ER Stress-Induced beta-Cell Apoptosis is Linked to Novel Select Lipid Signaling at the Transcriptional Level: Implications in T1D Development

Lei, X.; Challa, A. K.; Nozell, S. E.; Ali, T.; Stephenson, D. J.; Nafzinger, A.; Hunter, C. S.; Wende, A. R.; Nakayasu, E. S.; Gai-Tusing, Y.; Chalfant, C. E.; Ramanadham, S.

doi:10.64898/2026.03.02.708596

bioRxiv · 10.64898/2026.03.02.708596

ER Stress-Induced beta-Cell Apoptosis is Linked to Novel Select Lipid Signaling at the Transcriptional Level: Implications in T1D Development

Lei, X.·Challa, A. K.·Nozell, S. E.·Ali, T.·Stephenson, D. J.·Nafzinger, A.·Hunter, C. S.·Wende, A. R.·Nakayasu, E. S.·Gai-Tusing, Y.·Chalfant, C. E.·Ramanadham, S.

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Abstract

Type 1 diabetes (T1D) is a consequence of {beta}-cell death. ER stress precedes T1D onset and prolonged ER stress in {beta}-cells can lead to {beta}-cell apoptosis. We reported that lipid signaling generated by the Ca2+-independent phospholipase A2{beta} (iPLA2{beta}), encoded by Pla2g6, participates in ER stress-mediated {beta}-cell apoptosis. {beta}-Cell membranes are enriched in arachidonic acid containing glycerophospholipids and the iPLA2{beta} catalyzes the hydrolysis of arachidonic acid in ER stressed {beta}-cells. Metabolism of arachidonic acid leads to the generation of various proinflammatory lipids, raising the possibility that they contribute to ER stress and {beta}-cell death leading to T1D. However, molecular mechanisms by which such {beta}-cell-iPLA2{beta}-derived lipid (iDL) signaling contributes to {beta}-cell apoptosis are not understood. It is well known that ER stress-mediated {beta}-cell apoptosis is associated with induction of transcription factors, NF{kappa}B and STAT1. We report here that both induce Pla2g6 and, unexpectedly, we find that iPLA2{beta}, which lacks DNA-binding motifs, associates with NFkB, Stat1, and Pla2g6 promoter regions. Consistently, p65-NF{kappa}B and pSTAT1 induction is reduced with select inhibition or knockdown of iPLA2{beta}. Surprisingly, iPLA2{beta} expression is also reduced by select inhibition of iPLA2{beta}, raising the possibility of feedback regulation by iDLs. In support, we find that select iDLs, recognized to be proinflammatory, enhance association of iPLA2{beta} with Pla2g6, Nfkb, and Stat1 promoter regions leading to induction of all three gene products and {beta}-cell apoptosis. Our findings reveal previously unrecognized transcriptional regulation by iDL signaling and, iPLA2{beta} itself, that leads to gene products that promote {beta}-cell apoptosis. Analogous findings in human islets validate this mechanism raising the possibility that targeting select lipid signaling can reduce ER stress in {beta}-cells and ameliorate T1D development.

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Lei, X., Challa, A. K., Nozell, S. E., Ali, T., Stephenson, D. J., Nafzinger, A., Hunter, C. S., Wende, A. R., Nakayasu, E. S., Gai-Tusing, Y., Chalfant, C. E., Ramanadham, S.. 2026-03-04. ER Stress-Induced beta-Cell Apoptosis is Linked to Novel Select Lipid Signaling at the Transcriptional Level: Implications in T1D Development. https://doi.org/10.64898/2026.03.02.708596

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