Browsing by Subject "Lipid metabolism"
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Item Glycerol-3-phosphate acyltransferase regulates T cell effector function and metabolism(2013-08) Faris, Robert Allen, Jr.; Jolly, Christopher A.The aged T cell is characterized by decreased responsiveness to stimulation. Aging is associated with reduced membrane glycerophospholipid (GPL) to cholesterol ratios so it is interesting that deletion of mitochondrial glycerol-3-phosphate acyltransferase-1 which catalyzes the first step in de novo GPL synthesis induces an aged T cell phenotype in otherwise healthy mice. GPAT-1 could regulate T cell function through three possible mechanisms: maintenance of membrane GPL ratios and membrane based signaling, providing a specific substrate for downstream signaling, or direct regulation of cellular metabolism. Therefore, the goal of this project was to determine whether these mechanisms contribute to the dysfunctional T cell phenotype observed with decreased GPAT-1 activity. T cell stimulation requires significant upregulation of metabolic processes to drive clonal expansion and cytokine production. T cell dysfunction in GPAT-1 knockout mice may be partially explained by altered metabolic function. We found that GPAT-1 KO T cells have significantly reduced basal respiration rates and spare respiratory capacity which is not compensated for by increased glycolytic metabolism suggesting an inherent metabolic defect in GPAT-1 KO T cells. To better understand mechanistically how GPAT-1 regulates T cell function we moved into the Jurkat T cell line and found that shRNA mediated knockdown of the human isoform of GPAT-1 (GPAM) recapitulated key aspects of the dysfunctional T cell phenotype we observed in the mouse including highly significant reductions in IL-2 production and altered membrane GPL to cholesterol ratios. Phosphatidic acid addition was not capable of rescuing these deficiencies suggesting that GPAT-1/GPAM activity is required for proper T cell function. This was the first time that GPAT-1 activity has been shown to be important for T cell function in a non-murine model system and strongly suggests that GPAT-1/GPAM deficiency regulates T cell function at the cellular level. We further demonstrate that phosphorylation of ZAP-70 a proximal effector of T cell activation is significantly reduced in GPAM knock down Jurkat T cells, suggesting that membrane based signaling is dysfunctional. Taken together these data suggest that GPAT-1 is necessary for regulating cellular energy demands in T cells and essential for optimal T cell activation following stimulation.Item Transgenerational transfer of dietary lipids and its consequences for offspring physiology in a marine teleost(2021-08-10) Hou, Zhenxin; Fuiman, Lee A.; Esbaugh, Andrew J.; Thomas, Peter; Tiziani, StefanoMaternal provisioning of nutrients can play a key role in the growth, development and long-term fitness of offspring. In teleosts, the composition of maternally derived nutrients (in yolk and oil) depends partly on maternal diet. This dissertation investigates the process of maternal-offspring nutrient transfer and the transgenerational effects of maternal nutrition on offspring physiology in a marine teleost, red drum (Sciaenops ocellatus). Results of 21 diet-shift experiments, from which the fatty acid profiles of the diets and eggs were compared, showed that 15 fatty acids in eggs were correlated with their levels in the recent diet, and the rate of incorporation of fatty acids into eggs was proportional to the magnitude of the diet shift. Further assessment revealed that maternal diet affected egg triglyceride (TG) content but not other lipid classes. Parental dietary variations rapidly affected the fatty acid composition of all major lipid classes in eggs (TG, wax ester/steryl ester (WE/SE), and phosphatidylcholine (PC)), with greater effects on neutral lipids (TG, WE/SE) than on the polar lipid (PC). Rates at which embryos and larvae utilized 15 fatty acids varied with maternal diet and were proportional to their initial concentrations in eggs. Rates of utilization of the oil globule were also affected by maternal diet, resulting in differences in oil globule size at the first feeding stage. Effects of different maternal diets on larval fatty acid compositions persisted at the time of onset of exogenous feeding and afterward. In addition, prolonged effects of maternal nutrition on larval lipid metabolism (nutritional programming) were documented. At 21 days post-hatching (dph), larvae reared under common conditions from eggs produced by adults on different diets showed differences in total fatty acid accumulation and fatty acid profiles (especially polyunsaturated fatty acids in TG). Collectively, these research findings demonstrate some of the profound transgenerational effects of maternal nutrition on offspring physiology. The altered lipid metabolism of offspring resulting from variations in parental diet may have consequences for larval physiological processes and behavioral performance, which may ultimately influence their survival and fitness