Molecular mechanism of hypoxia-mediated hepatic gluconeogenesis by transcriptional regulation
Molecular mechanism of hypoxia-mediated hepatic gluconeogenesis by transcriptional regulation
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DOI：
10.1016/j.febslet.2005.03.097
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发表时间：
2005-05-23
期刊：
影响因子：
3.5
通讯作者：
Cheong, J
中科院分区：
文献类型：
--
作者：
Choi, JH;Park, MJ;Cheong, J
到目前为止，已知缺氧在转录水平上增加糖酵解酶的表达。在这里，我们表明缺氧增加肝葡萄糖输出和HIF-1和ATF-2介导的磷酸烯醇式丙酮酸羧激酶（PEPCK）的反式激活的证据，这起着至关重要的作用，作为一个限速酶在肝脏中的基因。HIF-1通过其同源结合元件直接与特异性PEPCK启动子区域结合，并与辅激活因子CBP形成活性复合物。此外，ATF-2还参与调节与HIF-1和CBP的转录复合物中的缺氧依赖性PEPCK转录。有趣的是，视黄酸（RA）信号转导诱导PEPCK启动子上的HIF-1的募集，这是由HIF-1和ATF-2与辅激活因子CBP的功能性相互作用引起的。综上所述，这些结果表明，缺氧信号通过增加促血管生成酶的基因表达导致肝脏葡萄糖的产生和释放，可能在向其他组织（如内皮细胞、脑细胞和肌肉细胞）提供葡萄糖中起作用。(c)2005年欧洲生物化学学会联合会。Elsevier B. V.出版，保留所有权利。
Until now, it is known that hypoxia increases the glycolytic enzyme expression at the transcriptional level. Here, we show evidence that hypoxia increases hepatic glucose output and HIF-1 and ATF-2-mediated transactivation of phosphoenolpyruvate carboxykinase (PEPCK), which plays a critical role as a rate-limiting enzyme in gluconeogenesis, gene in liver. HIF-1 directly bound to the specific PEPCK promoter region through its cognate binding element and found as an active complex with coactivator CBP. Additionally, ATF-2 was also involved to regulate hypoxia-dependent PEPCK transcription in the transcriptional complex with HIF-1 and CBP. Interestingly, retinoic acid (RA) signaling induced the recruitment of HIF-1 on the PEPCK promoter, resulting from the functional interaction of HIF-1 and ATF-2 with coactivator CBP. Taken together, these results suggest that hypoxia signaling leads the hepatic glucose production and release via the increased gene expression of gluconeogenic enzymes, possibly playing a role in providing glucose to other tissues, such as endothelial, brain and muscle cells. (c) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.