Regulation of Β-Cell Death by ADP-ribosylhydrolase ARH3 Via Lipid Signaling in Insulitis

SummaryLipids have been implicated as mediators of insulitis and β-cell death in type 1 diabetes development, but the mechanisms underlying this association are poorly understood. Here, we investigated the changes in islet/β-cell lipid composition using three models of insulitis: human islets and EndoC-βH1 β-cells treated with the cytokines IL-1β and IFN-γ, and islets from non-obese diabetic mice. Across all three models, lipidomic analyses showed a consistent change in abundance of the lysophosphatidylcholine, phosphatidylcholine and triacylglycerol species. We also showed that lysophosphatidylcholine and its biosynthetic enzyme PLA2G6 are enriched in murine islets. We determined that the ADP-ribosyl-acceptor glycohydrolase ARH3 is regulated by cytokines downstream of PLA2G6, which in turn regulates proteins involved in apoptosis, lipid metabolism, antigen processing and presentation and chemokines. ARH3 reduced cytokine-induced apoptosis, which may represent a negative feedback mechanism. Overall, these data show the importance of lipid metabolism in regulating β-cell death in type 1 diabetes.HighlightsLipidomics of 3 insulitis models revealed commonly regulated lipid classes.Identification of 35 proteins regulated by cytokines via PLA2G6 signaling.ARH3 reduces cytokine-induced apoptosis via PLA2G6 regulation.ARH3 regulates the levels of proteins related to insulitis and type 1 diabetes.