2012年9月8日 訊 /生物谷BIOON/ --來(lái)自美國(guó)弗吉尼亞理工大學(xué)和德州大學(xué)西南醫(yī)學(xué)中心的研究人員發(fā)現(xiàn),，微小的RNA鏈(microRNA, miRNA)影響我們的細(xì)胞如何燃燒脂肪和糖,。這一發(fā)現(xiàn)為生物學(xué)家們開始尋找治療肥胖癥和相關(guān)的健康問題打下基礎(chǔ),。
根據(jù)這周發(fā)表在PNAS期刊上的一項(xiàng)研究，當(dāng)兩種miRNA從小鼠的遺傳物質(zhì)中缺失時(shí)，依賴高脂肪飲食的小鼠抵抗肥胖。這項(xiàng)發(fā)現(xiàn)提示著靶向這兩種特異性的miRNA的治療方法可能有助于抑制肥胖流行癥,。
一度被認(rèn)為是垃圾DNA，研究人員如今知道m(xù)iRNA在基因如何影響人類健康和行為方面發(fā)揮著重要作用,。它們已知與心臟病,、糖尿病、丙型肝炎,、淋巴瘤和乳腺癌相關(guān)聯(lián),。盡管之前已知miRNA與肥胖者相關(guān)聯(lián)，但是這些新的發(fā)現(xiàn)是第一次確定miRNA和細(xì)胞代謝之間存在關(guān)聯(lián),。
德州大學(xué)西南醫(yī)學(xué)中心研究人員對(duì)小鼠進(jìn)行基因改造而不能產(chǎn)生miR-378和它的表親miR-378*,，從而導(dǎo)致相對(duì)苗條的動(dòng)物也能夠快速地將細(xì)胞食物轉(zhuǎn)化為能量。
論文通信作者Eric N. Olson博士說,，“我們不知道這兩個(gè)miRNA的功能,，但是我們感興趣的是，它們來(lái)源自與代謝相關(guān)的一個(gè)基因,，而且它們?cè)诙喾N組織中表達(dá),，如肌肉、脂肪組織和肝臟,。當(dāng)我們對(duì)小鼠進(jìn)行基因改造以致于它們丟失這些miRNA,，它就允許這些小鼠的細(xì)胞比未經(jīng)過處理的同窩仔畜燃燒更多的能量和擁有更大的肥胖抵抗能力。這兩個(gè)miRNA似乎作為代謝的關(guān)鍵性調(diào)節(jié)物而發(fā)揮功能,，這提示著開發(fā)旨在抑制它們的藥物將具有抵抗肥胖的積極影響,。”
Olson實(shí)驗(yàn)室研究了miRNA變化對(duì)不同疾病的影響，如心臟病和也被稱作路格里克氏病(Lou Gehrig's disease)的肌肉萎縮性側(cè)索硬化癥(amyotrophic lateral sclerosis),。
在當(dāng)前的研究中,，弗吉尼亞理工大學(xué)研究人員從肝臟和骨骼肌中分離出線粒體。當(dāng)測(cè)量線粒體利用脂肪時(shí),，他們發(fā)現(xiàn)一種釋放能量的氧化過程的活性增加，這就佐證這種發(fā)現(xiàn)：小鼠體內(nèi)miRNA缺失導(dǎo)致能量開銷增加,，并且抵抗肥胖,，即便是給小鼠喂食高脂肪飲食時(shí)，也是如此,。(生物谷Bioon.com)
doi: 10.1073/pnas.1207605109
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PMID:
Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*
Michele Carrera, Ning Liua, Chad E. Gruetera, Andrew H. Williamsa,1, Madlyn I. Frisardb, Matthew W. Hulverb, Rhonda Bassel-Dubya, and Eric N. Olson
Obesity and metabolic syndrome are associated with mitochondrial dysfunction and deranged regulation of metabolic genes. Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) is a transcriptional coactivator that regulates metabolism and mitochondrial biogenesis through stimulation of nuclear hormone receptors and other transcription factors. We report that the PGC-1β gene encodes two microRNAs (miRNAs), miR-378 and miR-378*, which counterbalance the metabolic actions of PGC-1β. Mice genetically lacking miR-378 and miR-378* are resistant to high-fat diet-induced obesity and exhibit enhanced mitochondrial fatty acid metabolism and elevated oxidative capacity of insulin-target tissues. Among the many targets of these miRNAs, carnitine O-acetyltransferase, a mitochondrial enzyme involved in fatty acid metabolism, and MED13, a component of the Mediator complex that controls nuclear hormone receptor activity, are repressed by miR-378 and miR-378*, respectively, and are elevated in the livers of miR-378/378* KO mice. Consistent with these targets as contributors to the metabolic actions of miR-378 and miR-378*, previous studies have implicated carnitine O-acetyltransferase and MED13 in metabolic syndrome and obesity. Our findings identify miR-378 and miR-378* as integral components of a regulatory circuit that functions under conditions of metabolic stress to control systemic energy homeostasis and the overall oxidative capacity of insulin target tissues. Thus, these miRNAs provide potential targets for pharmacologic intervention in obesity and metabolic syndrome.
