MicroRNA-27a decreases the level and efficiency of the LDL receptor and contributes to the dysregulation of cholesterol homeostasis.
MicroRNA-27a decreases the level and efficiency of the LDL receptor and contributes to the dysregulation of cholesterol homeostasis.
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DOI：
10.1016/j.atherosclerosis.2015.08.023
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发表时间：
2015-10
期刊：
影响因子：
5.3
通讯作者：
Done SC
中科院分区：
文献类型：
--
作者：
Alvarez ML;Khosroheidari M;Eddy E;Done SC
动脉粥样硬化是心脏病发作和中风的主要原因，其一个重要的危险因素是血液中低密度脂蛋白胆固醇（LDL-C）的升高。低密度脂蛋白受体（LDLR）是从循环中清除LDL-C的主要途径，其水平可通过他汀类药物（高血LDL-C的主要治疗药物）升高。然而，他汀类药物的效率较低，因为它们也会增加靶向LDLR降解的PCSK 9。由于microRNA最近已成为胆固醇稳态的关键调节因子，我们的目标是确定潜在的基于microRNA的治疗方法，以降低血液LDL-C和预防动脉粥样硬化。我们在HepG 2细胞中过表达并敲低miR-27 a，以使用PCR阵列、Elisas和Western印迹评估其对LDLR途径中关键参与者表达的影响。我们发现，miR-27 a不仅通过直接结合其3′非翻译区，还通过诱导PCSK 9增加3倍间接降低LDLR水平40%，从而增强LDLR降解。有趣的是，miR-27 a还直接降低了LRP 6和LDLRAP 1，这是LDLR途径中的另外两个关键参与者，它们是肝脏中LDLR-LDL-C复合物有效内吞所必需的。使用锁核酸抑制miR-27 a诱导LDLR水平增加70%，因此，由于其不仅对LDLR而且对PCSK 9的理想作用，其将是高胆固醇血症的更有效治疗。本文提供的结果为miR-27 a作为预防动脉粥样硬化的新型治疗靶点的潜力提供了证据。
A strong risk factor for atherosclerosis– the leading cause of heart attacks and strokes– is the elevation of low-density lipoprotein cholesterol (LDL-C) in blood. The LDL receptor (LDLR) is the primary pathway for LDL-C removal from circulation, and their levels are increased by statins --the main treatment for high blood LDL-C. However, statins have low efficiency because they also increase PCSK9 which targets LDLR for degradation. Since microRNAs have recently emerged as key regulators of cholesterol homeostasis, our aim was to identify potential microRNA-based therapeutics to decrease blood LDL-C and prevent atherosclerosis. We over expressed and knocked down miR-27a in HepG2 cells to assess its effect on the expression of key players in the LDLR pathway using PCR Arrays, Elisas, and Western blots. We found that miR-27a decreases LDLR levels by 40% not only through a direct binding to its 3′ untranslated region but also indirectly by inducing a 3-fold increase in PCSK9, which enhances LDLR degradation. Interestingly, miR-27a also directly decreases LRP6 and LDLRAP1, two other key players in the LDLR pathway that are required for efficient endocytosis of the LDLR-LDL-C complex in the liver. The inhibition of miR-27a using lock nucleic acids induced a 70% increase in LDLR levels and, therefore, it would be a more efficient treatment for hypercholesterolemia because of its desirable effects not only on LDLR but also on PCSK9. The results presented here provide evidence supporting the potential of miR-27a as a novel therapeutic target for the prevention of atherosclerosis.