Regulation and mechanism of mouse miR-130a/b in metabolism-related inflammation
Regulation and mechanism of mouse miR-130a/b in metabolism-related inflammation
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小鼠miR-130a/b在代谢相关炎症中的调控及机制
DOI：
10.1016/j.biocel.2016.02.021
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发表时间：
2016
影响因子：
4
通讯作者：
Xiaodong Chen
中科院分区：
文献类型：
--
作者：
Hailiang Zheng;Xiangkun Dong;Na Liu;Wenmin Xia;Lulu Zhou;Xiaojun Chen;Zaiqing Yang;Xiaodong Chen
越来越多的证据表明，microRNA参与调节免疫反应和代谢，这是生存的最基本要求之一。在此，我们研究microRNA-130 a/B在控制代谢相关炎症中的作用和机制。我们的研究结果表明，miR-130 a/B通过直接结合3 '非翻译区显著抑制TNFα和Sp1的表达。过表达的miR-130 a/B通过缩短mRNA半衰期降低NF-κB mRNA和蛋白水平。在小鼠原代肝细胞中，过表达的miR-130 a/B可减轻LPS或FFA处理引起的TNFα、Sp1、NF-κB和PPARγ翻译水平的上调。此外，C/EBPα减弱miR-130 a的启动子活性，但增强miR-130 b的启动子活性。进行性缺失和突变表明分别位于miR-130 a或B启动子的−1033/−1021 bp或−130/−116 bp区域的C/EBPα结合基序是其启动子活性所必需的组分。染色质免疫沉淀（ChIP）分析显示C/EBPα可直接与miR-130 a/B启动子DNA相互作用。结论：miR-130 a/B受C/EBPα转录调控，通过抑制Sp1-TLR 4-NF-κB/P65-TNFα通路，调节PPARγ等脂代谢关键基因的翻译水平，调控代谢相关的炎症过程。
Increasing evidence suggests that microRNAs are involved in regulating immune response and metabolism, which are among the most fundamental requirements for survival. Here we investigate the contribution and mechanism of microRNA-130a/b in controlling metabolism-related inflammation. Our findings indicate that miR-130a/b significantly inhibits TNFα and Sp1 expression by directly binding to their 3'-untranslated regions. Overexpressed miR-130a/b decreases the NF-κB mRNA and protein levels by shortening mRNA half-life. In mice primary hepatocytes, over-expressed miR-130a/b ameliorates the up-regulation of TNFα, Sp1, NF-κB and PPARγ translational levels elicited by LPS or FFAs treatment. Further, C/EBPα attenuates the promoter activity of miR-130a, but enhances that of miR-130b. The progressive deletions and mutations show that the C/EBPα binding motif situated at −1033/−1021 bp or −130/−116 bp region of miR-130a or b promoter respectively is an essential component required for their promoter activity. Chromatin immunoprecipitation (ChIP) assays reveal that C/EBPα can directly interact with miR-130a/b promoter DNA. Conclusively, these data suggest that miR-130a/b, regulated transcriptionally by C/EBPα, can control metabolism-related inflammatory process through inhibiting Sp1-TLR4-NF-κB/P65-TNFα pathway and regulating translational levels of PPARγ and other key genes involved in lipid metabolism.