Year: 2024
Type: article
Abstract: BACKGROUND: Lipids are 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 phosphatidylcholines with polyunsaturated fatty acids and their hydrolyzing 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 ADP-ribosylhydrolase ARH3. The mechanism involves omega-3 fatty acid-mediated reduction of the histone methylation polycomb complex PRC2 component Suz12, upregulating the expression of Arh3, which in turn decreases 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. Video Abstract.
Source: Cell Communication and Signaling
Authors: Soumyadeep Sarkar, Cailin Deiter, Jennifer E. Kyle, Michelle A. Guney, Dylan Sarbaugh, Ruichuan Yin, Xiangtang Li, Yi Cui, Mireia Ramos-Rodriguez, Carrie D. Nicora, Farooq Syed, Jonas Juan-Mateu, Charanya Muralidharan, Lorenzo Pasquali, Carmella Evans-Molina, Decio L. Eizirik, Bobbie-Jo M. Webb-Robertson, Kristin Burnum-Johnson, Galya Orr, Julia Laskin, Thomas O. Metz, Raghavendra G. Mirmira, Lori Sussel, Charles Ansong, Ernesto S. Nakayasu
Institutions: Pacific Northwest National Laboratory, University of Colorado Anschutz, Purdue University West Lafayette, Environmental Molecular Sciences Laboratory, Nanostring Technologies (United States), Universitat Pompeu Fabra, Indiana University Indianapolis, Indiana University School of Medicine, Indiana University – Purdue University Indianapolis, Université Libre de Bruxelles, Barcelona Institute of Science and Technology, Centre for Genomic Regulation, University of Chicago
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,290
Funders: U.S. Department of Energy, U.S. Department of Veterans Affairs, Ball Brothers Foundation, Battelle, Oregon Health and Science University, George and Frances Ball Foundation, Human Islet Research Network, Fonds De La Recherche Scientifique - FNRS, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory Directed Research and Development, Pacific Northwest National Laboratory
Awards: G1074056680, iPLA2beta-mediated alternative splicing and beta-cell death in type 1 diabetes, G2988778103, Biomarkers Of Beta Cell Stress In Type 1 Diabetes (BetaMarker), G4276290260, Multi-omic 3D tissue maps for a Human BioMolecular Atlas, Role of 12-lipoxygenase and 12-HETE signaling in beta-cell dysfunction, G5726405315, G5747062680, Mechanisms of Beta Cell Function in Health and Disease, G6365575238, G832612391, Interferon Signaling in the T1D Islet Microenvironment, Integrated Islet Distribution Program (U24) - 2021, Indiana Diabetes Research Center, Control of beta cell function and survival by RYR2-mediated calcium signals, Transcriptional and Translational Mechanisms Governing Beta Cell Function, Diabetes Research and Training Center , Single Cell Resolution Omics Analysis of T1D islets, Alternative RNA splicing events contribute to the onset of islet dysfunction in T1D
OpenAlex ID: W4391998886