Modulation of hepatocyte nuclear factor-4alpha function by the peroxisome-proliferator-activated receptor-gamma co-activator-1alpha in the acute-phase response.
Modulation of hepatocyte nuclear factor-4alpha function by the peroxisome-proliferator-activated receptor-gamma co-activator-1alpha in the acute-phase response.
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DOI：
10.1042/bj20080355
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发表时间：
2008-10-15
期刊：
影响因子：
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通讯作者：
Burke PA
中科院分区：
文献类型：
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作者：
Wang Z;Burke PA
HNF-4α（hepatocyte nuclear factor-4α）是肝脏特异性基因表达的关键调节因子。为了解HNF-4α在急性期反应（APR）中的调控机制，在损伤细胞模型中研究了转录共激活因子p300、PGC-1α（过氧化物酶体增殖物激活受体γ共激活因子1α）和SRC-1 α（类固醇受体共激活因子）的作用。我们先前已经证明，HNF-4α敏感性APR基因Apo B（载脂蛋白B）、TTR（甲状腺素运载蛋白）和α1-AT（α1-抗胰蛋白酶）在细胞因子刺激后在DNA结合和转录水平上受到调节。我们现在发现，共激活因子通过ApoB、TTR或α1-AT启动子中的HNF-4α结合位点对HNF-4α敏感基因的反式激活具有不同的影响。PGC-1α强烈增强ApoB和α1-AT的反式激活，并在较小程度上增强TTR的反式激活，而SRC-1α和p300仅对这三个基因有微弱或无影响。更重要的是，发现PGC-1α在响应细胞因子处理的HNF-4α结合能力的调节中具有新的作用。通过体外和体内的方法，电泳迁移率变化和染色质免疫沉淀试验，我们证明了细胞因子诱导的HNF-4α-DNA结合能力的降低可以通过PGC-1α的过表达而消除。细胞因子处理不会显著改变HNF-4α和PGC-1α的蛋白水平，但它确实减少了PGC-1α向HNF-4α结合位点的募集，从而降低了转录活性。这些结果确立了PGC-1α对HNF-4α功能的重要性，并描述了一种新的HNF-4α依赖性调节机制，参与了对损伤的反应。
HNF-4α (hepatocyte nuclear factor-4α) is a key regulator of liver-specific gene expression. To understand the mechanisms governing the regulation of HNF-4α function during the APR (acute-phase response), the effects of transcription co-activators, including p300, PGC-1α (peroxisome-proliferator-activated receptor-γ co-activator-1α) and SRC (steroid receptor co-activator)-1α were investigated in an injury cell model. We have shown previously that the HNF-4α-sensitive APR genes ApoB (apolipoprotein B), TTR (transthyretin) and α1-AT (α1-antitrypsin) were regulated at the DNA binding and transcriptional levels after cytokine stimulation. We now show that co-activators have a differential impact on the transactivation of HNF-4α-sensitive genes via HNF-4α-binding sites in ApoB, TTR or α1-AT promoters. PGC-1α strongly enhances the transactivation of ApoB and α1-AT and, to a lesser extent, of TTR, whereas SRC-1α and p300 only have a weak or no effect on these three genes. More importantly, it was found that PGC-1α has a novel role in the modulation of the binding ability of HNF-4α in response to cytokine treatment. Using in vitro and in vivo approaches, electrophoretic mobility-shift and chromatin immunoprecipitation assays, we demonstrate that the reduced HNF-4α-DNA binding ability induced by cytokines is eliminated by overexpression of PGC-1α. Cytokine treatment does not significantly alter the protein levels of HNF-4α and PGC-1α, but it does reduce the recruitment of PGC-1α to HNF-4α-binding sites and thereby decreases transcriptional activity. These results establish the importance of PGC-1α for HNF-4α function and describe a new HNF-4α-dependent regulatory mechanism that is involved in the response to injury.