We are examining whole body and organ metabolism in humans using stable isotopic tracers and mass spectrometry.Animal models are used to answer certain key questions and complement human studies. Sulfur amino acid metabolism in non alcoholic fatty liver disease (NAFLD). Hepatic steatosis results in altered microsomal metabolism, lipid peroxidation,increased reactive oxygen species(ROS),and a decrease in ATP. We hypothesize that lower ATP and methionine adenosyl transferase activity caused by ROS, results in decreased rate of production of SAM, glutathione and methionine transsulfuration.These hypotheses are being examined in a patients with NAFLD. Triglyceride fatty acid cycling and glyceroneogenesis: Since adipose tissue cannot utilize glycerol due to lack of glycerokinase activity, the glycerol-3-phosphate required for triglyceride synthesis has to be generated either from glucose or from pyruvate. The production of glycerol-3-phosphate from pyruvate, or glyceroneogenesis, appears to be the major pathway in-vivo regulted by cytosolic phosphoenolpyruvate carboxykinase (PEPCK).We are examining the regulation of glyceroneogenesis in humans and in transgenic animals. Computational models for in-vivo metabolism. We are relating cellular metabolic processes to tissue/organ and whole body physiological responses through mechanistic, quantitative and predictive computational models.A model for the whole body metabolism with incorporation of adipose tissue responses is being developed. Model simulations are compared with experimentally observed data.
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