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PreprintCited by 6Pancreatic function and diabetesDiabetes and associated disordersAutophagy in Disease and Therapy

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

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

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Sarkar, Soumyadeep, Deiter, Cailin, Kyle, Jennifer E., Guney, Michelle A., Sarbaugh, Dylan, Yin, Ruichuan, Li, Xiangtang, Cui, Yi, Ramos-Rodriguez, Mireia, Nicora, Carrie D., Syed, Farooq, Juan-Mateu, Jonas, Muralidharan, Charanya, Pasquali, Lorenzo, Evans-Molina, Carmella, Eizirik, Decio L., Webb-Robertson, Bobbie-Jo M., Burnum-Johnson, Kristin, Orr, Galya, Laskin, Julia, Metz, Thomas O., Mirmira, Raghavendra G., Sussel, Lori, Ansong, Charles, Nakayasu, Ernesto·2023·Cell Communication and Signaling
DOI 10.21203/rs.3.rs-3249824/v1PMC PMC10880366

Preprint — published as 10.1186/s12964-023-01437-1 · Paper page

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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.

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Metadata

Authors
Sarkar, S., Deiter, C., Kyle, J. E., Guney, M. A., Sarbaugh, D., Yin, R., Li, X., Cui, Y., Ramos-Rodriguez, M., Nicora, C. D., Syed, F., Juan-Mateu, J., Muralidharan, C., Pasquali, L., Evans-Molina, C., Eizirik, D. L., Webb-Robertson, B.-J. M., Burnum-Johnson, K., Orr, G., Laskin, J., Metz, T. O., Mirmira, R. G., Sussel, L., Ansong, C., & Nakayasu, E.
Affiliations
  • Pacific Northwest National Laboratory (US)
  • University of Colorado Anschutz (US)
  • Purdue University West Lafayette (US)
  • University Pompeu Fabra
  • Indiana University Indianapolis (US)
  • Université Libre de Bruxelles (BE)
  • University of Chicago (US)
  • Universitat Pompeu Fabra (ES)
  • Indiana University School of Medicine
  • Pacific Northwest National Laboratory
Corresponding author
Nakayasu, Ernesto
ORCID
Venue
Cell Communication and Signaling
Publisher
Research Square Platform LLC
Published
2023-08-17
Volume
22
Issue
1
Pages
141-141
ISSN
1478-811X (ISSN-L)
DOI
10.21203/rs.3.rs-3249824/v1
PMC
PMC10880366
OpenAlex
W4391998886
Cited by
6
References
1
Citations by year
2025: 2 · 2024: 4
FWCI
2.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Communication and Signaling (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • U.S. Department of Energy (DE-AC05?, DE-AC05–76RLO01830)
  • U.S. Department of Veterans Affairs (I01-BX001733)
  • Ball Brothers Foundation
  • Battelle (DE-AC05)
  • Oregon Health and Science University
  • George and Frances Ball Foundation
  • Human Islet Research Network
  • Fonds De La Recherche Scientifique - FNRS
  • National Institutes of Health (DK105588)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126444, UC4DK104166, DK108101, U54DK127823, R01DK105588, DK093954, R01DK093954, U01DK127786, U24DK098085, P30DK097512, R01DK127236, R01DK060581, P30DK020595, UC4DK108101, U01DK127505)
  • Laboratory Directed Research and Development (DE-AC05-76RLO01830)
  • Pacific Northwest National Laboratory
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords
beta-cell death, insulitis, type 1 diabetes, lipid signaling, omega-3 fatty acids, lysophosphatidylcholine, triglycerides, cytokine-induced apoptosis, IL-1β, interferon-gamma, SUZ12
MeSH terms
Animals, Fatty Acids, Unsaturated, Humans, Islets of Langerhans, N-Glycosyl Hydrolases, Phosphatidylcholines, Fatty Acids, Omega-3, Cytokines, Cell Death, Mice

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