Fatty acid-mediated signaling as a target for developing type 1 diabetes therapies

Díaz Ludovico, Ivo; Sarkar, Soumyadeep; Elliott, Emily; Virtanen, Suvi M.; Erlund, Iris; Ramanadham, Sasanka; Mirmira, Raghavendra G.; Metz, Thomas O.; Nakayasu, Ernesto S.

doi:10.1080/14728222.2023.2259099

Cited by 3 publications

(3 citation statements)

References 143 publications

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“…This reaction also releases PUFAs, which are associated with both protection [ 46 ] and apoptosis of β cells in response pro-inflammatory cytokines [ 43 ]. ω-6 PUFAs are known precursors of immunomediators, such as prostaglandins, leukotrienes, and thromboxanes [ 47 ]. Some of these immunomediators have anti-inflammatory properties, while others are known to induce inflammation and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, reducing the ω-6/ω-3 ratio has been shown to protect INS-1 β cells against cytokine-induced apoptosis [ 46 ]. Moreover, increased content of ω-3 fatty acids fatty acids in erythrocyte membranes has been shown to be associated with reduced risk of developing islet autoimmunity [ 47 ]. Therefore, shifting the fatty acid composition on the β-cell membrane may shift the balance towards protection against apoptotic signaling.…”

Section: Discussionmentioning

confidence: 99%

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

Sarkar,

Deiter,

Kyle

et al. 2024

Cell Commun Signal

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Sarkar,

Deiter,

Kyle

et al. 2024

Cell Commun Signal

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“…We previously showed that omega-3 fatty acids improves the expression of ARH3 by reducing the level of Suz12, a component of the histone methylation polycomb PCR2 [13]. Omega-3s are anti-inflammatory fatty acids that regulate the expression of pro-inflammatory cytokines and chemokines by engaging the G protein coupled receptor GPR120, inhibiting the activity of the pro-inflammatory transcription factor NF-κB, and activating the anti-inflammatory transcription factor peroxisome proliferator activated receptor γ [27]. The signal transduction of the GPR120 involves the sequestration of the NF-κB activator Tab1, but this scenario is not completely understood.…”

Section: Discussionmentioning

confidence: 99%

Reduction of chemokine CXCL9 expression by omega-3 fatty acids via ADP-ribosylhydrolase ARH3 in MIN6 insulin-producing cells

You,

Sarkar,

Deiter

et al. 2024

Preprint

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Type 1 diabetes (T1D) results from the autoimmune destruction of the insulin producing β cells of the pancreas. Omega-3 fatty acids protect β cells and reduce the incident of T1D. However, how omega-3 fatty acids act on β cells is not well understood. We have shown that omega-3 fatty acids reduce pro-inflammatory cytokine-mediated β-cell apoptosis by upregulating the expression of the ADP-ribosylhydrolase ARH3. Here, we further investigate the β-cell protection mechanism by ARH3 by performing siRNA of its gene Adprhl2 in MIN6 insulin-producing cells followed by treatment with a cocktail of the pro-inflammatory cytokines IL-1β + IFN-γ + TNF-α, and proteomics analysis. ARH3 regulated proteins from several pathways related to the nucleus (splicing, RNA surveillance and nucleocytoplasmic transport), mitochondria (metabolic pathways) and endoplasmic reticulum (protein folding). ARH3 also regulated the levels of cytokine-signaling proteins related to the antigen processing and presentation, and chemokine-signaling pathway. We further studied the role of ARH in regulating the chemokine CXCL9. We confirmed that ARH3 reduces the cytokine-induced expression of CXCL9 by ELISA. We also found that CXCL9 expression is regulated by omega-3 fatty acids. In conclusion, we showed that omega-3 fatty acids regulate CXCL9 expression via ARH3, which might have a role in protecting β cells from immune attack and preventing T1D development.

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Arachidonic acid alleviates autoimmune diabetes in NOD mice

Zhao,

Chen,

Xiao

et al. 2024

International Immunopharmacology

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Fatty acid-mediated signaling as a target for developing type 1 diabetes therapies

Cited by 3 publications

References 143 publications

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

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

Reduction of chemokine CXCL9 expression by omega-3 fatty acids via ADP-ribosylhydrolase ARH3 in MIN6 insulin-producing cells

Arachidonic acid alleviates autoimmune diabetes in NOD mice

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