Apr 24, 2014

The role of islet lipid composition remodeling in regulation of beta-cell death via ADP-ribosyl-acceptor glycohydrolase ARH3 signaling in insulitis

BioRxiv : the Preprint Server for Biology
Amir ShahmoradiCharles Ansong

Abstract

Lipids have been implicated as mediators of insulitis and β-cell death in type 1 diabetes development, but it is poorly understood how islet lipid profiles are changed in response to the signaling pathways triggered by insulitis. Here, we investigated the changes in islet/β-cell lipid composition using three models of insulitis and type 1 diabetes progression: isolated human islets and EndoC-βH1 β-cells treated with the proinflammatory cytokines IL-1β and IFN-γ, and islets from non-obese diabetic (NOD) mice isolated before the onset of diabetes. Lipidomic analyses of these three models showed a consistent change in abundance of the lysophosphatidylcholine, phosphatidylcholine and triacylglycerol species. Immunohistochemistry and fluorescence in-situ hybridization showed an enrichment of lysophosphatidylcholine biosynthetic enzyme PLA2G6 in mouse islets. These results were consistent with the lipid profiles obtained using mass spectrometry imaging, which showed an enrichment of lysophosphatidylcholine in mouse islets. Furthermore, we determined that the ADP-ribosyl-acceptor glycohydrolase ARH3 is regulated by cytokines downstream of PLA2G6 and that this regulation may represent a negative feedback mechanism that reduces cytokine...Continue Reading

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