Foxa2 regulates multiple pathways of insulin secretion.
The regulation of insulin secretion by pancreatic beta 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 3beta) in pancreatic beta 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.
Lantz
Kristen A
KA
Department of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Vatamaniuk
Marko Z
MZ
Brestelli
John E
JE
Friedman
Joshua R
JR
Matschinsky
Franz M
FM
Kaestner
Klaus H
KH
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000172:deficiency / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology; D051542:Hepatocyte Nuclear Factor 3-beta; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D007668:Kidney / Q000166:cytology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors; D015533:Transcriptional Activation
D015094:3-Hydroxyacyl CoA Dehydrogenases; D018528:ATP-Binding Cassette Transporters; D000596:Amino Acids; D004268:DNA-Binding Proteins; D005947:Glucose; D051542:Hepatocyte Nuclear Factor 3-beta; D007328:Insulin; D008156:Luciferases; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009687:Nuclear Proteins; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D015534:Trans-Activators; D014157:Transcription Factors; C577507:ABCC8 protein, human; C577508:Abcc8 protein, mouse; C496503:Foxa2 protein, mouse