Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides.
Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides.
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DOI：
10.1038/nature10486
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发表时间：
2011-10-19
期刊：
影响因子：
64.8
通讯作者：
Moore, Kathryn J.
中科院分区：
文献类型：
--
作者：
Rayner, Katey J.;Esau, Christine C.;Hussain, Farah N.;McDaniel, Allison L.;Marshall, Stephanie M.;van Gils, Janine M.;Ray, Tathagat D.;Sheedy, Frederick J.;Goedeke, Leigh;Liu, Xueqing;Khatsenko, Oleg G.;Kaimal, Vivek;Lees, Cynthia J.;Fernandez-Hernando, Carlos;Fisher, Edward A.;Temel, Ryan E.;Moore, Kathryn J.
心血管疾病(CVD)仍然是西化国家死亡的主要原因，尽管有降低低密度脂蛋白胆固醇的最佳药物治疗。针对这一残留风险的新疗法的追求集中在提高高密度脂蛋白胆固醇水平，以利用其动脉粥样硬化保护作用。MicroRNAs已成为脂代谢的重要转录后调节因子，成为治疗干预的新靶点。MicroRNA-33a和b(miR-33a/b)是分别嵌入固醇反应元件结合蛋白基因SREBF2和SREBF1的内含子microRNA，它们抑制胆固醇转运体ABCA1的表达，ABCA1是高密度脂蛋白生物发生的关键调节因子。最近在小鼠身上的研究表明，拮抗miR-33a可能是提高血浆高密度脂蛋白和预防动脉粥样硬化的有效策略，然而，由于小鼠缺乏miR-33b这一事实，这些发现对人类来说是复杂的，而miR-33b只存在于高等哺乳动物的SREBF1基因中。在这里，我们在非洲绿猴身上展示了系统性地注射同时针对miR-33a和miR-33b的抗miR寡核苷酸，增加了肝脏ABCA1的表达，并诱导血浆高密度脂蛋白在12周内持续增加。值得注意的是，在这个非人灵长类动物模型中，miR-33拮抗还增加了参与脂肪酸氧化的靶基因miR-33的表达(CROT、CPT1A、HADHB、PRKAA1)，减少了参与脂肪酸合成的基因(SREBF1、FASN、ACLY、ACACA)，导致血浆VLDL甘油三酯水平显著降低，这是以前在小鼠中未观察到的发现。这些数据表明，在一个与人类高度相关的模型中，对miR-33a和b的药理抑制是一种有希望的治疗策略，可以提高血浆高密度脂蛋白和极低密度脂蛋白甘油三酯，用于治疗增加心血管疾病风险的血脂异常。
Cardiovascular disease (CVD) remains the leading cause of mortality in westernized countries, despite optimum medical therapy to lower LDL cholesterol. The pursuit of novel therapies to target this residual risk has focused on raising levels of HDL cholesterol in order to exploit its atheroprotective effects. MicroRNAs have emerged as important post-transcriptional regulators of lipid metabolism, and are thus a new class of targets for therapeutic intervention. MicroRNA-33a and b (miR-33a/b) are intronic microRNAs embedded in the sterol response element binding protein genes SREBF2 and SREBF1, respectively, that repress expression of the cholesterol transporter ABCA1, a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL and protecting from atherosclerosis, however extrapolation of these findings to humans is complicated by the fact that mice lack miR-33b which is present only in the SREBF1 gene of higher mammals. Here we show in African green monkeys that systemic delivery of an anti-miR oligonucleotide that targets both miR-33a and miR-33b increases hepatic expression of ABCA1 and induces a sustained increase in plasma HDL over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in the oxidation of fatty acids (CROT, CPT1A, HADHB, PRKAA1) and reduced genes involved in fatty acid synthesis (SREBF1, FASN, ACLY, ACACA), resulting in a marked suppression of plasma VLDL triglyceride levels, a finding not previously observed in mice. These data establish, in a model highly relevant to humans, that pharmacological inhibition of miR-33a and b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglycerides for the treatment of dyslipidemias that increase cardiovascular disease risk.
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DOI：
10.1126/science.1189123
发表时间：
2010-06-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Najafi-Shoushtari SH;Kristo F;Li Y;Shioda T;Cohen DE;Gerszten RE;Näär AM
通讯作者：
Näär AM
影响因子：
4.8
作者：
Gerin, Isabelle;Clerbaux, Laure-Alix;Bommer, Guido T.
通讯作者：
Bommer, Guido T.
DOI：
10.1073/pnas.1005191107
发表时间：
2010-07-06
影响因子：
11.1
作者：
Marquart, Tyler J.;Allen, Ryan M.;Baldan, Angel
通讯作者：
Baldan, Angel
DOI：
10.1126/science.1189862
发表时间：
2010-06-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Rayner KJ;Suárez Y;Dávalos A;Parathath S;Fitzgerald ML;Tamehiro N;Fisher EA;Moore KJ;Fernández-Hernando C
通讯作者：
Fernández-Hernando C
影响因子：
37.8
作者：
Alberti, K. G. M. M.;Eckel, Robert H.;Smith, Sidney C., Jr.
通讯作者：
Smith, Sidney C., Jr.