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Abstract ID 97694 Poster Board 357 Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease affecting one-third of the population worldwide. As part of the spectrum of the disease, triglyceride accumulates in the liver and enhances de novo lipogenesis, thereby exacerbating hepatic injury in a destructive cycle. If untreated, NAFLD can lead to non-alcoholic steatohepatitis (NASH) and eventually to liver cirrhosis and, finally, cancer. Research in recent years has advanced our understanding of the etiology behind lipid accumulation in the liver; however, the underlying molecular mechanisms at play are still unknown. Therefore, new research is needed to delineate the molecular underpinnings of triglyceride accumulation in NAFLD. One of the major causes behind this etiology is obesity, primarily due to heavy consumption of high fructose and high fat rich diet. Since cells cannot uptake fructose directly, it needs to be metabolized by the liver, where excess fructose activates inflammation and the De novo hepatic lipogenesis pathway. Formyl peptide receptor 2 (FPR2) is a membrane-bound G-protein coupled receptor from the FPR family, which has both proinflammatory and anti-inflammatory roles in different organs. However, its role in fatty liver disease still remains unknown. Therefore, we aimed to investigate the role of FPR2 in high fructose and high fat diet induced fatty liver disease using male and female C57BL/6 mice. Briefly, mice were fed fructose alone or in combination with high fat diet for 22 weeks. Our histological and biochemical study clearly showed significant hepatosteatosis in fructose alone as well as in combination with high fat diet in both male and female groups. FPR2 protein expression in the liver was found significantly higher in the cytoplasmic fraction of the high fat plus fructose diet group, but the membrane fraction showed significantly reduced expression compared to the chow group, suggesting diet-centric FPR2 regulation. Therefore, to untangle this puzzle, we further aimed to study the role of FPR2 using the HepG2 cell line, an appropriate in-vitro model to study lipogenic gene expression patterns similar to those observed in in-vivo settings. Based on our preliminary results, HepG2 cells were treated with 5.5, 10, 25, 50, and 100mM fructose for 24, 48, 72, and 96hrs. Cell viability results showed no toxicity at any tested fructose concentrations and time points. Next, FPR2 protein expression will be measured using fructose-treated cellular cytoplasmic and membrane fractions. Based on preliminary results, next, we will replicate similar experiments using 250 mM palmitic acid for 24, 48, 72, and 96hrs. Change in hepatic lipid accumulation will be measured as an experimental outcome which will be determined by including Oil Red O staining, cell lysate, and supernatant triglyceride measurement. Similar experiment will be recapitulated in our established FPR2 silenced HepG2 cells to investigate the mechanism. Further, fructose and palmitic acid-treated cell lysates will be subjected to measure lipogenesis and lipolysis-related proteins and mRNA expressions. Once we fully understand the role of FPR2 in hepatocytes, further detailed studies will be carried out using appropriate mouse models in the future. Collectively, understanding a novel role of FPR2 will possibly bring a potential future therapeutic target for fatty liver disease treatment. This research is supported by Seed Grant, a research funding award from St. John9s University, New York.
Islam et al. (Mon,) studied this question.