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Regulation and mechanism of mouse miR-130a/b in metabolism-related inflammation

Zheng, Hailiang, Dong, Xiangkun, Liu, Na, Xia, Wenmin, Zhou, Lulu, Chen, Xiaojun, Yang, Zaiqing, Chen, Xiaodong
The international journal of biochemistry & cell biology 2016 v.74 pp. 72-83
3' untranslated regions, DNA, chromatin, gene overexpression, genes, half life, hepatocytes, immune response, inflammation, lipid metabolism, mice, microRNA, mutation, precipitin tests, transcription (genetics), transcription factor NF-kappa B, translation (genetics), tumor necrosis factor-alpha
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/−1021bp or −130/−116bp 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.