Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity

	Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity
	Zhou, B; Li, C; Qi, W; Zhang, Y; Zhang, F; Wu, JX; Hu, YN; Wu, DM; Liu, Y; Yan, TT
刊名	DIABETOLOGIA
	2012
卷号	55 期号:7 页码:2032-2043
关键词	Hepatocytes Insulin resistance Locked nucleic acid MicroRNA
通讯作者	Zhai, QW (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Key Lab Nutr & Metab, 294 Taiyuan Rd, Shanghai 200031, Peoples R China.,qwzhai@sibs.ac.cn
英文摘要	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. 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. 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. 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.
学科主题	Endocrinology & Metabolism
类目[WOS]	Endocrinology & Metabolism
关键词[WOS]	CELL-DIFFERENTIATION ; 3T3-L1 ADIPOCYTES ; SIGNALING PATHWAY ; RAT MODEL ; MICRORNA ; RESISTANCE ; MICE ; EXPRESSION ; DISEASE ; TARGET
收录类别	SCI
语种	英语
WOS记录号	WOS:000305215200022
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/623]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Zhou, B,Li, C,Qi, W,et al. Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity[J]. DIABETOLOGIA,2012,55(7):2032-2043.
APA	Zhou, B.,Li, C.,Qi, W.,Zhang, Y.,Zhang, F.,...&Zhai, QW.(2012).Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity.DIABETOLOGIA,55(7),2032-2043.
MLA	Zhou, B,et al."Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity".DIABETOLOGIA 55.7(2012):2032-2043.