最近對小鼠進行的研究工作表明,，微RNA-33a是類脂代謝的一個重要調(diào)控因子，其抑制會增加血漿高密度脂蛋白（HDL）和降低動脈粥樣硬化,。Rayner等人在將這些發(fā)現(xiàn)延伸到非人靈長類動物（非洲綠猴）方面邁出了重要一步，這些動物像人類一樣，但與小鼠不同，都表達miR-33a 和 miR-33b,。 它們發(fā)現(xiàn),，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樣,，反miR-33增加血漿HDL,，但也有減少密度非常低的脂蛋白“甘油三酸酯”的附加有益效應，從而使這種“antagomir”療法成為治療會增加心血管疾病風險的血脂異常的一個候選方法,。(生物谷 Bioon.com)

doi:10.1038/nature10486
PMC:
PMID:
Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides

Katey J. Rayner,1 Christine C. Esau,2 Farah N. Hussain,1 Allison L. McDaniel,3 Stephanie M. Marshall,3 Janine M. van Gils,1 Tathagat D. Ray,1 Frederick J. Sheedy,1 Leigh Goedeke,1 Xueqing Liu,2 Oleg G. Khatsenko,2 Vivek Kaimal,2 Cynthia J. Lees,4 Carlos Fernandez-Hernando,1 Edward A. Fisher,1 Ryan E. Temel3, 5 & Kathryn J. Moore1, 5

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 effects. 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 (refs ), 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 atherosclerosis; 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 and PRKAA1) and reduced the expression of genes involved in fatty acid synthesis (SREBF1, FASN, ACLY and ACACA), 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.