miR-33 links SREBP-2 induction to repression of sterol transporters
miR-33 links SREBP-2 induction to repression of sterol transporters
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DOI：
10.1073/pnas.1005191107
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发表时间：
2010-07-06
影响因子：
11.1
通讯作者：
Baldan, Angel
中科院分区：
文献类型：
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作者：
Marquart, Tyler J.;Allen, Ryan M.;Baldan, Angel
固醇调节元件结合蛋白2（SREBP-2）和肝X受体（LXR）控制分别刺激细胞胆固醇摄取和合成以及胆固醇流出的拮抗性转录程序。SREBP-2的临床重要性在用他汀类药物治疗的高胆固醇血症患者中被揭示，他汀类药物通过增加SREBP-2及其靶点LDL受体的肝脏表达来降低低密度脂蛋白（LDL）胆固醇水平。在这里，我们发现miR-33在SREBP-2中编码，并且两种mRNA共表达。我们还鉴定了ABCA 1和ABCG 1的3' UTR中的序列，这两个甾醇转运蛋白基因先前都被证明是由LXR调节的，作为miR-33介导的沉默的靶点。我们的数据表明，LXR依赖性胆固醇流出到ApoAI和血清中，通过miR-33过表达得到改善，相反，通过miR-33沉默得到刺激。最后，我们发现，ABCA 1 mRNA和蛋白质以及血浆HDL水平在肝脏过表达miR-33后下降，而在肝脏miR-33沉默后增加。这些结果提出了新的方法来管理高胆固醇血症患者。
The sterol regulatory element binding protein 2 (SREBP-2) and the liver X receptor (LXR) control antagonistic transcriptional programs that stimulate cellular cholesterol uptake and synthesis, and cholesterol efflux, respectively. The clinical importance of SREBP-2 is revealed in patients with hypercholesterolemia treated with statins, which reduce low-density lipoprotein (LDL) cholesterol levels by increasing hepatic expression of SREBP-2 and its target, the LDL receptor. Here we show that miR-33 is encoded within SREBP-2 and that both mRNAs are coexpressed. We also identify sequences in the 3' UTR of ABCA1 and ABCG1, sterol transporter genes both previously shown to be regulated by LXR, as targets for miR-33-mediated silencing. Our data show that LXR-dependent cholesterol efflux to both ApoAI and serum is ameliorated by miR-33 overexpression and, conversely, stimulated by miR-33 silencing. Finally, we show that ABCA1 mRNA and protein and plasma HDL levels decline after hepatic overexpression of miR-33, whereas they increase after hepatic miR-33 silencing. These results suggest novel ways to manage hypercholesterolemic patients.