FOXN3 Regulates Hepatic Glucose Utilization.
FOXN3 Regulates Hepatic Glucose Utilization.
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DOI：
10.1016/j.celrep.2016.05.056
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发表时间：
2016-06-21
期刊：
影响因子：
8.8
通讯作者：
Schlegel A
中科院分区：
文献类型：
--
作者：
Karanth S;Zinkhan EK;Hill JT;Yost HJ;Schlegel A
FOXN3基因第一内含子的SNP(Rs8004664)与人类空腹血糖相关。我们发现风险等位基因携带者肝脏转录抑制因子FOXN3的表达水平较高。在禁食期间，大鼠Foxn3蛋白和斑马鱼Foxn3转录本下调，这一过程在人类HepG2肝癌细胞中重现。斑马鱼FOXN3或人FOXN3的转基因过表达增加了斑马鱼肝脏糖异生基因的表达，增加了全幼体游离葡萄糖和成体空腹血糖，也降低了糖酵解基因的表达。肝脏FOXN3的过表达抑制了mycb的表达，mycb的同源基因myc被认为直接刺激葡萄糖利用酶的表达。Rs8004664风险等位基因携带者降低了MYC转录丰度。人FOXN3与人FOXN3和斑马鱼mycb基因座的DNA序列结合。我们的结论是，rs8004664风险等位基因驱动FOXN3在空腹时过度表达，FOXN3调节空腹血糖。
A SNP (rs8004664) in the first intron of the FOXN3 gene is associated with human fasting blood glucose. We find that carriers of the risk allele have higher hepatic expression of the transcriptional repressor FOXN3. Rat Foxn3 protein and zebrafish foxn3 transcripts are downregulated during fasting, a process recapitulated in human HepG2 hepatoma cells. Transgenic overexpression of zebrafish foxn3 or human FOXN3 increases zebrafish hepatic gluconeogenic gene expression, whole-larval free glucose, and adult fasting blood glucose, and also decreases expression of glycolytic genes. Hepatic FOXN3 overexpression suppresses expression of mycb, whose ortholog MYC is known to directly stimulate expression of glucose-utilization enzymes. Carriers of the rs8004664 risk allele have decreased MYC transcript abundance. Human FOXN3 binds DNA sequences in the human FOXN3 and zebrafish mycb loci. We conclude that the rs8004664 risk allele drives excessive expression of FOXN3 during fasting and that FOXN3 regulates fasting blood glucose.