Posttranscriptional regulation of the prostaglandin E receptor spliced-isoform EP3- and its implication in pancreatic -cell failure

In Type 2 diabetes (T2D), elevated lipid levels have been suggested to contribute to insulin resistance and beta-cell dysfunction. We previously reported that the expression of the PGE2 receptor EP3 is elevated in islets of T2D individuals and is preferentially stimulated by palmitate, leading to beta-cell failure. The mouse EP3 receptor generates three isoforms by alternative splicing which differ in their C-terminal domain and are referred to as mEP3 alpha, mEP3 beta, and mEP3 gamma. We bring evidence that the expression of the mEP3 gamma isoform is elevated in islets of diabetic db/db mice and is selectively upregulated by palmitate. Specific knockdown of the mEP3 gamma isoform restores the expression of beta-cell-specific genes and rescues MIN6 cells from palmitate-induced dysfunction and apoptosis. This study indicates that palmitate stimulates the expression of the mEP3 gamma by a posttranscriptional mechanism, compared to the other spliced isoforms, and that the de novo synthesized ceramide plays an important role in FFA-induced mEP3 gamma expression in beta-cells. Moreover, induced levels of mEP3 gamma mRNA by palmitate or ceramide depend on p38 MAPK activation. Our findings suggest that mEP3 gamma gene expression is regulated at the posttranscriptional level and defines the EP3 signaling axis as an important pathway mediating beta-cell-impaired function and demise.