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Nature:调控因子RNA-33a可降低血脂

来源:EurekAlret 2011-10-24 14:42

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。(生物谷 Bioon.com)

 

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.

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