Human leukocyte antigen F locus adjacent transcript 10 (FAT10) is a ubiquitin-like protein that targets proteins for degradation. TNFα and IFNγ upregulate FAT10, which increases susceptibility to inflammation-driven diseases like nonalcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC). It is well established that inflammation contributes to fatty liver disease, but how inflammation contributes to upregulation and what genes are involved is still poorly understood. New evidence shows that FAT10 plays a role in mitophagy, autophagy, insulin signaling, insulin resistance, and inflammation which may be directly associated with fatty liver disease development. This review will summarize the current literature regarding FAT10 role in developing liver diseases and potential therapeutic targets for nonalcoholic/alcoholic fatty liver disease and hepatocellular carcinoma.

In this poster, we will discuss an infographic exercise that enables students to better understand and utilize the fundamental concepts of biochemistry. The biochemistry class is typically a capstone experience for undergraduates toward the completion of a biochemistry degree. Students typically enter this course from multiple biochemistry or biotechnology tracks which leads to variation in background knowledge and experience with synthesizing information. Thus students enter the biochemistry class with a wide array of experiences leading to an uneven playing field for instructors. Understanding metabolic pathways is a fundamental part of the biochemistry classes but due to their various backgrounds students struggle with studying the material. Our exercise requires that students collaboratively create a metabolic map that highlights regulatory points, evaluate their results through peer feedback, and finally design an infographic on the effects of a metabolic disorder on energy homeostasis. This infographic exercise encourages students to review the steps in metabolic pathways, apply concepts, analyze information, and enable them to construct new knowledge. This activity has the goal of using the ASBMB required core concept of energy transformation by developing skills in accessing, comprehending, and communicating science.

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.

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Obesity in humans can lead to metabolic problems such as glucose intolerance and insulin resistance, which may result from pancreatic islet dysregulation and reduced insulin sensitivity in the liver. LEW.1WR1 (1WR1) rats became more glucose intolerant than LEW/SsNHsd (SsNHsd) rats after 12 weeks on a moderate sucrose diet.1 We hypothesize that the 1WR1 rats develop decreased insulin sensitivity due to impaired islet function and liver responses to insulin. To test this hypothesis we measured blood hormone levels and islet and liver gene expression. The terminal blood insulin (14988+/- 4024 vs. 22703+/-5101 pg/mL; p=0.0085; n=7,7) and glucagon (127.3+/-73.31 vs. 188.6+/-46.87 pg/mL; p=0.0537; n=7,7) were higher in the the 1WR1 rats. Using qRT-PCR, we determined the islets of 1WR1 rats had 3 fold increased insulin (p<0.0001; n=3,3) and glucagon (p<0.0001; n=3,2) relative gene expression. Yet, the β-cell area (22.05+/-6.408 vs. 2.276 +/-1.284mm2; p=0.0016; n=3,4) was significantly reduced in 1WR1 rats. Islet Plin5 expression was upregulated in 1WR1 rats (5.388+/-0.3806 F.C.; p<0.0001; n=3,3) indicating increased lipid droplet production, while Cyclin D (0.5726+/-0.08797 F.C.; p=0.0035; n=3,2) was downregulated indicating decreased cell cycle proliferation. These results indicate that the islets of the 1WR1 rats were insensitive to insulin signaling, which may have been caused by increased lipid droplets and a decrease in compensatory islet area. We also measured the relative expression of insulin-sensitive genes in the liver tissue to determine if there were alterations in liver insulin signaling. Downregulation of Irs-2 (0.5840+/-0.001045 F.C.; p<0.0001; n=7,7) expression was likely caused by the upregulated fat10 gene in 1WR1 rats.2 Fat10 (2315+/-0.01380 F.C.; p<0.0001; n=4,6) expression in the liver was significantly increased. Foxo1 (2.644+/- 0.001211 F.C.; p<0.0001; n=7,7) expression, which is normally reduced by insulin, was upregulated which indicates reduced insulin sensitivity. Upregulated expression of Fgf21 (2.260+/-0.002376 F.C.; p<0.0001; n=6,7), which improves glucose homeostasis, in the liver is why the fasting blood glucose of 1WR1 rats were not significantly different from the SsNHsd rats.1 In conclusion, 1WR1 rats show increasingly impaired metabolism over time. These rats have increased insulin and glucagon levels coupled with liver fat10 overexpression leading to impaired gene regulation of insulin-responsive genes in the liver. These changes synergistically increase susceptibility to pathological obesity and metabolic disease. References: (1) Collins et al., Journal of the Endocrine Society. 2019 3(S1). (2) Ge, Q. et al., Frontiers in Physiology. 2018; 9(1051): 1–16.