近日，國(guó)際著名學(xué)術(shù)期刊Diabetologia在線刊登了中科院上海生命科學(xué)研究院營(yíng)養(yǎng)所翟琦巍研究組研究人員的最新研究成果“Downregulation of miR-181aupregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity,，”,。文章中，研究者研究發(fā)現(xiàn),，抑制非編碼小RNA miR-181a可以上調(diào)去乙?；窼IRT1的蛋白水平并改善胰島素抵抗。
胰島素抵抗是導(dǎo)致2型糖尿病的關(guān)鍵因素,。當(dāng)胰島素的靶器官肝臟,、骨骼肌、脂肪組織等對(duì)于胰島素的響應(yīng)變?nèi)鯐r(shí)，即發(fā)生胰島素抵抗,。緩解胰島素抵抗是目前防治2型糖尿病的重要途徑,。翟琦巍研究組的前期研究發(fā)現(xiàn)，蛋白質(zhì)去乙?；窼IRT1可以通過(guò)在染色質(zhì)水平抑制PTP1B表達(dá)從而改善胰島素敏感性,，并發(fā)現(xiàn)葡萄、藍(lán)莓等食物中存在的白藜蘆醇可以通過(guò)SIRT1改善胰島素敏感性(Cell Metabolism,， 2007,； 6(4)：307-19)。目前,，SIRT1對(duì)胰島素敏感性的調(diào)控作用已被國(guó)際同行廣泛認(rèn)可,，但SIRT1本身在生理病理?xiàng)l件下是如何被調(diào)控，并進(jìn)一步影響胰島素敏感性的機(jī)理還不太清楚,。
翟琦巍研究組博士研究生周犇,、李程等研究發(fā)現(xiàn)，一種非編碼小RNA miR-181a可以靶向Sirt1 mRNA的3’非翻譯區(qū),，抑制SIRT1翻譯,，但不影響其轉(zhuǎn)錄。在胰島素抵抗的細(xì)胞和動(dòng)物模型中,，miR-181a水平均顯著上調(diào),，并且糖尿病病人血清中miR-181a水平也顯著升高。細(xì)胞實(shí)驗(yàn)顯示,，過(guò)量表達(dá)miR-181a可以降低SIRT1蛋白水平,，并誘導(dǎo)胰島素抵抗；而胰島素抵抗?fàn)顟B(tài)下抑制miR-181a則可以上調(diào)SIRT1蛋白水平,，并增強(qiáng)胰島素敏感性(insulin sensitivity),。并且，利用過(guò)表達(dá)SIRT1的腺病毒,、SIRT1基因敲除小鼠等發(fā)現(xiàn),，miR-181a對(duì)于胰島素敏感性的調(diào)節(jié)作用依賴于SIRT1。
進(jìn)一步研究發(fā)現(xiàn),，小鼠體內(nèi)過(guò)表達(dá)miR-181a可以導(dǎo)致胰島素抵抗和糖代謝紊亂,，而給高脂飲食誘導(dǎo)的胰島素抵抗小鼠模型注射鎖核酸修飾的miR-181a反義核酸(anti-miR-181a)以抑制miR-181a能夠有效地提高SIRT1蛋白水平，并改善機(jī)體的葡萄糖耐受性,、肝臟和肌肉的胰島素敏感性,，下調(diào)血糖水平。
這些研究結(jié)果顯示,，miR-181a有可能成為胰島素抵抗相關(guān)疾?。ㄈ?型糖尿病等）的診斷或分型的標(biāo)志物,，以及治療的藥物靶點(diǎn)。
該研究獲得了中國(guó)科學(xué)院,、國(guó)家自然科學(xué)基金委,、科技部、上海市科委等機(jī)構(gòu)的資助,。（生物谷Bioon.com）
doi:10.1007/s00125-012-2539-8
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PMID:
Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity
B. Zhou, C. Li, W. Qi, Y. Zhang, F. Zhang, J. X. Wu, Y. N. Hu, D. M. Wu, Y. Liu and T. T. Yan, et al.
Aims/hypothesis Sirtuin-1 (SIRT1) is a potential therapeutic target to combat insulin resistance and type 2 diabetes. This study aims to identify a microRNA (miRNA) targeting SIRT1 to regulate hepatic insulin sensitivity. Methods Luciferase assay combined with mutation and immunoblotting was used to screen and verify the bioinformatically predicted miRNAs. miRNA and mRNA levels were measured by real-time PCR. Insulin signalling was detected by immunoblotting and glycogen synthesis. Involvement of SIRT1 was studied with adenovirus, inhibitor and SIRT1-deficient hepatocytes. The role of miR-181a in vivo was explored with adenovirus and locked nucleic acid antisense oligonucleotides. Results miR-181a targets the 3′ untranslated region (3′UTR) of Sirt1 mRNA through a miR-181a binding site, and downregulates SIRT1 protein abundance at the translational level. miR-181a is increased in insulin-resistant cultured hepatocytes and liver, and in the serum of diabetic patients. Overexpression of miR-181a decreases SIRT1 protein levels and activity, and causes insulin resistance in hepatic cells. Inhibition of miR-181a by antisense oligonucleotides increases SIRT1 protein levels and activity, and improves insulin sensitivity in hepatocytes. Ectopic expression of SIRT1 abrogates the effect of miR-181a on insulin sensitivity, and inhibition of SIRT1 activity or SIRT1 deficiency markedly attenuated the improvement in insulin sensitivity induced by antisense miR-181a. In addition, overexpression of miR-181a by adenovirus impairs hepatic insulin signalling, and intraperitoneal injection of locked nucleic acid antisense oligonucleotides for miR-181a improves glucose homeostasis in diet-induced obesity mice. Conclusions/interpretation miR-181a regulates SIRT1 and improves hepatic insulin sensitivity. Inhibition of miR-181a might be a potential new strategy for treating insulin resistance and type 2 diabetes.
