The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism.
The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism.
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DOI：
10.1016/j.cmet.2010.03.001
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发表时间：
2010-05-05
期刊：
影响因子：
29
通讯作者：
Johnson RS
中科院分区：
文献类型：
--
作者：
Zhang N;Fu Z;Linke S;Chicher J;Gorman JJ;Visk D;Haddad GG;Poellinger L;Peet DJ;Powell F;Johnson RS
抑制因子HIF-1α (FIH)是一种天冬酰胺羟化酶。FIH对HIF-α蛋白的羟基化可阻断HIF与转录共激活因子CBP/p300的关联，从而抑制转录激活。我们创造了具有FIH基因零突变的小鼠，并发现它在改变小鼠HIF功能的经典方面（如血管生成、红细胞生成或发育）方面几乎或没有可识别的作用。相反，它是一种重要的代谢调节剂：缺乏FIH的小鼠表现出体重减轻、代谢率升高、过度通气、葡萄糖和脂质稳态改善，并且对高脂肪饮食引起的体重增加和肝脏脂肪变性有抵抗力。神经元特异性的FIH缺失反映了全球零小鼠的一些主要代谢表型：这些小鼠体重减轻，代谢率增加，胰岛素敏感性增强，并且还可以防止高脂肪饮食引起的体重增加。这些结果表明，FIH在很大程度上通过神经系统调节代谢。
Factor Inhibiting HIF-1α (FIH) is an asparaginal hydroxylase. Hydroxylation of HIF-α proteins by FIH blocks association of HIFs with the transcriptional co-activators CBP/p300, thus inhibiting transcriptional activation. We have created mice with a null mutation in the FIH gene, and found that it has little or no discernable role in mice in altering classical aspects of HIF function, e.g., angiogenesis, erythropoiesis, or development. Rather, it is an essential regulator of metabolism: mice lacking FIH exhibit reduced body weight, elevated metabolic rate, hyperventilation, improved glucose and lipid homeostasis, and are resistant to high fat diet-induced weight gain and hepatic steatosis. Neuron-specific loss of FIH phenocopied some of the major metabolic phenotypes of the global null animals: those mice have reduced body weight, increased metabolic rate, enhanced insulin sensitivity, and are also protected against high fat diet-induced weight gain. These results demonstrate that FIH acts to a significant degree through the nervous system to regulate metabolism.
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