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

Abstract

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.

• Authors: B Zhou, C Li, W Qi, Y Zhang, F Zhang, J X Wu, Y N Hu, D M Wu, Y Liu, T T Yan, Q Jing, M F Liu, Q W Zhai
• Journal: Diabetologia (Diabetologia) Vol. 55 Issue 7 Pg. 2032-43 (Jul 2012) ISSN: 1432-0428 [Electronic] Germany
• PMID: 22476949 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• MicroRNAs
• RNA, Messenger
• mirn181 microRNA, mouse
• Sirt1 protein, mouse
• Sirtuin 1

Topics

• 3' Untranslated Regions (genetics)
• Animals
• Cells, Cultured
• Diabetes Mellitus, Type 2 (genetics, metabolism)
• Down-Regulation
• Humans
• Immunoblotting
• Insulin Resistance
• Liver (metabolism)
• Mice
• MicroRNAs (metabolism)
• Polymerase Chain Reaction (methods)
• RNA, Messenger (genetics, metabolism)
• Signal Transduction (genetics)
• Sirtuin 1 (genetics, metabolism)
• Up-Regulation