Hepatocyte nuclear factor 4alpha is implicated in endoplasmic reticulum stress-induced acute phase response by regulating expression of cyclic adenosine monophosphate responsive element binding protein H.
Hepatocyte nuclear factor 4alpha is implicated in endoplasmic reticulum stress-induced acute phase response by regulating expression of cyclic adenosine monophosphate responsive element binding protein H.
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DOI：
10.1002/hep.22439
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发表时间：
2008-10
期刊：
影响因子：
13.5
通讯作者：
Duncan, Stephen A.
中科院分区：
文献类型：
--
作者：
Luebke-Wheeler, Jennifer;Zhang, Kezhong;Battle, Michele;Si-Tayeb, Karim;Garrison, Wendy;Chhinder, Sodhi;Li, Jixuan;Kaufman, Randal J.;Duncan, Stephen A.
肝细胞中核激素受体HNF 4 α的缺失导致复杂的多效性表型，包括肝细胞分化阻滞和肝功能严重破坏。最近的分析表明，肝脏基因表达受到HNF 4 α缺失的严重影响，在HNF 4 α-/-胎肝中，567个基因的表达降低≥2.5倍（P ≤0.05）。虽然这些基因中有许多是直接靶点，但HNF 4 α也被证明可调节其他肝脏转录因子的表达，这增加了某些基因正常表达对HNF 4 α的依赖可能是间接的。我们推测，通过鉴定受HNF 4 α调控的转录因子，可能揭示HNF 4 α在控制肝功能中的作用，而这在以前并没有被认识到。在这里，我们确定CrebH作为一种转录因子，其mRNA可以在胚胎和成年小鼠肝脏中识别，并且其表达依赖于HNF 4 α。基因组DNA分析显示，在胎肝中，CrebH编码序列上游的HNF 4 α结合位点被HNF 4 α占据，并在瞬时转染分析中促进报告基因的转录激活。尽管CrebH在肝发生过程中高度表达，但CrebH-/-小鼠是存活的、健康的，并且在肝脏形成中没有明显的缺陷。然而，在用衣霉素治疗后，其诱导内质网（ER）应激反应，CrebH-/-小鼠显示急性期反应蛋白的表达减少。这些数据暗示HNF 4 α通过调节CrebH的表达在控制由ER应激诱导的肝脏急性期反应中具有作用。
Loss of the nuclear hormone receptor HNF4α in hepatocytes results in a complex pleiotropic phenotype that includes a block in hepatocyte differentiation and a severe disruption to liver function. Recent analyses have shown that hepatic gene expression is severely affected by the absence of HNF4α with expression of 567 genes reduced by ≥2.5-fold (P ≤0.05) in Hnf4α-/- fetal livers. While many of these genes are direct targets, HNF4a has also been shown to regulate expression of other liver transcription factors raising the possibility that the dependency on HNF4α for normal expression of some genes may be indirect. We postulated that the identification of transcription factors whose expression is regulated by HNF4α might reveal roles for HNF4α in controlling hepatic functions that were not previously appreciated. Here we identify CrebH as a transcription factor whose mRNA can be identified in both the embryonic and adult mouse liver and whose expression is dependent on HNF4α. Analyses of genomic DNA revealed an HNF4α binding site upstream of CrebH coding sequence that was occupied by HNF4α in fetal livers and facilitated transcriptional activation of a reporter gene in transient transfection analyses. Although CrebH is highly expressed during hepatogenesis, CrebH-/- mice were viable, healthy, and displayed no overt defects in liver formation. However, upon treatment with tunicamycin, which induces an endoplasmic reticulum (ER)-stress response, CrebH-/- mice displayed reduced expression of acute phase response proteins. These data implicate HNF4α in having a role in controlling the acute phase response of the liver induced by ER-stress through regulating expression of CrebH.
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影响因子：
5.3
作者：
Hayhurst, GP;Lee, YH;Gonzalez, FJ
通讯作者：
Gonzalez, FJ
影响因子：
2.6
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TARAVIRAS, S;MONAGHAN, AP;KELSEY, G
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KELSEY, G
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影响因子：
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Kaestner, KH
影响因子：
29.4
作者：
Garrison, WD;Battle, MA;Duncan, SA
通讯作者：
Duncan, SA