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MiR-184 expression is regulated by AMPK in pancreatic islets.

ABSTRACT: AMPK is a critical energy sensor and target for widely used antidiabetic drugs. In ? cells, elevated glucose concentrations lower AMPK activity, and the ablation of both catalytic subunits [?-cell-specific AMPK double-knockout (?AMPKdKO) mice] impairs insulin secretion in vivo and ?-cell identity. MicroRNAs (miRNAs) are small RNAs that silence gene expression that are essential for pancreatic ?-cell function and identity and altered in diabetes. Here, we have explored the miRNAs acting downstream of AMPK in mouse and human ? cells. We identified 14 down-regulated and 9 up-regulated miRNAs in ?AMPKdKO vs. control islets. Gene ontology analysis of targeted transcripts revealed enrichment in pathways important for ?-cell function and identity. The most down-regulated miRNA was miR-184 (miR-184-3p), an important regulator of ?-cell function and compensatory expansion that is controlled by glucose and reduced in diabetes. We demonstrate that AMPK is a potent regulator and an important mediator of the negative effects of glucose on miR-184 expression. Additionally, we reveal sexual dimorphism in miR-184 expression in mouse and human islets. Collectively, these data demonstrate that glucose-mediated changes in AMPK activity are central for the regulation of miR-184 and other miRNAs in islets and provide a link between energy status and gene expression in ? cells.-Martinez-Sanchez, A., Nguyen-Tu, M.-S., Cebola, I., Yavari, A., Marchetti, P., Piemonti, L., de Koning, E., Shapiro, A. M. J., Johnson, P., Sakamoto, K., Smith, D. M., Leclerc, I., Ashrafian, H., Ferrer, J., Rutter, G. A. MiR-184 expression is regulated by AMPK in pancreatic islets.

SUBMITTER: Martinez-Sanchez A

PROVIDER: S-EPMC6207280 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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MiR-184 expression is regulated by AMPK in pancreatic islets.

Martinez-Sanchez Aida A Nguyen-Tu Marie-Sophie MS Cebola Ines I Yavari Arash A Marchetti Piero P Piemonti Lorenzo L de Koning Eelco E Shapiro A M James AMJ Johnson Paul P Sakamoto Kei K Smith David M DM Leclerc Isabelle I Ashrafian Houman H Ferrer Jorge J Rutter Guy A GA

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20180108 5

AMPK is a critical energy sensor and target for widely used antidiabetic drugs. In β cells, elevated glucose concentrations lower AMPK activity, and the ablation of both catalytic subunits [β-cell-specific AMPK double-knockout (βAMPKdKO) mice] impairs insulin secretion in vivo and β-cell identity. MicroRNAs (miRNAs) are small RNAs that silence gene expression that are essential for pancreatic β-cell function and identity and altered in diabetes. Here, we have explored the miRNAs acting downstrea ...[more]

PMID: 29269398

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Project description:microRNAs (miRNAs) play an important role in pancreatic development and adult ?-cell physiology. Our hypothesis is based on the assumption that each islet cell type has a specific pattern of miRNA expression. We sought to determine the profile of miRNA expression in ?-and ?-cells, the main components of pancreatic islets, because this analysis may lead to a better understanding of islet gene regulatory pathways. Highly enriched (>98%) subsets of human ?-and ?-cells were obtained by flow cytometric sorting after intracellular staining with c-peptide and glucagon antibody. The method of sorting based on intracellular staining is possible because miRNAs are stable after fixation. MiRNA expression levels were determined by quantitative high throughput PCR-based miRNA array platform screening. Most of the miRNAs were preferentially expressed in ?-cells. From the total of 667 miRNAs screened, the Significant Analysis of Microarray identified 141 miRNAs, of which only 7 were expressed more in ?-cells (?-miRNAs) and 134 were expressed more in ?-cells (?-miRNAs). Bioinformatic analysis identified potential targets of ?-miRNAs analyzing the Beta Cell Gene Atlas, described in the T1Dbase, the web platform, supporting the type 1 diabetes (T1D) community. cMaf, a transcription factor regulating glucagon expression expressed selectively in ?-cells (TF?) is targeted by ?-miRNAs; miR-200c, miR-125b and miR-182. Min6 cells treated with inhibitors of these miRNAs show an increased expression of cMaf RNA. Conversely, over expression of miR-200c, miR-125b or miR-182 in the mouse alpha cell line ?TC6 decreases the level of cMAF mRNA and protein. MiR-200c also inhibits the expression of Zfpm2, a TF? that inhibits the PI3K signaling pathway, at both RNA and protein levels.In conclusion, we identified miRNAs differentially expressed in pancreatic ?- and ?-cells and their potential transcription factor targets that could add new insights into different aspects of islet biology and pathophysiology.

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MiR-184 expression is regulated by AMPK in pancreatic islets.

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MiR-184 expression is regulated by AMPK in pancreatic islets.

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