2017 Cardiovascular Research Day Abstract Book

76
Pancreatic Beta Cell Export of miR-375 to High-Density Lipoproteins is Regulated by Cellular
Ion Fluxes.
Leslie Sedgeman 1 • Carine Beysen, PhD 2 • Marisol Ramirez-Solano 3 • Quanhu Sheng, PhD 4 •
Yan Guo, PhD 4 • Scott Turner, PhD 2 • Kasey Vickers, PhD 3
1Molecular Physiology and Biophysics, Vanderbilt University • 2 Kinemed, Inc. • 3 Division of
Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center •
4Department of Cancer Biology, Vanderbilt University Medical Center
Graduate Student
microRNAs (miRNAs) are critical regulators of glucose metabolism and contribute to the
pathogenesis of Type 2 Diabetes (T2D). Recently, we reported that high-density lipoproteins (HDL)
transport and deliver functional miRNAs to recipient cells, including endothelial cells and
hepatocytes. However, the mechanism of export is not understood. Since miR-375 expression in the
islets is 10X greater than in other organs, we tested whether pancreatic beta cells have the ability to
export miR-375 to HDL through in vitro export assays, incubating HDL with INS1 beta cells or
primary human islets. Indeed, we found miR-375 to be readily exported to HDL from INS1 cells and
primary islets in vitro. To determine if cholesterol transporters contribute to HDL-miR-375 export
from beta cells, Abca1, Abcg1 and Scarb1 (SR-BI) were inhibited using siRNAs; however, we found
that knockdown of each of these transporters failed to affect the beta cell’s ability to export miR-
375 to HDL. On the other hand, inhibition of the KATP channel with tolbutamide resulted in the
suppression of HDL-miR-375 export. Similarly, export of miR-375 to HDL was blunted from islets of
two mouse models lacking functional KATP channels (Kir6.2 and SUR1 KO mice). Our work
suggests that miR-375 export to HDL is regulated by cellular dynamics, including ion fluzes in the
beta cell. We are currently investigating the relationship between HDL-miR-375 export, insulin
secretion, and miRNA processing in pancreatic beta cells to further elucidate the mechanism(s)
controlling HDL-miR-375 export. Collectively, results suggest that a large fraction of HDL-miRNAs
originate from pancreatic beta cells and HDL-miRNAs are exported independent of cholesterol
transporters.
92