循环来源miR-143-3p与IGF2竞争性结合IGF2R在代谢综合征胰岛素抵抗中的作用和机制研究

Metabolic syndrome (MetS) is a complex metabolic condition caused by abnormal adipose deposition and function, dyslipidemia and hyperglycemia.Insulin resistance (IR) is the key feature of the metabolic syndrome, IR is the most accepted unifying theory explaining the pathophysiology of the metabolic syndrome. In the search for improved and novel therapeutic strategies, microRNAs (miRNAs) have been shown to be interesting targets due to their regulatory role on gene networks controlling different crucial aspects of metabolism, including lipid and glucose homeostasis. Recently, mRNAs and miRNAs have been identified in exosomes, which can be taken up by neighboring or distant cells and subsequently modulate recipient cells. This suggests an active sorting mechanism of exosomal miRNAs, since the miRNA profiles of exosomes may differ from those of the parent cells. Exosomal miRNAs play an important role in disease progression. The discovery of circulating miRNAs suggest that miRNAs may be involved in facilitating metabolic crosstalk between organs as well as serving as novel biomarkers of diseases.An unconventional role for miRNA showed that let-7 activates Toll-like receptor 7 and causes neurodegeneration.. In our previous work, the genome-wide circulating miRNA profiles were detected via microarray in 8 MetS and normal controls, elevated miR-143-3p was selected and validated in individual serum and urine samples from 50 MetS and 50 controls. Associations between circulating miR-143-3p levels and parameters related to insulin resistance (HOMA-IR) was further assessed. Furthermore, we demonstrated that IGF2R (and/or IGFBP5) was potential target of miR-143-3p by searching three widespread used bioinformatics databases and preliminary validation.The ligands of the IGF system are insulin, IGF1 and IGF2. IGFs exert their biological effects by binding to the type 1 IGF receptor (IGF-1R) and insulin receptor (IR). Hybrid receptors of IGF1R and IR also bind IGFs. The type 2 IGF receptor (IGF2R) binds IGF2 alone. It is thought to have a role in IGF2 clearance rather than signaling.IGF2 exerts its biological effects through IGF1R and the A isoform of IR (IR-A).We proposed our hypothesis that knockdown the circulating miR-143-3p may protect against insulin resistance in the metabolic syndrome through targeting IGF2R and/or IGFBP5, and activating the signaling pathway of insulin.The results of the above hypothesis may have implications for diagnostic and therapeutic approaches, also suggest that miR-143-3p has potential as a therapeutic agent in MetS.

近期研究证明miRNA不再只是以miRISC的形式参与mRNA转录后调控，而是通过外泌体释放到胞外或体液循环，与细胞表面受体直接相互作用，产生信号。在我们前期工作的社区人群样本的microRNA芯片检测及验证结果中，发现了miR-143-3p在MetS患者血清和尿液中异常高表达，并与胰岛素抵抗功能相关，且IGF2呈剂量和时间依赖效应式促进miR-143-3p的表达水平。后续实验证明了miR-143-3p可以作用于IGF2R的3’UTR发挥基因沉默效应（部分作用IGFBP5）；而另一方面，该项目试图证明由外泌体运输的体液循环miR-143-3p直接作用于IGF2R受体，并与IGF2竞争性结合IGF2R，导致体液循环内游离IGF2增多，增加的IGF2进一步促进miR-143-3p的表达，形成一个逐步放大效应的反馈通路，进而影响胞内胰岛素下游经典的信号通路的传递，促发胰岛素抵抗作用。

在我们前期工作的社区人群样本的microRNA芯片检测及验证结果中，发现了miR-143-3p在MetS患者血清和尿液中异常高表达，并与胰岛素抵抗功能相关，且IGF2呈剂量和时间依赖效应式促进miR-143-3p的表达水平。后续实验证明了miR-143-3p可以作用于IGF2R的3’UTR发挥基因沉默效应（部分作用IGFBP5）；而另一方面，该项目试图证明由外泌体运输的体液循环miR-143-3p直接作用于IGF2R受体，并与IGF2竞争性结合IGF2R，导致体液循环内游离IGF2增多，增加的IGF2进一步促进miR-143-3p的表达，形成一个逐步放大效应的反馈通路，进而影响胞内胰岛素下游经典的信号通路的传递，促发胰岛素抵抗作用。

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