lncRNA Eif4g2 improves palmitate-induced dysfunction of mouse β-cells via modulation of Nrf2 activation

Chronic oxidative stress resulting from hyperlipidemia is thought to be a key pathogenic driver of pancreatic β-cell dysfunction in leading to the onset of type 2 diabetes mellitus (T2DM). Long non-coding RNAs (lncRNAs) have been increasingly recognized to regulate dysfunction within pancreatic β-cells in the context of T2DM. In the present study, we sought to comprehensively analyze the roles of lncRNAs in dysfunctional β-cells and mouse islets. Analyses of INS-1E cells were performed by RNA-seq and qRT-PCR after treating with or without 0.5 mM palmitate for 4 days, leading us to identify the novel lncRNA Eif4g2 (lncEif4g2) as a functional regulator within these cells. When we overexpressed lncEif4g2 in INS-1E β-cells and mouse islets, this was sufficient for the reversal of palmitate-mediated reductions in cell viability, insulin production, ATP production by mitochondria, and creation of intracellular reactive oxygen species (ROS) and the dysfunction of mouse islets, with nuclear factor erythroid 2 related factor 2 (Nrf2) activation also being observed. In contrast, when lncEif4g2 was knocked down this led INS-1E cells and mouse islets to become more sensitive to palmitate-induced dysfunction, with reduced Nrf2 nuclear translocation also being detected. When antioxidants were used to treat INS-1E cells and mouse islets, however, these negative effects were reversed. Additional functional analyses revealed lncEif4g2 to be capable of directly binding to miR-3074-5p in β-cells, with the expression of lncEif4g2 and miR-3074-5p being negatively correlated with one another. We further found that cAMP-responsive element binding-protein (CREB) was a miR-3074-5p target gene in these cells, thus at least in part serving as a functional mediator of the lncEif4g2/miR-3074-5p axis within dysfunctional β-cells. In summary, our results thus reveal that lncEif4g2 is able to indirectly regulate the expression of CREB via targeting miR-3074-5p in INS-1E cells and mouse islets, thereby leading to enhanced Nrf2 activation.