Contribution of Intronic miR-338-3p and Its Hosting Gene AATK to Compensatory β-Cell Mass Expansion.
The elucidation of the mechanisms directing β-cell mass regeneration and maintenance is of interest, because the deficit of β-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 β-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 β-cells in vitro and promoted survival under proapoptotic conditions without affecting the capacity of β-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 β-cells. We found that the adeno-associated viral construct increased the fraction of proliferating β-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 β-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 β-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 β-cell mass expansion.
Department of Fundamental Neurosciences (C.J., R.R.), University of Lausanne, 1005 Lausanne, Switzerland; Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology (V.J., E.A., F.B.), School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain; Diabetes and Obesity Research Program (R.L.), Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, 2010 New South Wales, Australia; and Montreal Diabetes Research Center and Centre de Recherche du Centre Hospitalier de l'Université de Montréal (M.-L.P., M.P.), and Departments of Nutrition, Biochemistry and Molecular Medicine, University of Montreal, Quebec, H2X 0A9 Canada.
Cécile
C
Jacovetti
Veronica
V
Jimenez
Eduard
E
Ayuso
Ross
R
Laybutt
Marie-Line
ML
Peyot
Marc
M
Prentki
Fatima
F
Bosch
Romano
R
Regazzi
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation; D004958:Estradiol / Q000502:physiology; D005260:Female; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D034622:RNA Interference; D017208:Rats, Wistar
D051017:Apoptosis Regulatory Proteins; C573089:MIRN338 microRNA, rat; D035683:MicroRNAs; D004958:Estradiol; C573090:AATK protein, rat; D011505:Protein-Tyrosine Kinases