Selenoprotein P Expression Is Controlled through Interaction of the Coactivator PGC-1α with FoxO1a and Hepatocyte Nuclear Factor 4α Transcription Factors
Selenoprotein P Expression Is Controlled through Interaction of the Coactivator PGC-1α with FoxO1a and Hepatocyte Nuclear Factor 4α Transcription Factors
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DOI：
10.1002/hep.22526
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发表时间：
2008-12-01
期刊：
影响因子：
13.5
通讯作者：
Steinbrenner, Holger
中科院分区：
文献类型：
--
作者：
Speckmann, Bodo;Walter, Philippe L.;Steinbrenner, Holger
硒蛋白P(Sep)是血浆中的主要硒蛋白，虽然在许多器官中都有表达，但主要由肝脏产生。最近，我们报道了叉头盒转录因子FoxO1a对肝癌细胞中Sep启动子活性的刺激和胰岛素的抑制作用。在这里，我们证明了这将转化为胰岛素对Sep的产生和分泌的微调。过表达PGC-1α可增强FoxO1a对Sep启动子活性的刺激作用。我们在FoxO反应元件daf16结合元件2(DBE2)上游的人Sep启动子中发现了一个新的肝细胞核因子(HNF)-4α的功能结合部位，称为肝细胞核因子结合元件1。肝细胞核因子结合元件1的点突变单独或与DBE2一起降低了Sep启动子的基础活性和对PGC-1α的反应性。此外，PGC-1α诱导的糖皮质激素地塞米松显著促进培养的大鼠肝细胞SEP信使RNA水平和蛋白分泌，而胰岛素抑制地塞米松对PGC-1α和SEP的刺激作用。在基础Sep低表达的脑源性神经母细胞瘤细胞系中，PGC-1α和FoxO1a共同刺激了Sep的转录，HNF-4α的过表达增强了这一作用。结论：协同激活因子PGC-1α与转录因子FoxO1a和HNF-4α协同作用，保证了Sep在肝脏中的高水平表达。因此，SEP的产生与葡萄糖异生酶葡萄糖-6-磷酸酶的调节相似。由于肝脏SEP的产生对硒在全身的分布是至关重要的，本研究确定PGC-1α是硒稳态的关键调节因子。(《肝病》2008；48：1998-2006)
Selenoprotein P (Sep), the major selenoprotein in plasma, is produced mainly by the liver, although Sep expression is detected in many organs. Recently, we reported stimulation of Sep promoter activity by the forkhead box transcription factor FoxO1a in hepatoma cells and its attenuation by insulin. Here, we demonstrate that this translates into fine-tuning of Sep production and secretion by insulin. Overexpression of peroxisomal proliferator activated receptor-gamma coactivator 1 alpha (PGC-1 alpha) enhanced the stimulatory effect of FoxO1a on Sep promoter activity. We identified a novel functional binding site for hepatocyte nuclear factor (HNF)-4 alpha, termed hepatocyte nuclear factor binding element 1, in the human Sep promoter directly upstream of the FoxO-responsive element daf16-binding element 2 (DBE2). Point mutations in hepatocyte nuclear factor binding element 1 alone or together with DBE2 decreased basal activity and responsiveness of the SeP promoter to PGC-1 alpha. Moreover, the PGC-1 alpha-inducing glucocorticoid dexamethasone strongly enhanced Sep messenger RNA levels and protein secretion in cultured rat hepatocytes, whereas insulin suppressed the stimulation of both PGC-1 alpha and Sep caused by dexamethasone treatment. In a brain-derived neuroblastoma cell line with low basal Sep expression, Sep transcription was stimulated by PGC-1 alpha together with FoxO1a, and overexpression of HNF-4 alpha potentiated this effect. Conclusion: High-level expression of Sep in liver is ensured by concerted action of the coactivator PGC-1 alpha and the transcription factors FoxO1a and HNF-4 alpha. Hence, the production of Sep is regulated similarly to that of the gluconeogenic enzyme glucose-6-phosphatase. As hepatic Sep production is crucial for selenium distribution throughout the body, the present study establishes PGC-1 alpha as a key regulator of selenium homeostasis. (HEPATOLOGY 2008;48:1998-2006.)