Effect of interferon gamma on neutral lipid levels, lipid droplet formation, and antiviral responses in pancreatic islets and INS‐1 β cells

Abstract

Interferon (IFN)‐regulated pathways play a critical role in the development of type 1 diabetes (T1D) following exposure to environmental insults including viral infection. IFNs have been shown to modulate lipid metabolism in both immune and non‐hematopoietic cells in response to pathogens. Little is known, however, about the impact of IFN signaling on lipid metabolism in pancreatic β cells and whether IFN‐induced changes in β cell lipid metabolism are associated with antiviral responses and β cell dysfunction. To characterize islet lipid changes potentially mediated by IFNs during initiation of β cell autoimmunity in vivo, juvenile LEW.1WR1 rats (an IFN‐dependent, inducible‐T1D model) were treated with the viral analog polyinosinic:polycytidylic (PIC) every other day for 6 days then islets were isolated 16h and 48h post last treatment for gene expression and non‐targeted lipidomics, respectively. Islets from PIC‐treated animals displayed a robust induction of IFN gamma (IFNγ) target genes, e.g. IFNγ‐inducible protein and ubiquitin D, and significantly increased islet triacylglyceride (TAG) and non‐esterified fatty acids (NEFA). Similar increases in TAG and NEFA were observed when isolated human islets were treated ex vivo for 24h with mixtures of IFNγ and IL1β, or IFNγ and TNFα, suggesting that IFNγ drives TAG synthesis or accumulation. To investigate the direct effect of IFNγ, INS‐1 β cells were treated with IFNγ for 24h. Consistent with the in vivo and ex vivo islet results, IFNγ‐treated cells had significantly higher TAG levels. IFNγ also increased mRNA levels of genes involved in lipid droplet (LD) formation and clustering (e.g. perilipins and fat‐induced storage membrane protein 1) and led to the appearance of clusters of large cytoplasmic LDs. Treatment of INS‐1 cells with IFNγ also increased NEFA levels, most notably arachidonic acid. Although the source for increased TAG and NEFA is uncertain, IFNγ induced fatty acid synthase (FASN) gene expression suggesting increased de novo FA synthesis. IFNγ‐mediated changes in lipid metabolism were associated with impaired insulin secretion. IFNγ, however, did not increase the expression of endoplasmic reticulum (ER) stress markers, but sensitized INS‐1 cells to TNFα‐ or IL1β‐induced ER stress and apoptosis. Importantly, pretreatment of INS‐1 β cells with IFNγ for 12 h markedly increased PIC‐induced expression of antiviral genes (e.g. Ifnb, Mx1) and this synergistic response was abrogated by the FASN inhibitor C75. Inhibition of FASN with C75 also led to a redistribution of IFNγ‐mediated LD clusters into more discrete LDs. Overall, these data suggest that IFNγ promotes LD formation and clustering in β cells, and these LD clusters serve as scaffolds to enhance expression of antiviral response genes. Unfortunately, these lipid metabolism changes are also associated with impaired secretory function and increased susceptibility to cytokine‐induced ER stress and β cell death.Support or Funding InformationJDRF grant 3‐SRE‐2014‐43‐Q‐R to LKO.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.