Loss of HNF-1α function in mice leads to abnormal expression of genes involved in pancreatic islet development and metabolism
Loss of HNF-1α function in mice leads to abnormal expression of genes involved in pancreatic islet development and metabolism
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DOI：
10.2337/diabetes.50.11.2472
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发表时间：
2001-11-01
期刊：
影响因子：
7.7
通讯作者：
Stoffel, M
中科院分区：
文献类型：
--
作者：
Shih, DQ;Screenan, S;Stoffel, M
肝细胞核因子 1 α (HNF-1 α) 突变导致胰腺 β 细胞胰岛素分泌反应受损，从而导致青少年 3 型成熟期糖尿病。研究了正常 β 细胞功能所必需的 50 个基因的表达，以更好地确定 Hnf-1 α (-/-) 小鼠胰岛素分泌缺陷的分子机制。我们发现 Hnf-1 α (-/-) 小鼠中编码葡萄糖转运蛋白 2 (Glut2)、中性和碱性氨基酸转运蛋白、肝丙酮酸激酶 (L-Pk) 和胰岛素的基因的稳态 mRNA 水平降低。此外，我们确定 Hnf-1 α (-/-) 小鼠中几种富含胰岛的转录因子（包括 Pdx-1、Hnf-4 α 和 Neuro-D1/Beta-2）的表达降低。胰岛 mRNA 水平的这些变化在新生动物中已经很明显，表明 Hnf-1 α 功能的丧失而不是慢性高血糖是基因表达改变的主要原因。该表达谱是胰岛特异性的，与肝细胞不同，我们在肝细胞中发现 Hnf-1 α (-/-) 小鼠肝脏中 Glut2、L-Pk 和 Hnf-4 α 的正常表达。小异二聚体伴侣 (Shp-1) 是一种孤儿受体，可与 Hnf-4a 异二聚化并抑制其转录活性，在 Hqf-1 α (-/-) 胰岛中的表达也有所减少。我们对 0.58 kb Shp-1 启动子进行了表征，并确定 Shp-1 表达的降低可能是通过 Hnf-4a 的下调间接介导的。我们进一步表明Shp-1可以通过抑制Hnf-4α功能来抑制其自身的转录激活，从而建立反馈自动调节环路。我们的结果表明，Hnf-1 α 功能的丧失会导致参与葡萄糖刺激的胰岛素分泌、胰岛素合成和 β 细胞分化的基因表达发生改变。
Mutations in hepatocyte nuclear factor 1 alpha (HNF-1 alpha) lead to maturity-onset diabetes of the young type 3 as a result of impaired insulin secretory response in pancreatic beta -cells. The expression of 50 genes essential for normal beta -cell function was studied to better define the molecular mechanism underlying the insulin secretion defect in Hnf-1 alpha (-/-) mice. We found decreased steady-state mRNA levels of genes encoding glucose transporter 2 (Glut2), neutral and basic amino acid transporter, liver pyruvate kinase (L-Pk), and insulin in Hnf-1 alpha (-/-) mice. In addition, we determined that the expression of several islet-enriched transcription factors, including Pdx-1, Hnf-4 alpha, and Neuro-D1/Beta-2, was reduced in Hnf-1 alpha (-/-) mice. These changes in pancreatic islet mRNA levels were already apparent in newborn animals, suggesting that loss of Hnf-1 alpha function rather than chronic hyperglycemia is the primary cause of the altered gene expression. This expression profile was pancreatic islet-specific and distinct from hepatocytes, where we found normal expression of Glut2, L-Pk, and Hnf-4 alpha in the liver of Hnf-1 alpha (-/-) mice. The expression of small heterodimer partner (Shp-1), an orphan receptor that can heterodimerize with Hnf-4a and inhibit its transcriptional activity, was also reduced in Hqf-1 alpha (-/-) islets. We characterized a 0.58-kb Shp-1 promoter and determined that the decreased expression of Shp-1 may be indirectly mediated by a downregulation of Hnf-4a. We further showed that Shp-1 can repress its own transcriptional activation by inhibiting Hnf-4 alpha function, thereby establishing a feedback autoregulatory loop. Our results indicate that loss of Hnf-1 alpha function leads to altered expression of genes involved in glucose-stimulated insulin secretion, insulin synthesis, and beta -cell differentiation.