Cholesterogenic lanosterol 14α-demethylase (CYP51) is an immediate early response gene
Cholesterogenic lanosterol 14α-demethylase (CYP51) is an immediate early response gene
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DOI：
10.1210/en.2005-0781
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发表时间：
2005-12-01
期刊：
影响因子：
4.8
通讯作者：
Rozman, D
中科院分区：
文献类型：
--
作者：
Fink, M;Acimovic, J;Rozman, D
羊毛甾醇14 α-脱甲基酶（CYP 51）通过甾醇调节元件结合蛋白（SREBP）响应胆固醇反馈调节。CYP 51基因启动子的近端含有一个保守区，其调控元件包括GC box、cAMP反应元件（CRE-like）和固醇调控元件（SRE）。在富脂（SREBP-贫）条件下，CYP 51 mRNA逐渐下降，启动子活性减弱，并且在CYP 51-SRE 1位点未观察到DNA-蛋白质复合物。大多数cAMP依赖性反式激活通过单个CRE（CYP 51-CRE 2）介导。将JEG-3细胞暴露于cAMP依赖性信号通路的介质毛喉素，引起CYP 51的立即早期反应，这在任何胆固醇基因之前都没有描述过。CYP 51 mRNA在2小时内增加4倍，并在4小时后降至基础水平。诱导型cAMP早期阻遏物（ICER）参与转录的衰减。过表达的CREB/CRE调节剂（CREM）不依赖于SREBP而反式激活含有CYP 51-CRE 2的小鼠/人CYP 51启动子，ICER降低CREB诱导的转录。除了增加CYP 51 mRNA外，毛喉素还影响JEG-3细胞中甾醇的从头生物合成。观察到羊毛甾醇（CYP 51的底物）的消耗增加以及羊毛甾醇后胆固醇生成的调节，表明cAMP依赖性刺激与胆固醇反馈调节相互作用。CRE-2对cAMP依赖性的反式激活至关重要，而SRE似乎不太重要。有趣的是，当CREB不是限制性的时，增加量的SREBP-1a不能反式激活CYP 51启动子高于仅CREB水平，这表明激素可能在体内调节胆固醇生成中具有重要作用。
Lanosterol 14 alpha-demethylase (CYP51) responds to cholesterol feedback regulation through sterol regulatory element binding proteins (SREBPs). The proximal promoter of CYP51 contains a conserved region with clustered regulatory elements: GC box, cAMP-response elements (CRE-like), and sterol regulatory element (SRE). In lipid-rich (SREBP-poor) conditions, the CYP51 mRNA drops gradually, the promoter activity is diminished, and no DNA-protein complex is observed at the CYP51-SRE1 site. The majority of cAMP-dependent transactivation is mediated through a single CRE (CYP51-CRE2). Exposure of JEG-3 cells to forskolin, a mediator of the cAMP-dependent signaling pathway, provokes an immediate early response of CYP51, which has not been described before for any cholesterogenic gene. The CYP51 mRNA increases up to 4-fold in 2 h and drops to basal level after 4 h. The inducible cAMP early repressor (ICER) is involved in attenuation of transcription. Overexpressed CRE-binding protein (CREB)/CRE modulator (CREM) transactivates the mouse/human CYP51 promoters containing CYP51-CRE2 independently of SREBPs, and ICER decreases the CREB-induced transcription. Besides the increased CYP51 mRNA, forskolin affects the de novo sterol biosynthesis in JEG-3 cells. An increased consumption of lanosterol, a substrate of CYP51, is observed together with modulation of the postlanosterol cholesterogenesis, indicating that cAMP-dependent stimuli cross-talk with cholesterol feedback regulation. CRE-2 is essential for cAMP-dependent transactivation, whereas SRE seems to be less important. Interestingly, when CREB is not limiting, the increasing amounts of SREBP-1a fail to transactivate the CYP51 promoter above the CREB-only level, suggesting that hormones might have an important role in regulating cholesterogenesis in vivo.