Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, 250021, China.
The Second Department of Surgery, Hospital of Traditional Chinese Medicine, Lingcheng, Dezhou, Shandong Province, 253500, China.
Biochem Biophys Res Commun. 2018 Oct 2;504(2):422-426. doi: 10.1016/j.bbrc.2018.08.205. Epub 2018 Sep 6.
Hypercholesterolemia is an important risk factor for coronary heart disease. Although a lot of research has been conducted, the regulation of cholesterol metabolism is still largely unknown. Some miRNAs have been found to play critical role in the cholesterol metabolism. MiR-98 is a miRNA whose function has been reported mainly in tumorigenesis. In this study, we elucidate a novel role of miR-98 in cholesterol metabolism. We found that the expression of miR-98 was decreased significantly in hypercholesterolemic patients compared with healthy control subjects. Furthermore, we identified that SREBP-2, an important transcriptional factor in cholesterol metabolism, was a direct target of miR-98. Overexpression of miR-98 significantly repressed the 3'-UTR reporter activities of SREBP-2 in a dose-dependent manner in HepG2 cells, while the effect of miR-98 was blocked when the binding site of miR-98 within the SREBP-2 3'-UTR was mutated. And overexpression of miR-98 reduced both the mRNA and protein levels of HMGCR and LDLR significantly in vitro, which are two target genes of SREBP-2. Furthermore, MiR-98 overexpression reduced the intracellular total cholesterol levels dramatically. Moreover, we overexpressed the miR-98 by lentiviral tail vein injection in vivo. Compared with the control mice, the miR-98 overexpression mice showed lower serum cholesterol level and decreased SREBP-2, HMGCR as well as LDLR expression. Our data confirmed that reduced expression of miR-98 potentially contributes to disturbance of cholesterol metabolism. MiR-98 might be a novel therapeutic target to hypercholesterolemia.
高胆固醇血症是冠心病的一个重要危险因素。尽管已经进行了大量的研究，但胆固醇代谢的调节在很大程度上仍然未知。一些 miRNA 已被发现在胆固醇代谢中发挥关键作用。miR-98 是一种 miRNA，其功能主要在肿瘤发生中得到报道。在本研究中，我们阐明了 miR-98 在胆固醇代谢中的一个新作用。我们发现，与健康对照组相比，高胆固醇血症患者的 miR-98 表达显著降低。此外，我们鉴定出 SREBP-2，胆固醇代谢中的一个重要转录因子，是 miR-98 的直接靶标。在 HepG2 细胞中，miR-98 的过表达以剂量依赖性方式显著抑制 SREBP-2 的 3'-UTR 报告基因活性，而当 miR-98 在 SREBP-2 3'-UTR 中的结合位点发生突变时，miR-98 的作用被阻断。并且，miR-98 的过表达显著降低了体外 HMGCR 和 LDLR 的 mRNA 和蛋白水平，这是 SREBP-2 的两个靶基因。此外，miR-98 的过表达显著降低了细胞内总胆固醇水平。此外，我们通过慢病毒尾静脉注射在体内过表达 miR-98。与对照组小鼠相比，miR-98 过表达小鼠的血清胆固醇水平较低，SREBP-2、HMGCR 和 LDLR 的表达降低。我们的数据证实，miR-98 的表达降低可能导致胆固醇代谢紊乱。miR-98 可能是治疗高胆固醇血症的一个新靶点。
