Contribution of intronic miR-338-3p and its hosting gene AATK to compensatory beta-cell mass expansion
The elucidation of the mechanisms directing beta-cell mass regeneration and maintenance is of interest, because the deficit of beta-cell mass contributes to diabetes onset and progression. We previously found that the level of the microRNA (miRNA) miR-338-3p is decreased in pancreatic islets from rodent models displaying insulin resistance and compensatory beta-cell mass expansion, including pregnant rats, diet-induced obese mice, and db/db mice. Transfection of rat islet cells with oligonucleotides that specifically block miR-338-3p activity increased the fraction of proliferating beta-cells in vitro and promoted survival under proapoptotic conditions without affecting the capacity of beta-cells to release insulin in response to glucose. Here, we evaluated the role of miR-338-3p in vivo by injecting mice with an adeno-associated viral vector permitting specific sequestration of this miRNA in beta-cells. We found that the adeno-associated viral construct increased the fraction of proliferating beta-cells confirming the data obtained in vitro. miR-338-3p is generated from an intron of the gene coding for apoptosis-associated tyrosine kinase (AATK). Similarly to miR-338-3p, we found that AATK is down-regulated in rat and human islets and INS832/13 beta-cells in the presence of the cAMP-raising agents exendin-4, estradiol, and a G-protein-coupled Receptor 30 agonist. Moreover, AATK expression is reduced in islets of insulin resistant animal models and selective silencing of AATK in INS832/13 cells by RNA interference promoted beta-cell proliferation. The results point to a coordinated reduction of miR-338-3p and AATK under insulin resistance conditions and provide evidence for a cooperative action of the miRNA and its hosting gene in compensatory beta-cell mass expansion.
|ISBN||1944-9917 (Electronic) 0888-8809 (Linking)|
|Authors||Jacovetti, C. ; Jimenez, V. ; Ayuso, E. ; Laybutt, R. ; Peyot, M. L. ; Prentki, M. ; Bosch, F. ; Regazzi, R.;|
|Publisher Name||MOLECULAR ENDOCRINOLOGY|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/25751313|