Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, St Louis, MO 63104, USA.
Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12228-32. doi: 10.1073/pnas.1005191107. Epub 2010 Jun 21.
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.
固醇调节元件结合蛋白 2（SREBP-2）和肝 X 受体（LXR）分别控制着刺激细胞胆固醇摄取和合成以及胆固醇外排的拮抗转录程序。在接受他汀类药物治疗的高胆固醇血症患者中，SREBP-2 的临床重要性得以显现，他汀类药物通过增加 SREBP-2 及其靶标 LDL 受体的肝表达来降低 LDL 胆固醇水平。在这里，我们表明 miR-33 编码在 SREBP-2 内，并且这两种 mRNA 是共表达的。我们还鉴定了 ABCA1 和 ABCG1 的 3'UTR 中的序列，这两个固醇转运基因先前均显示受 LXR 调节，是 miR-33 介导沉默的靶标。我们的数据表明，LXR 依赖性胆固醇外排至 ApoAI 和血清均被 miR-33 的过表达所改善，而被 miR-33 的沉默所刺激。最后，我们表明 miR-33 在肝脏中的过表达会导致 ABCA1 mRNA 和蛋白以及血浆 HDL 水平下降，而在肝脏中沉默 miR-33 则会增加这些水平。这些结果表明了管理高胆固醇血症患者的新方法。
