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Foxa2 regulates multiple pathways of insulin secretion
Kristen A. Lantz, … , Franz M. Matschinsky, Klaus H. Kaestner
Kristen A. Lantz, … , Franz M. Matschinsky, Klaus H. Kaestner
Published August 16, 2004
Citation Information: J Clin Invest. 2004;114(4):512-520. https://doi.org/10.1172/JCI21149.
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Article Metabolism Article has an altmetric score of 6

Foxa2 regulates multiple pathways of insulin secretion

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Abstract

The regulation of insulin secretion by pancreatic β cells is perturbed in several diseases, including adult-onset (type 2) diabetes and persistent hyperinsulinemic hypoglycemia of infancy (PHHI). The first mouse model for PHHI has a conditional deletion of the gene encoding the winged-helix transcription factor Foxa2 (Forkhead box a2, formerly Hepatocyte nuclear factor 3β) in pancreatic β cells. Using isolated islets, we found that Foxa2 deficiency resulted in excessive insulin release in response to amino acids and complete loss of glucose-stimulated insulin secretion. Most PHHI cases are associated with mutations in SUR1 (Sulfonylurea receptor 1) or KIR6.2 (Inward rectifier K+ channel member 6.2), which encode the subunits of the ATP-sensitive K+ channel, and RNA in situ hybridization of mutant mouse islets revealed that expression of both genes is Foxa2 dependent. We utilized expression profiling to identify additional targets of Foxa2. Strikingly, one of these genes, Hadhsc, encodes short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase, deficiency of which has been shown to cause PHHI in humans. Hadhsc is a direct target of Foxa2, as demonstrated by cotransfection as well as in vivo chromatin immunoprecipitation experiments using isolated islets. Thus, we have established Foxa2 as an essential activator of genes that function in multiple pathways governing insulin secretion.

Authors

Kristen A. Lantz, Marko Z. Vatamaniuk, John E. Brestelli, Joshua R. Friedman, Franz M. Matschinsky, Klaus H. Kaestner

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Figure 6

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Identification of a conserved Foxa2-binding site in intron 1 of the Hadh...
Identification of a conserved Foxa2-binding site in intron 1 of the Hadhsc gene, encoding schad. (A) Mouse Hadhsc is located on chromosome 3 and contains 8 exons. Exons are represented as vertical black bars, with bar width indicative of exon size. The 28-base region of the 1st Hadhsc intron shown is 93% conserved (26 of 28 bases) among mouse, rat, and human and includes the identical Foxa2-binding site shown in bold. (B) ChIP using mouse islets and a Foxa2 antibody followed by PCR confirmed the binding site on Hadhsc shown in A. Glut2 (a known Foxa2 target) served as a positive PCR control and MyoD is the negative PCR control. (C) Real-time PCR of purified DNA from ChIP eluates using primers for Hadhsc confirms the occupancy of this intron enhancer by Foxa2. Input (filled squares) and Foxa2 (open circles) Ct values were approximately 25 and 30, respectively. IgG (filled triangles) served as the ChIP control. (D) Cotransfection experiments with a luciferase construct containing 100 bp of Hadhsc intron 1 (pGL3-Hadhsc) and a Foxa2 expression plasmid (pHD-Foxa2) result in 3-fold activation compared with transfections with antisense Foxa2 (pHD-Foxa2 AS). n = 3 and ***P ≤ 0.0001 by Student’s t test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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