A Regulatory Role for MicroRNA 33☆ in Controlling Lipid Metabolism Gene Expression
A Regulatory Role for MicroRNA 33☆ in Controlling Lipid Metabolism Gene Expression
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DOI：
10.1128/mcb.01714-12
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发表时间：
2013-06-01
影响因子：
5.3
通讯作者：
Fernandez-Hernando, Carlos
中科院分区：
文献类型：
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作者：
Goedeke, Leigh;Vales-Lara, Frances M.;Fernandez-Hernando, Carlos
hsa-miR-33a和hsa-miR-33b是分别位于固醇调控元件结合蛋白2和1基因（Srebp-2和-1）内的内含子microrna (mirna)，最近已被证明与其宿主基因一致调节脂质稳态。尽管miR-33a和-b的功能作用已被高度研究，但其乘客链miR-33a（星型）和-b（星型）的作用仍不清楚。在这里，我们证明miR-33a（星型）和-b（星型）在人类、小鼠和非人灵长类动物组织中积累到稳态水平，并且与其姊妹链具有相似的脂质代谢靶基因网络。与miR33类似，miR-33（star）抑制参与胆固醇外排（ABCA1和NPC1）、脂肪酸代谢（CROT和CPT1a）和胰岛素信号传导（IRS2）的关键酶。此外，miR-33（star）还靶向脂质代谢的关键转录调节因子，包括SRC1、SRC3、nfc和RIP140。重要的是，抑制miR-33或miR-33（star）可以挽救过表达pre-miR-33的细胞中的靶基因表达。与此一致的是，miR-33（star）的过表达减少了人肝细胞中的脂肪酸氧化。总之，这些数据支持miRNA（星型）物种的调节作用，并表明miR-33通过miR-33/miR-33（星型）双链的两条臂调节脂质代谢。
hsa-miR-33a and hsa-miR-33b, intronic microRNAs (miRNAs) located within the sterol regulatory element-binding protein 2 and 1 genes (Srebp-2 and -1), respectively, have recently been shown to regulate lipid homeostasis in concert with their host genes. Although the functional role of miR-33a and -b has been highly investigated, the role of their passenger strands, miR-33a(star) and -b(star), remains unclear. Here, we demonstrate that miR-33a(star) and -b(star) accumulate to steady-state levels in human, mouse, and nonhuman primate tissues and share a similar lipid metabolism target gene network as their sister strands. Analogous to miR33, miR-33(star) represses key enzymes involved in cholesterol efflux (ABCA1 and NPC1), fatty acid metabolism (CROT and CPT1a), and insulin signaling (IRS2). Moreover, miR-33(star) also targets key transcriptional regulators of lipid metabolism, including SRC1, SRC3, NFYC, and RIP140. Importantly, inhibition of either miR-33 or miR-33(star) rescues target gene expression in cells overexpressing pre-miR-33. Consistent with this, overexpression of miR-33(star) reduces fatty acid oxidation in human hepatic cells. Altogether, these data support a regulatory role for the miRNA(star) species and suggest that miR-33 regulates lipid metabolism through both arms of the miR-33/miR-33(star) duplex.