New PCSK9 inhibitor miR-552-3p reduces LDL-C via enhancing LDLR in high fat diet-fed mice
New PCSK9 inhibitor miR-552-3p reduces LDL-C via enhancing LDLR in high fat diet-fed mice
复制标题
新型 PCSK9 抑制剂 miR-552-3p 通过增强高脂肪饮食喂养小鼠的 LDLR 来降低 LDL-C
DOI：
10.1016/j.phrs.2021.105562
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发表时间：
2021-03-25
影响因子：
9.3
通讯作者：
Ren, Jin
中科院分区：
文献类型：
--
作者：
Ma, Ningning;Fan, Lei;Ren, Jin
PCSK9已成为治疗高脂血症的一个有前景的新靶点。PCSK9 siRNA在临床试验中的有效性提示了探索更多基于遗传抑制的PCSK9抑制剂治疗高脂血症的可行性。MicroRNAs （miRNAs）是一类内源性非编码小rna，可以在转录和/或翻译水平上调控基因。在这里，我们通过AlphaLISA和Western blotting从TargetScan数据库预测中筛选可能在PCSK9蛋白水平上具有抑制活性的mirna，其中miR-5523p的抑制作用最强。MiR-552-3p可以结合到PCSK9的3‘非翻译区（3’ utr）抑制翻译，并与PCSK9的启动子相互作用抑制转录。进一步的体外和体内实验证实了miR-552-3p对PCSK9及其下游效应物的影响：在高脂饮食（HFD）喂养的小鼠中，miR-552-3p可以提高LDLR蛋白水平，促进HepG2细胞对LDL-C的摄取，降低血清LDL-C。总之，我们的研究结果首次发现miR-552-3p是一种新的PCSK9抑制剂，具有双重抑制机制，这表明miR-552-3p可能在高脂血症的治疗中应用。
PCSK9 has emerged as a promising new therapeutic target for hyperlipidemia. The efficacy of PCSK9 siRNA in clinic trials clues the feasibility of exploring more PCSK9 inhibitors based on genetic inhibition in the treatment of hyperlipidemia. MicroRNAs (miRNAs) as a class of endogenous non-coding small RNAs can regulate genes at transcriptional and/or translational level. Here, we screened miRNAs from the prediction of TargetScan database with possible inhibitory activities in PCSK9 protein level via AlphaLISA and Western blotting, in which miR-5523p was selected out for its strongest inhibitory effect. MiR-552-3p could bind to the 3' untranslated region (3'UTR) of PCSK9 to inhibit translation and interact with the promoter of PCSK9 to suppress transcription. Further in vitro and in vivo experiments proved the effects of miR-552-3p on PCSK9 and downstream effectors: it could increase LDLR protein level, promote LDL-C uptake in HepG2 cells and lower serum LDL-C in high fat diet (HFD)fed mice. In conclusion, our findings firstly identified miR-552-3p as a new PCSK9 inhibitor with the dualinhibition mechanism, which suggested the possible application of miR-552-3p in the treatment of hyperlipidemia.