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Volume 73, Issue Supplement_1
June 2024
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OR: Islet Biology—Apoptosis| June 14 2024
XIAOYONG LEI;
XIAOYONG LEI
Birmingham, AL, Richland, WA, Chicago, IL, South Chesterfield, VA
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ANIL KUMAR CHALLA;
ANIL KUMAR CHALLA
Birmingham, AL, Richland, WA, Chicago, IL, South Chesterfield, VA
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YING TUSING;
YING TUSING
Birmingham, AL, Richland, WA, Chicago, IL, South Chesterfield, VA
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ERNESTO NAKAYASU;
ERNESTO NAKAYASU
Birmingham, AL, Richland, WA, Chicago, IL, South Chesterfield, VA
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RAGHAVENDRA G. MIRMIRA;
RAGHAVENDRA G. MIRMIRA
Birmingham, AL, Richland, WA, Chicago, IL, South Chesterfield, VA
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CHARLES E. CHALFANT;
CHARLES E. CHALFANT
Birmingham, AL, Richland, WA, Chicago, IL, South Chesterfield, VA
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SASANKA RAMANADHAM
SASANKA RAMANADHAM
Birmingham, AL, Richland, WA, Chicago, IL, South Chesterfield, VA
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Diabetes 2024;73(Supplement_1):340-OR
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XIAOYONG LEI, ANIL KUMAR CHALLA, YING TUSING, ERNESTO NAKAYASU, RAGHAVENDRA G. MIRMIRA, CHARLES E. CHALFANT, SASANKA RAMANADHAM; 340-OR: Transcriptional Activation in Beta-Cells during ER Stress Linking iPLA2beta with NFkB. Diabetes 14 June 2024; 73 (Supplement_1): 340–OR. https://doi.org/10.2337/db24-340-OR
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ER stress in β-cells has been reported to precede T1D development and we reported that the Ca2+-independent phospholipase A2β (iPLA2β) participates in ER stress-mediated β-cell apoptosis. Recently, we found that reduction in iPLA2β lowers T1D incidence. The iPLA2β hydrolyzes β-cell membrane glycerophospholipids to release arachidonic acid, which can be metabolized to inflammatory eicosanoids. Herein, we used insulinoma cells, human islets, spontaneously diabetes-prone NOD mice, and CRISPR-modified β-cells to address processes linking iPLA2β and ER stress. We find that cytokine-induced ER stress induces iPLA2β-mediated eicosanoid production, in association with NFκB activation and β-cell apoptosis. Surprisingly, inhibition or decreased iPLA2β expression also reduced NFκB activation at the transcriptional and protein levels. These observations were recapitulated in human and NOD.iPLA2β-/- islet β-cells and suggested potential regulatory links between iPLA2β and NFκB. To assess this at the molecular level, ChIP analyses were performed using MIN6 cells and not unexpectedly, an association between the transcription factor NFκB and PLA2G6, gene that encodes iPLA2β was observed. Intriguingly, ER stress also promoted association of iPLA2β with NF κ B and PLA2G6. Whereas inhibition of iPLA2β did not affect these associations, CRISPR-mediated reduction of iPLA2β significantly reduced both interactions. These observations suggest that iPLA2β protein itself, and not its lipid products, triggers transcriptional events to regulate its own production and that of apoptotic factors. Curiously, the iPLA2β protein is not recognized to have a DNA binding motif, therefore, suggesting that non-lipid co-factors likely link iPLA2β with target genes. Our findings identify a novel role for iPLA2β in modulating transcriptional events that are triggered during the development of ER stress, leading to β-cell death and T1D onset.
Disclosure
X. Lei: None. A. Challa: None. Y. Tusing: None. E. Nakayasu: None. R.G. Mirmira: None. C.E. Chalfant: None. S. Ramanadham: None.
Funding
NIH/NIDDK R01DK110292Beatson Foundation #2023-20UAB DRC P30 DK079626UAB Department of CDIBUAB Comprehensive Diabetes Center
© 2024 by the American Diabetes Association
2024
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
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