最近对小鼠进行的研究工作表明，微RNA-33a是类脂代谢的一个重要调控因子，其抑制会增加血浆高密度脂蛋白（HDL）和降低动脉粥样硬化。 Rayner等人在将这些发现延伸到非人灵长类动物（非洲绿猴）方面迈出了重要一步，这些动物像人类一样，但与小鼠不同，都表达miR-33a 和 miR-33b。 它们发现，反miR-33在抑制miR-33a 和 miR-33b方面都是有效的。正如在小鼠研究中所看到的那样，反miR-33增加血浆HDL，但也有减少密度非常低的脂蛋白“甘油三酸酯”的附加有益效应，从而使这种“antagomir”疗法成为治疗会增加心血管疾病风险的血脂异常的一个候选方法。
相关英文论文摘要：
Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides
Cardiovascular disease remains the leading cause of mortality in westernized countries, despite optimum medical therapy to reduce the levels of low-density lipoprotein (LDL)-associated cholesterol. The pursuit of novel therapies to target the residual risk has focused on raising the levels of high-density lipoprotein (HDL)-associated cholesterol in order to exploit its atheroprotective effects1. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of lipid metabolism and are thus a new class of target for therapeutic intervention. MicroRNA-33a and microRNA-33b (miR-33a/b) are intronic miRNAs whose encoding regions are embedded in the sterol-response-element-binding protein genes SREBF2 and SREBF1, respectively. These miRNAs repress expression of the cholesterol transporter ABCA1, which is a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL levels and providing protection against atherosclerosis6; however, extrapolating these findings to humans is complicated by the fact that mice lack miR-33b, which is present only in the SREBF1 gene of medium and large mammals. Here we show in African green monkeys that systemic delivery of an anti-miRNA oligonucleotide that targets both miR-33a and miR-33b increased hepatic expression of ABCA1 and induced a sustained increase in plasma HDL levels over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in fatty acid oxidation (CROT, CPT1A, HADHB andPRKAA1) and reduced the expression of genes involved in fatty acid synthesis (SREBF1, FASN, ACLY andACACA), resulting in a marked suppression of the plasma levels of very-low-density lipoprotein (VLDL)-associated triglycerides, a finding that has not previously been observed in mice. These data establish, in a model that is highly relevant to humans, that pharmacological inhibition of miR-33a and miR-33b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglyceride levels for the treatment of dyslipidaemias that increase cardiovascular disease risk.
英文论文链接：https://www.nature.com/nature/journal/v478/n7369/full/nature10486.html
