MicroRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1) exhibit reduced HDL-C in vivo.
MicroRNA-33b knock-in mice for an intron of sterol regulatory element-binding factor 1 (Srebf1) exhibit reduced HDL-C in vivo.
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DOI：
10.1038/srep05312
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发表时间：
2014-06-16
影响因子：
4.6
通讯作者：
Ono K
中科院分区：
文献类型：
--
作者：
Horie T;Nishino T;Baba O;Kuwabara Y;Nakao T;Nishiga M;Usami S;Izuhara M;Nakazeki F;Ide Y;Koyama S;Sowa N;Yahagi N;Shimano H;Nakamura T;Hasegawa K;Kume N;Yokode M;Kita T;Kimura T;Ono K
microRNA（miRs）是一类非蛋白质编码的小分子RNA，它与特定的mRNA结合，抑制mRNA的翻译或促进mRNA的降解。最近的报道，包括我们的，表明miR-33 a位于内含子的固醇调节元件结合蛋白（SREBP）2控制胆固醇稳态，并可能成为治疗动脉粥样硬化的治疗靶点。灵长类动物，而不是啮齿类动物，从SREBF 1的内含子表达miR-33 b。因此，需要将miR-33 b转基因插入Srebf 1内含子中的人源化小鼠来解决其体内功能。我们成功建立了miR-33 b敲入（KI）小鼠，发现已知miR-33 a靶基因（如ABCA 1、ABCG 1和SREBP-1）的蛋白水平与野生型小鼠相比有所降低。因此，miR-33 b KI小鼠的巨噬细胞通过apoA-I和HDL-C的胆固醇流出能力降低。此外，与对照小鼠相比，即使在miR-33 b KI异源小鼠中，HDL-C水平也降低了近35%。这些结果表明，miR-33 b可能是人类HDL-C水平低于小鼠的原因，并且miR-33 b可能用于调节其宿主基因SREBF 1的反馈机制。我们的小鼠也将有助于阐明miR-33 a/B在不同遗传疾病模型中的作用。
MicroRNAs (miRs) are small non-protein-coding RNAs that bind to specific mRNAs and inhibit translation or promote mRNA degradation. Recent reports, including ours, indicated that miR-33a located within the intron of sterol regulatory element-binding protein (SREBP) 2 controls cholesterol homeostasis and can be a possible therapeutic target for treating atherosclerosis. Primates, but not rodents, express miR-33b from an intron of SREBF1. Therefore, humanized mice, in which a miR-33b transgene is inserted within a Srebf1 intron, are required to address its function in vivo. We successfully established miR-33b knock-in (KI) mice and found that protein levels of known miR-33a target genes, such as ABCA1, ABCG1, and SREBP-1, were reduced compared with those in wild-type mice. As a consequence, macrophages from the miR-33b KI mice had a reduced cholesterol efflux capacity via apoA-I and HDL-C. Moreover, HDL-C levels were reduced by almost 35% even in miR-33b KI hetero mice compared with the control mice. These results indicate that miR-33b may account for lower HDL-C levels in humans than those in mice and that miR-33b is possibly utilized for a feedback mechanism to regulate its host gene SREBF1. Our mice will also aid in elucidating the roles of miR-33a/b in different genetic disease models.
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DOI：
10.1073/pnas.0908268106
发表时间：
2009-11-10
影响因子：
11.1
作者：
Horiguchi, Masahito;Inoue, Tadashi;Nakamura, Tomoyuki
通讯作者：
Nakamura, Tomoyuki
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.
影响因子：
6.5
作者：
Basso, F;Freeman, L;Brewer, HB
通讯作者：
Brewer, HB
影响因子：
17.1
作者：
Rottiers V;Obad S;Petri A;McGarrah R;Lindholm MW;Black JC;Sinha S;Goody RJ;Lawrence MS;deLemos AS;Hansen HF;Whittaker S;Henry S;Brookes R;Najafi-Shoushtari SH;Chung RT;Whetstine JR;Gerszten RE;Kauppinen S;Näär AM
通讯作者：
Näär AM