title: MicroRNA-15a positively regulates insulin synthesis by inhibiting uncoupling protein-2 expression.
abstract: MicroRNAs are small noncoding RNAs that have been highly conserved during evolution and have been implicated to play an important role in many diseases, including diabetes. Several reports indicated the function of miRNAs in insulin production. However, the mechanisms by which miRNAs regulate this process remain poorly understood. Here we found that the expression of miR-15a was up-regulated in the presence of high glucose for 1h, whereas prolonged periods of high glucose exposure resulted in depressed expression of miR-15a, and the change in expression levels of miR-15a coincided with insulin biosynthesis. Moreover, ectopic expression of miR-15a promoted insulin biosynthesis in MIN6 cells, whereas its repression was sufficient to inhibit insulin biosynthesis. Further, we verified that miR-15a directly targeted and inhibited uncoupling protein-2 (UCP-2) gene expression. miR-15a mimics inhibited UCP-2 3'UTR luciferase reporter activity. Western blot analysis showed that miR-15a inhibited endogenous UCP-2 protein levels, and resulted in the increase in oxygen consumption and reduced ATP generation. This study suggests miR-15a is a mediator of β cell function and insulin biosynthesis, thus offering a new target for the development of preventive or therapeutic agents against diabetes.
authors.affiliation: Department of Endocrinology & Metabolism, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
authors.forename: Liang-Liang
authors.initials: LL
authors.lastname: Sun
authors.forename: Bei-Ge
authors.initials: BG
authors.lastname: Jiang
authors.forename: Wen-Tong
authors.initials: WT
authors.lastname: Li
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: Zou
authors.forename: Yong-Quan
authors.initials: YQ
authors.lastname: Shi
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Liu
mesh_terms: D020413:3' Untranslated Regions; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D007328:Insulin / Q000096:biosynthesis* / Q000235:genetics; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009924:Organ Culture Techniques; D010100:Oxygen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014475:Uncoupling Agents / Q000494:pharmacology; D000071246:Uncoupling Protein 2
chemical_list: D020413:3' Untranslated Regions; D007328:Insulin; D007473:Ion Channels; D035683:MicroRNAs; C544301:Mirn15a microRNA, mouse; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D014475:Uncoupling Agents; D000071246:Uncoupling Protein 2; D000255:Adenosine Triphosphate; D010100:Oxygen