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

Wang, Haiyan; Maechler, Pierre; Hagenfeldt-Johansson, Kerstin Arlette; Wollheim, Claes

doi:10.1093/emboj/17.22.6701

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Title		Dominant-negative suppression of HNF-1alpha function results in defective insulin gene transcription and impaired metabolism-secretion coupling in a pancreatic beta-cell line
Authors		Wang, Haiyan Maechler, Pierre Hagenfeldt-Johansson, Kerstin Arlette Wollheim, Claes
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/biosynthesis — Base Sequence — Binding Sites — Calcium/metabolism — Cell Line — Cell Membrane/physiology — DNA Primers — DNA-Binding Proteins — Down-Regulation — Genes, Dominant — Glucose/metabolism — Hepatocyte Nuclear Factor 1 — Hepatocyte Nuclear Factor 1-alpha — Hepatocyte Nuclear Factor 1-beta — Humans — Insulin/genetics — Islets of Langerhans/cytology/metabolism — Leucine/metabolism — Membrane Potentials — Nuclear Proteins — Promoter Regions, Genetic — Transcription Factors/genetics/metabolism — Transcription, Genetic — Tumor Cells, Cultured
Identifiers		DOI: 10.1093/emboj/17.22.6701 PMID: 9822613
Full text		Article (Published version) (664 Kb) - Free access
Structures		Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme
Citation (ISO format)		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. doi: 10.1093/emboj/17.22.6701 https://archive-ouverte.unige.ch/unige:35088