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2017 Cardiovascular Research Day Abstract Book

77 The Role of ApoC-III

77 The Role of ApoC-III in the immune system Alison Kohan, PhD 1 • Cayla Rodia 1 1Nutritional Sciences, University of Connecticut Faculty While we know that CD4+CD25+Foxp3+ regulatory T cells (Tregs) are a powerful tool in the resolution of gut inflammation, and that their secretion of IL-10 is critical to inflammatory bowel disease (IBD) remission, there is a major gap in identifying mechanisms for increasing Tregs in the intestine. Recently, we have found that intestinal Tregs and plasma IL-10 are dramatically increased in mice overexpressing human apoC-III. These intestinal Tregs significantly protect apoC- III transgenic mice mice from experimental colitis, including weight loss, diarrhea, and TNF-α secretion. While apoC-III overexpression is protective, loss of apoC-III in apoC-III-/- mice severely impacts colitis sensitivity; more than 50% of apoC-III-/- mice die in response to dextran sodium sulfate (DSS)-colitis induction, compared to wild-type controls that all survive. Supporting our studies in these mouse models are human studies which show that both plasma and ileal apoC-III levels are reduced in patients during active IBD flare-ups. We have now determined that apoC-III acts specifically on Tregs and CD103+dendritic cells in the intestine and mesenteric lymph nodes, and that treatment of Tregs ex vivo with apoC-III-containing lipoproteins inhibits their ability to take up extracellular fatty acids. This inhibitory role of apoC-III on lipid uptake is well known, but this is the first time this role has been described in Tregs, thus defining a new and biologically important function of this apolipoprotein in the immune system. We hypothesize that a critical function of apoC-III is to regulate lipid uptake and metabolism in intestinal Tregs, which results in increased tolerogenicity in the gut. 93

78 Understanding inhibition of lipoprotein lipase by angiopoietin-like protein 4 Aspen Gutgsell 1 • Saskia Neher, PhD 1 1Biochemistry and Biophysics, UNC Chapel Hill Graduate Student More than three million cases of hypertriglyceridemia are diagnosed every year in the United States. Hypertriglyceridemia, or elevated levels of plasma triglycerides, is a major risk factor cardiovascular disease and the leading cause of death worldwide. Two major sources of plasma triglycerides are dietary fat and stored fat in adipose tissue. Triglycerides are packaged into lipoprotein particles and reahernmoved from circulation by lipoprotein lipase (LPL) in the capillaries of muscle, heart, and adipose tissue. In the absence of LPL, patients have severe hypertriglyceridemia, life-threatening pancreatitis, and fatty skin lesions. A family of proteins known as angiopoietin-like proteins (ANGPTL3, 4 and 8) temporally regulate LPL to control the delivery of fatty acids to certain tissues. More specifically, ANGPTL4 inhibits LPL in adipose tissue during periods of fasting. Recently, genome wide association and exome sequence studies identified individuals with loss of function mutations in ANGPTL4 as having a unique lipid profile that significantly decreases their risk for developing cardiovascular disease. Their profile consists of low plasma triglycerides and high levels of “good” cholesterol, commonly known as HDL. The direct relationship between LPL activity and plasma triglyceride levels lends LPL as an ideal target for triglyceride lowering therapeutics. More specifically, preserving LPL activity by blocking ANGPTL4 inhibition is hypothesized to generate a “cardio protective” lipid profile by lowering plasma triglycerides and increasing HDL cholesterol in patients with high triglycerides. However, the interaction between LPL and ANGPTL4 is poorly understood as no structural information is available. It was originally believed ANGPTL4 irreversibly inhibits LPL by dissociating it into inactive monomers. However, our group has shown that ANGPTL4 noncompetitively inhibits LPL, while leaving the active dimeric structure intact. Since this discovery, little information has surfaced regarding exactly how or where ANGPTL4 and LPL interact. Therefore, our aim is to characterize the ANGPTL4/LPL interaction and generate a structural model for this complex. 94

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