ER Stress-Induced β-Cell Apoptosis is Linked to Novel Select Lipid Signaling at the Transcriptional Level: Implications in T1D Developmen <i>t</i>

Type 1 diabetes (T1D) is a consequence of β-cell death. ER stress precedes T1D onset and prolonged ER stress in β-cells can lead to β-cell apoptosis. We reported that lipid signaling generated by the Ca ²⁺ -independent phospholipase A ₂ β (iPLA ₂ β), encoded by <i>Pla2g6</i> , participates in ER stress-mediated β-cell apoptosis. β-Cell membranes are enriched in arachidonic acid containing glycerophospholipids and the iPLA ₂ β catalyzes the hydrolysis of arachidonic acid in ER stressed β-cells. Metabolism of arachidonic acid leads to the generation of various proinflammatory lipids, raising the possibility that they contribute to ER stress and β-cell death leading to T1D. However, molecular mechanisms by which such β-cell-iPLA ₂ β-derived lipid (iDL) signaling contributes to β-cell apoptosis are not understood. It is well known that ER stress-mediated β-cell apoptosis is associated with induction of transcription factors, NFκB and STAT1. We report here that both induce <i>Pla2g6</i> and, unexpectedly, we find that iPLA ₂ β, which lacks DNA-binding motifs, associates with <i>NFkB</i> , <i>Stat1</i> , and <i>Pla2g6</i> promoter regions. Consistently, p65-NFκB and pSTAT1 induction is reduced with select inhibition or knockdown of iPLA ₂ β. Surprisingly, iPLA ₂ β expression is also reduced by select inhibition of iPLA ₂ β, raising the possibility of feedback regulation by iDLs. In support, we find that select iDLs, recognized to be proinflammatory, enhance association of iPLA ₂ β with <i>Pla2g6</i> , <i>Nfkb</i> , and <i>Stat1</i> promoter regions leading to induction of all three gene products and β-cell apoptosis. Our findings reveal previously unrecognized transcriptional regulation by iDL signaling and, iPLA ₂ β itself, that leads to gene products that promote β-cell apoptosis. Analogous findings in human islets validate this mechanism raising the possibility that targeting select lipid signaling can reduce ER stress in β-cells and ameliorate T1D development.