Foxa2 regulates multiple pathways of insulin secretion.
Foxa2 regulates multiple pathways of insulin secretion.
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DOI：
10.1172/jci21149
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发表时间：
2004-08
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影响因子：
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通讯作者：
Kristen A. Lantz;M. Vatamaniuk;John Brestelli;Joshua R. Friedman;F. Matschinsky;K. Kaestner
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文献类型：
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作者：
Kristen A. Lantz;M. Vatamaniuk;John Brestelli;Joshua R. Friedman;F. Matschinsky;K. Kaestner
胰腺β细胞对胰岛素分泌的调节在几种疾病中受到干扰，包括成人发病（2型）糖尿病和婴儿期持续性高胰岛素血症性低血糖症（PHHI）。PHHI的第一个小鼠模型在胰腺β细胞中具有编码翼状螺旋转录因子Foxa 2（叉头框a2，以前称为肝细胞核因子3 β）的基因的条件性缺失。使用分离的胰岛，我们发现Foxa 2缺陷导致响应于氨基酸的过度胰岛素释放和葡萄糖刺激的胰岛素分泌的完全丧失。大多数PHHI病例与SUR 1（磺酰脲受体1）或KIR6.2（内向整流K（+）通道成员6.2）的突变有关，它们编码ATP敏感性K（+）通道的亚基，突变小鼠胰岛的RNA原位杂交显示这两种基因的表达均依赖于Foxa 2。我们利用表达谱来鉴定Foxa 2的其他靶标。引人注目的是，这些基因之一Hadhsc编码短链L-3-羟酰基辅酶A脱氢酶，其缺陷已被证明会导致人类PHHI。Hadhsc是Foxa 2的直接靶标，如通过共转染以及使用分离的胰岛的体内染色质免疫沉淀实验所证明的。因此，我们已经确定Foxa 2作为在控制胰岛素分泌的多个途径中起作用的基因的必需激活剂。
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.