Foxa2-dependent hepatic gene regulatory networks depend on physiological state
Foxa2-dependent hepatic gene regulatory networks depend on physiological state
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DOI：
10.1152/physiolgenomics.90376.2008
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发表时间：
2009-07-01
影响因子：
4.6
通讯作者：
Kaestner, Klaus H.
中科院分区：
文献类型：
--
作者：
Bochkis, Irina M.;Schug, Jonathan;Kaestner, Klaus H.
Bochkis IM，Schug J，Rubins NE，Chopra AR，O'Malley BW，Kaestner KH. Foxa 2依赖性肝脏基因调控网络依赖于生理状态。Physiol Genomics 38：186-195，2009.首次发表于2009年5月5日; doi：10.1152/physiolgenomics.90376.2008。胆汁酸是由肝脏产生的强有力的洗涤剂，以帮助吸收膳食脂质。我们最近报道了Foxa 2在胆汁酸代谢中的新作用。翼螺旋转录因子Foxa 2是防止喂食富含胆酸饮食的小鼠肝内胆汁淤积和肝损伤所必需的。在这里，我们使用功能基因组学来研究Foxa 2如何以胆酸依赖的方式调节其靶点。我们发现，肝脏对急性肝损伤的反应所必需的多种信号通路在Foxa 2缺陷小鼠的肝脏中受损，这表明肝细胞中Foxa 2的缺失会大规模影响肝脏。我们还发现了不同的前馈调节环控制Foxa 2依赖性靶点的胆酸依赖性或非依赖性的方式。我们发现Foxa 2与不同的转录因子相互作用，以实现适合于每个生理状态的基因表达反应。
Bochkis IM, Schug J, Rubins NE, Chopra AR, O'Malley BW, Kaestner KH. Foxa2-dependent hepatic gene regulatory networks depend on physiological state. Physiol Genomics 38: 186-195, 2009. First published May 5, 2009; doi: 10.1152/physiolgenomics.90376.2008.-Bile acids are powerful detergents produced by the liver to aid in the absorption of dietary lipids. We recently reported a novel role for Foxa2 in bile acid metabolism. The winged helix transcription factor Foxa2 is required to prevent intrahepatic cholestasis and liver injury in mice fed a cholic acid-enriched diet. Here, we use functional genomics to study how Foxa2 regulates its targets in a cholic acid-dependent manner. We found that multiple signaling pathways essential for the hepatic response to acute liver injury are impaired in livers of Foxa2-deficient mice, suggesting that the deletion of Foxa2 in the hepatocyte affects the liver on a large scale. We also discovered distinct feed-forward regulatory loops controlling Foxa2-dependent targets in a cholic acid-dependent or -independent manner. We show that Foxa2 interacts with different transcription factors to achieve gene expression responses appropriate for each physiologic state.