A Combination of HNF-4 and Foxo1 Is Required for Reciprocal Transcriptional Regulation of Glucokinase and Glucose-6-phosphatase Genes in Response to Fasting and Feeding
A Combination of HNF-4 and Foxo1 Is Required for Reciprocal Transcriptional Regulation of Glucokinase and Glucose-6-phosphatase Genes in Response to Fasting and Feeding
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DOI：
10.1074/jbc.m806179200
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发表时间：
2008-11-21
影响因子：
4.8
通讯作者：
Fukamizu, Akiyoshi
中科院分区：
文献类型：
--
作者：
Hirota, Keiko;Sakamaki, Jun-ichi;Fukamizu, Akiyoshi
葡萄糖激酶(GK)和葡萄糖-6-磷酸酶(G6Pase)分别调节生理上相反的代谢级联反应、糖酵解和糖异生中的限速反应。这些基因的表达在肝脏中对禁食和进食的反应是相反的。我们探索了营养条件对这些基因转录调控的机制，发现HNF-4和Foxo1的相互作用在这一过程中起着重要的作用。在GK基因调控中，Foxo1抑制HNF-4增强的G6Pase基因转录，而与HNF-4协同激活G6Pase基因转录。在没有胰岛素刺激的情况下，Foxo1的这些相反的作用同时发生在细胞中，并且这种基因特异性作用是启动子上下文依赖的。有趣的是，GK和G6Pase启动子中的HNF-4结合元件(HBE)是胰岛素刺激的GK基因激活和胰岛素介导的G6Pase基因抑制所必需的。事实上，小鼠体内成像显示，突变GK和G6Pase启动子中的HBE显著削弱了它们对营养状态的反应，即使在存在完整的Foxo1结合位点(胰岛素反应序列)的情况下也是如此。因此，在GK和G6Pase基因对禁食/摄食条件的生理反应中，Foxo1明显解码这两个基因的启动子上下文，并以不同的方式调节HBE的功能，从而导致相反的基因转录结果。
Glucokinase (GK) and glucose-6-phosphatase (G6Pase) regulate rate-limiting reactions in the physiologically opposed metabolic cascades, glycolysis and gluconeogenesis, respectively. Expression of these genes is conversely regulated in the liver in response to fasting and feeding. We explored the mechanism of transcriptional regulation of these genes by nutritional condition and found that reciprocal function of HNF-4 and Foxo1 plays an important role in this process. In the GK gene regulation, Foxo1 represses HNF-4-potentiated transcription of the gene, whereas it synergizes with HNF-4 in activating the G6Pase gene transcription. These opposite actions of Foxo1 concomitantly take place in the cells under no insulin stimulus, and such gene-specific action was promoter context-dependent. Interestingly, HNF-4-binding elements (HBEs) in the GK and G6Pase promoters were required both for the insulin-stimulated GK gene activation and insulin-mediated G6Pase gene repression. Indeed, mouse in vivo imaging showed that mutating the HBEs in the GK and G6Pase promoters significantly impaired their reactivity to the nutritional states, even in the presence of intact Foxo1-binding sites (insulin response sequences). Thus, in the physiological response of the GK and G6Pase genes to fasting/feeding conditions, Foxo1 distinctly decodes the promoter context of these genes and differently modulates the function of HBE, which then leads to opposite outcomes of gene transcription.