Regulation of β-cell death by ADP-ribosylhydrolase ARH3 via lipid signaling in insulitis

Abstract

Abstract Background. Lipids have been implicated as regulators of insulitis and β-cell death in type 1 diabetes development, but the underlying mechanisms are poorly understood. Here, we investigated how the islet lipid composition and downstream signaling regulate β-cell death. Methods. We performed lipidomics using three models of insulitis: human islets and EndoC-βH1 β cells treated with the pro-inflammatory cytokines interlukine-1β and interferon-γ, and islets from pre-diabetic non-obese mice. We also performed mass spectrometry and fluorescence imaging to determine the localization of lipids and enzyme in islets. RNAi, apoptotic assay and qPCR were performed to determine the role of a specific factor in lipid-mediated cytokine signaling. Results. Across all three models, lipidomic analyses showed a consistent increase of lysophosphatidylcholine species and phosphatidylcholines with polyunsaturated fatty acids and a reduction of triacylglycerol species. Imaging assays showed that phosphatidylcholine with polyunsaturated fatty acids and converting enzyme phospholipase PLA2G6 are enriched in islets. In downstream signaling, omega-3 fatty acids reduce cytokine-induced β-cell death by improving the expression of adenosine diphosphate ribosylhydrolase ARH3. The mechanism involves omega-3 fatty acid-induced degradation of the histone methylation polycomb complex PRC2 component Suz12, releasing the expression of Arh3, which in turn reduces cell apoptosis. Conclusions. Our data provide insights into the change of lipidomics landscape in β cells during insulitis and identify a protective mechanism by omega-3 fatty acids.