Expansion of adult β-cell mass in response to increased metabolic demand is dependent on HNF-4α
Expansion of adult β-cell mass in response to increased metabolic demand is dependent on HNF-4α
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DOI：
10.1101/gad.1535507
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发表时间：
2007-04-01
影响因子：
10.5
通讯作者：
Kaestner, Klaus H.
中科院分区：
文献类型：
--
作者：
Gupta, Rana K.;Gao, Nan;Kaestner, Klaus H.
无法扩大功能性胰腺 β 细胞量来应对代谢需求的增加是 2 型糖尿病的一个标志。谱系追踪研究表明，现有 β 细胞的复制是成年小鼠 β 细胞扩增的主要机制。在这里，我们证明 β 细胞的增殖反应依赖于孤儿核受体肝细胞核因子 4 α (HNF-4 α)，该基因在青少年发病型糖尿病 1 (MODY1) 中发生突变。对胰腺 β 细胞中缺乏 HNF-4 α 的小鼠分离胰岛的微阵列表达谱进行计算分析表明，HNF-4 α 调节 β 细胞中的选定基因，其中许多基因与增殖有关。使用 β 细胞扩增的生理模型，我们表明 HNF-4 α 是 β 细胞复制和胰岛中 Ras/ERK 信号级联激活所必需的。这种表型与 HNF-4 α 突变体中致瘤性 5 (ST5) 抑制的下调相关，我们将其确定为 β 细胞中 ERK 磷酸化的新型调节剂和 HNF-4 α 体内的直接转录靶标。总之，这些结果表明，HNF-4 α 对于成人 β 细胞团响应代谢需求增加的生理扩张至关重要。
The failure to expand functional pancreatic beta-cell mass in response to increased metabolic demand is a hallmark of type 2 diabetes. Lineage tracing studies indicate that replication of existing beta-cells is the principle mechanism for beta-cell expansion in adult mice. Here we demonstrate that the proliferative response of beta-cells is dependent on the orphan nuclear receptor hepatocyte nuclear factor-4 alpha (HNF-4 alpha), the gene that is mutated in Maturity-Onset Diabetes of the Young 1 (MODY1). Computational analysis of microarray expression profiles from isolated islets of mice lacking HNF-4 alpha in pancreatic beta-cells reveals that HNF-4 alpha regulates selected genes in the beta-cell, many of which are involved in proliferation. Using a physiological model of beta-cell expansion, we show that HNF-4 alpha is required for beta-cell replication and the activation of the Ras/ERK signaling cascade in islets. This phenotype correlates with the down-regulation of suppression of tumorigenicity 5 (ST5) in HNF-4 alpha mutants, which we identify as a novel regulator of ERK phosphorylation in beta-cells and a direct transcriptional target of HNF-4 alpha in vivo. Together, these results indicate that HNF-4 alpha is essential for the physiological expansion of adult beta-cell mass in response to increased metabolic demand.