to severe defects in insulin secretory responses to glucose and leucine, resulting from impaired glucose utilization and mitochondrial oxidation. The nutrient-evoked ATP production and subsequent changes in plasma membrane potential and intracellular Ca2+ were diminished by suppression of HNF-1alpha function. These results suggest that HNF-1alpha function is essential for maintaining insulin storage and nutrient-evoked release. The defective mitochondrial oxidation of metabolic substrates causes impaired insulin secretion, indicating a molecular basis for the diabetic phenotype of MODY3 patients.
Keywords Adenosine Triphosphate/biosynthesisBase SequenceBinding SitesCalcium/metabolismCell LineCell Membrane/physiologyDNA PrimersDNA-Binding ProteinsDown-RegulationGenes, DominantGlucose/metabolismHepatocyte Nuclear Factor 1Hepatocyte Nuclear Factor 1-alphaHepatocyte Nuclear Factor 1-betaHumansInsulin/geneticsIslets of Langerhans/cytology/metabolismLeucine/metabolismMembrane PotentialsNuclear ProteinsPromoter Regions, GeneticTranscription Factors/genetics/metabolismTranscription, GeneticTumor Cells, Cultured
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PMID: 9822613
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WANG, Haiyan et al. Dominant-negative suppression of HNF-1alpha function results in defective insulin gene transcription and impaired metabolism-secretion coupling in a pancreatic beta-cell line. In: EMBO Journal, 1998, vol. 17, n° 22, p. 6701-13. https://archive-ouverte.unige.ch/unige:35088

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Deposited on : 2014-03-28

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