Regulation of lipid metabolism by miRNAs

他汀类药物通过抑制胆固醇生物合成途径中的关键酶HMG-CoA还原酶来降低血浆胆固醇。 他汀类药物已经彻底改变了心血管治疗，但相对较大比例的治疗患者仍然继续发展心血管疾病;因此，需要替代靶点和方法。 最近，小RNA，特别是miRNA，已被证明是许多基因的关键调节因子。 为了研究miRNAs在脂质代谢中的可能作用，我们检测了来自喂食高脂肪饮食3周的小鼠肝脏的miRNAs的差异表达。 此外，检查了来自食物喂养的小鼠与高脂肪喂养的小鼠的肝脏的mRNA谱和蛋白质组。发现5种上调超过2倍的miRNA靶向胆固醇生物合成途径中的几个基因。 使用含有受影响mRNA的3个非翻译区的报告基因构建体，鉴定了miRNA的靶位点。 发现将鉴定的miRNA转染到肝细胞中减少乙酸盐掺入胆固醇。这就提出了一种可能性，即作用于这些miRNA的启动子和/或miRNA本身的小分子药物可能用于阻断胆固醇合成并以类似于他汀类药物的机制减少动脉粥样硬化。 未来的研究将涉及这些miRNAs的启动子的详细分析，并确定这些miRNAs可能靶向的其他基因的谱。

Statin class drugs lower plasma cholesterol by repressing HMG-CoA Reductase, a key enzyme in the biosynthetic pathway of cholesterol. Statins have revolutionized cardiovascular treatment but a relatively large fraction of treated patients still go on to develop cardiovascular disease; therefore, alternative targets and approaches are needed. Recently small RNAs, and in particular miRNAs, have been shown to be key regulators of many genes. In order to examine a possible role of miRNAs in lipid metabolism, we examined the differential expression of miRNAs from the liver of mice fed a high fat diet for 3 weeks. In addition, the mRNA profile and proteome of the liver from chow fed versus high fat fed mice was examined. 5 miRNAs, which were up-regulated by more than 2-fold, were found to target several genes within the cholesterol biosynthetic pathway. Using reporter constructs containing the 3 untranslated region of the affected mRNAs, the target sites for the miRNAs were identified. Transfection of the identified miRNAs into hepatic cells was found to decrease acetate incorporation into cholesterol. This raises the possibility that small molecule drugs that act on the promoters of these miRNAs and or the miRNAs themselves could possibly be used to block cholesterol synthesis and reduce atherosclerosis in a mechanism similar to statins. Future studies will involve a detailed analysis of the promoter of these miRNAs and determining the spectrum of other genes that these miRNAs may target.