Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation
Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation
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DOI：
10.1042/bj20111748
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发表时间：
2012-04-01
影响因子：
4.1
通讯作者：
Haro, Diego
中科院分区：
文献类型：
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作者：
Luisa De Sousa-Coelho, Ana;Marrero, Pedro F.;Haro, Diego
营养缺乏或饥饿常常与氨基酸限制相关。氨基酸饥饿会启动信号转导级联，首先激活激酶 GCN2（一般控制非去阻抑物 2）、eIF2（真核起始因子 2）磷酸化、整体蛋白质合成减少和 ATF4（激活转录因子 4）增加。 ATF4 调节涉及适应饮食压力的多种基因。禁食期间肝脏会诱导激素 FGF21（成纤维细胞生长因子 21），其表达会诱导模拟长期禁食的代谢状态。因此，FGF21 对于诱导肝脂肪氧化、生酮和糖异生以及对饥饿的适应性代谢反应至关重要的代谢过程至关重要。在本研究中，我们发现小鼠肝脏和培养的 HepG2 细胞中的氨基酸剥夺可诱导 FGF21。我们已经确定人类 FGF21 基因作为 ATF4 的靶基因，并且我们在人类 FGF21 基因的 5' 调控区中定位了两个保守的 ATF4 结合序列，它们负责该基因的 ATF4 依赖性转录激活。这些结果将 FGF21 基因诱导添加到由 ATF4 水平增加启动的转录程序中，并为营养剥夺下诱导 FGF21 基因表达提供了新机制。
Nutrient deprivation or starvation frequently correlates with amino acid limitation. Amino acid starvation initiates a signal transduction cascade starting with the activation of the kinase GCN2 (general control non-derepressible 2) phosphorylation of eIF2 (eukaryotic initiation factor 2), global protein synthesis reduction and increased ATF4 (activating transcription factor 4). ATF4 modulates a wide spectrum of genes involved in the adaptation to dietary stress. The hormone FGF21 (fibroblast growth factor 21) is induced during fasting in liver and its expression induces a metabolic state that mimics long-term fasting. Thus FGF21 is critical for the induction of hepatic fat oxidation, ketogenesis and gluconeogenesis, metabolic processes which are essential for the adaptive metabolic response to starvation. In the present study, we have shown that FGF21 is induced by amino acid deprivation in both mouse liver and cultured HepG2 cells. We have identified the human FGF21 gene as a target gene for ATF4 and we have localized two conserved ATF4-binding sequences in the 5' regulatory region of the human FGF21 gene, which are responsible for the ATF4-dependent transcriptional activation of this gene. These results add FGF21 gene induction to the transcriptional programme initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation.