2120-P: Knockdown of ETV5 Enhances Nitric Oxide (NO) Production and Caspase-Independent Cell Death in Pancreatic Beta Cells

ETV5 (E-twenty six variant gene 5) belongs to the E-twenty six transcription factor family that regulates various biological processes including proliferation, differentiation and apoptosis. Genome-wide association studies linked ETV5 with human obesity. ETV5 is expressed in insulin producing pancreatic beta cells and its deletion in Etv5-/- mice results in less weight gain during high fat diet and impaired glucose tolerance due to reduced insulin exocytosis and less β-cell mass. Against this background we investigated whether ETV5 is regulated by nutritional states in pancreatic beta cells and whether ETV5 plays a role in proliferation and survival during diabetogenic stresses. Insulin producing rat insulinoma-derived INS-1E cells and generated shEtv5-INS1E cells with Dox-inducible Etv5 knockdown served as models. The obtained results demonstrate that ETV5 production is not regulated by low and high glucose or serum deprivation. ETV5 is time and dose-dependently induced by streptozotocin (STZ) and palmitate (PA) to significant levels after 24 h while alloxan has no effect. STZ and PA induce Etv5 gene expression also in primary mouse islets. Knockdown of Etv5 did not change proliferation in expanding INS-1E β-cells but significantly further enhanced STZ- and PA-mediated loss of viability despite same activation of apoptotic effector caspases-3/7 as in control cells. Instead, Etv5 knockdown increased NO production under basal conditions and enhanced necrotic cell death in response to STZ and PA. In conclusion, this study provided initial evidence that ETV5 plays a currently not completely characterized role in the survival of pancreatic insulin producing β-cell during diabetogenic stress.