Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2
Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2
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DOI：
10.1194/jlr.m700443-jlr200
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发表时间：
2008-02-01
影响因子：
6.5
通讯作者：
Park, Sahng Wook
中科院分区：
文献类型：
--
作者：
Jeong, Hyun Jeong;Lee, Hyun-Sook;Park, Sahng Wook
前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK 9）是枯草杆菌酶家族中的一员，能促进肝脏中LDL受体的内化和降解，从而控制血浆中LDL胆固醇的水平。在这里，我们表明PCSK 9在HepG 2细胞中的表达完全依赖于甾醇的存在或不存在。PCSK 9基因的最小启动子区含有固醇调节元件（SRE），其使得PCSK 9的转录依赖于固醇。核形式的固醇调节元件结合蛋白-1（SREBP-1）和SREBP-2的表达显著增加了PCSK 9的启动子活性。在体外翻译的核形式的SREBP显示与SRE的相互作用，而在SRE的突变废除其结合。在小鼠体内的研究表明，Pcsk 9蛋白和mRNA显着减少禁食和增加再喂养。然而，在饮食中补充2%的胆固醇阻止了Pcsk的增加。Pcsk 9 mRNA在小鼠肝脏中的表达量与Srebp-2核形式的变化相关。综上所述，这表明在HepG 2细胞中PCSK 9的表达在转录水平上受到固醇的调控，并且SREBP-1和SREBP-2都可以通过其近端启动子区的SRE在体外转录激活PCSK 9。然而，在体内，这表明，固醇依赖性调节PCSK 9主要是由SREBP-2介导的。
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the subtilases that promotes the internalization and degradation of LDL receptor in liver and thereby controls the level of LDL cholesterol in plasma. Here, we show that the expression of PCSK9 in HepG2 cells is completely dependent on the absence or presence of sterols. The minimal promoter region of the PCSK9 gene contains a sterol-regulatory element (SRE), which makes the transcription of PCSK9 dependent on sterols. Expression of nuclear forms of sterol-regulatory element binding protein-1 (SREBP-1) and SREBP-2 dramatically increased the promoter activity of PCSK9. In vitro-translated nuclear forms of SREBPs showed interactions with SRE, whereas mutations in SRE abolished their binding. In vivo studies in mice showed that Pcsk9 protein and mRNA were decreased significantly by fasting and increased by refeeding. However, supplementation with 2% cholesterol in the diet prevented the increase in Pcsk9. The amounts of Pcsk9 mRNA in livers of refed mice showed correlated regulation by the changes in the nuclear form of Srebp-2. In summary, it is suggested that the expression of PCSK9 is regulated by sterol at the transcriptional level in HepG2 cells and that both SREBP-1 and SREBP-2 can transcriptionally activate PCSK9 via SRE in its proximal promoter region in vitro. However, in vivo, it is suggested that the sterol-dependent regulation of PCSK9 is mediated predominantly by SREBP-2.