microRNA-483 Protects Pancreatic ß-Cells by Targeting ALDH1A3.

ABSTRACT

Pancreatic ß-cell dysfunction is central to the development and progression of type 2 diabetes. Dysregulation of microRNAs (miRNAs) has been associated with pancreatic islet dysfunction in type 2 diabetes. Previous study has shown that miR-483 is expressed relatively higher in ß-cells than in α-cells. To explore the physiological function of miR-483, we generated a ß-cell-specific knockout mouse model of miR-483. Loss of miR-483 enhances high-fat diet-induced hyperglycemia and glucose intolerance by the attenuation of diet-induced insulin release. Intriguingly, mice with miR-483 deletion exhibited loss of ß-cell features, as indicated by elevated expression of aldehyde dehydrogenase family 1, subfamily A3 (Aldh1a3), a marker of ß-cell dedifferentiation. Moreover, Aldh1a3 was validated as a direct target of miR-483 and overexpression of miR-483 repressed Aldh1a3 expression. Genetic ablation of miR-483 also induced alterations in blood lipid profile. Collectively, these data suggest that miR-483 is critical in protecting ß-cell function by repressing the ß-cell disallowed gene Aldh1a3. The dysregulated miR-483 may impair insulin secretion and initiate ß-cell dedifferentiation during the development of type 2 diabetes.