The broad and long-term objective of the research proposed in this grant application is the investigation of the regulation of BCAA metabolism by dietary carbohydrate and lipid when catabolism of body protein is increased. An increase in body protein catabolism would be induced by administration of either clofibrate, cytokines (e.g., Tumor Necrosis Factor), or steroid hormone to rats. More specifically, the investigators plan to investigate the effect of dietary carbohydrate and fat on utilization of BCAA for protein synthesis and for oxidation and on release of BCAA following protein degradation. In particular, their studies will focus on oxidation of leucine and valine to various carbon fragments by whole body, intact liver and muscle, subcellular fractions of liver and muscle, such as mitochondria, cytosol, and peroxisomes. The mechanism of alteration of each step in oxidation will be investigated by the study of associated enzyme, including BCAA transaminase, BCKA dehydrogenase, BCKA dehydrogenase kinase, isovaleryl-CoA dehydrogenase, and 3-methylcrotonyl-CoA carboxylase, and 2-methyl branched chain acyl-Co dehydrogenase. In view of the importance of BCKA dehydrogenase in regulation of BCAA oxidation, these studies will focus on the activity of this enzyme. The activity of BCKA dehydrogenase is altered by phosphorylation-dephosphorylation of the enzyme protein. The investigators plan to investigate the influence of nutrition on this molecular mechanism of regulation of BCCA oxidation. Finally, the investigators plan to investigate a clinical application of the result of these studies in rats. The efficiency of the caloric composition, as determined in studies in rats, will be investigated for maintaining parameters of protein and BCAA metabolism after a major surgery in patients with gastrointestinal cancer. The results of these studies will provide new information on a) metabolism of BCAA which comprises 46% of daily requirement of essential amino acids and b) proper design of composition of calorie source for patients with protein catabolism.
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