Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on HNF-4alpha.
Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on HNF-4alpha.
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发表时间：
2007
影响因子：
10.5
通讯作者：
Rana K. Gupta;N. Gao;Regina K. Gorski;P. White;O. Hardy;Kiran Rafiq;John Brestelli;Guang-hui Chen-Guang-hui
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文献类型：
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作者：
Rana K. Gupta;N. Gao;Regina K. Gorski;P. White;O. Hardy;Kiran Rafiq;John Brestelli;Guang-hui Chen-Guang-hui
未能扩大功能性胰岛β细胞团以回应增加的代谢需求是2型糖尿病的一个特征。谱系追踪研究表明，复制现有的贝塔细胞是成年小鼠贝塔细胞扩张的主要机制。在这里，我们证明了β细胞的增殖反应依赖于孤儿核受体肝细胞核因子-4α(HNF-4α)，该基因在青年成熟型糖尿病(MODY1)中发生突变。对胰腺β细胞中缺乏HNF-4α的小鼠分离胰岛的微阵列表达谱计算分析表明，HNF-4α调节β细胞中选定的基因，其中许多基因与增殖有关。利用β细胞增殖的生理学模型，我们证明了胰岛中的β细胞复制和RAS/ERK信号通路的激活需要HNF-4α。这种表型与HNF-4α突变体中肿瘤致瘤性抑制因子5(ST5)的下调有关，我们发现ST5是β细胞中ERK磷酸化的新调节因子，也是HNF-4α在体内的直接转录靶点。综上所述，这些结果表明，HNF-4α对于成人β细胞团的生理性扩张是必不可少的，以响应增加的代谢需求。
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-4alpha (HNF-4alpha), 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-4alpha in pancreatic beta-cells reveals that HNF-4alpha 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-4alpha 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-4alpha mutants, which we identify as a novel regulator of ERK phosphorylation in beta-cells and a direct transcriptional target of HNF-4alpha in vivo. Together, these results indicate that HNF-4alpha is essential for the physiological expansion of adult beta-cell mass in response to increased metabolic demand.