MiR-337-3p lowers serum LDL-C level through targeting PCSK9 in hyperlipidemic mice.
MiR-337-3p lowers serum LDL-C level through targeting PCSK9 in hyperlipidemic mice.
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DOI：
10.1016/j.metabol.2021.154768
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发表时间：
2021-03
期刊：
影响因子：
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通讯作者：
Xiaoding Xu;Yunxia Dong;Ningning Ma;Wei-wei Kong;Chuwei Yu;Likun Gong;Jing Chen-;Jin Ren
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作者：
Xiaoding Xu;Yunxia Dong;Ningning Ma;Wei-wei Kong;Chuwei Yu;Likun Gong;Jing Chen-;Jin Ren
降低高脂血症患者血清低密度脂蛋白胆固醇（LDL-C）水平是降低动脉粥样硬化性心血管疾病（ASCVD）风险的有效策略。miR-337- 3 p在肿瘤增殖和转移、脂肪细胞布朗宁和缺血性脑损伤等方面具有重要的调控作用，但miR-337 - 3 p与LDL-C的关系尚不清楚。结果miR-337 - 3 p在多种高脂血症小鼠模型中的表达明显降低，且与血清LDL-C水平呈负相关。在体内证实了miR-337- 3 p对血清LDL-C的改善作用后，我们发现PCSK 9可能是miR-337- 3 p的一个作用靶点，并通过体外实验进一步证实了这一点。miR-337- 3 p可直接与PCSK 9 3′UTR和启动子相互作用，抑制PCSK 9的翻译和转录。此外，敲低PCSK 9的DiI-LDL摄取试验结果表明，miR-337- 3 p促进HepG 2细胞中LDL-C的吸收依赖于PCSK 9，结论我们发现miR-337 - 3 p在调节PCSK 9表达和LDL-C水平中具有新的功能。提示miR-337- 3 p可能成为开发抗高血压药物的新靶点。
BackgroundReducing serum low-density lipoprotein cholesterol (LDL-C) in hyperlipemia is recognized as an effective strategy to minimize the risk of atherosclerotic cardiovascular disease (ASCVD). MiR-337-3p has already been discovered to play regulatory roles in tumor proliferation and metastasis, adipocyte browning and ischemic brain injury, etc. However, the association between miR-337-3p and LDL-C is unknown.MethodsGene Expression Omnibus (GEO) dataset and two hyperlipidemic murine models were used to analyze the potential relationship between miR-337-3p and LDL-C. AAV-mediated liver-directed miRNA overexpression in high fat diet (HFD)-fed mouse model was used to examine the effect of miR-337-3p on LDL-C and WB/RT-PCR/ELISA/luciferase assays were used to investigate the underlying mechanism.ResultsThe expressions of miR-337-3p were obviously lower in multiple hyperlipidemic mouse models and had a negative correlation with serum LDL-C levels. After confirming the effect of miR-337-3p on the improvement of serum LDL-C in vivo, we discovered PCSK9 might be a possible target of miR-337-3p, which was further proved by in vitro experiments. MiR-337-3p could directly interact with both the PCSK9 3′UTR and promoter to inhibit PCSK9 translation and transcription. Furthermore, the result from DiI-LDL uptake assay under the knockdown of PCSK9 demonstrated that miR-337-3p promoting the absorption of LDL-C in HepG2 cells was dependent on PCSK9, and the result from LDLR−/− mouse model indicated that miR-337-3p regulating LDL-C was dependent on PCSK9/LDLR pathway.ConclusionWe discovered a new function of miR-337-3p in regulating PCSK9 expression and LDL-C absorption, suggesting miR-337-3p might be a new therapeutic target for the development of antihyperlipidemic drug.