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In this project we will continue to elucidate the factors that regulate fatty acid oxidation in human muscle. Our general hypothesis is that the rate of entry of fatty acids into the mitochondria determines the rate of fatty acid oxidation. The capacity for transport of fatty acid into the mitochondria is determined by the activity of the enzyme carnitine palmitoyltransferase 1 (CPT-I), and at any given activity of CPT-I, the availability of fatty acids within the cytoplasm will determine the actual rate of transport and thus oxidation. We therefore propose that the rate of muscle fatty acids oxidation is determined by both availability of fatty acids and by factors that control mitochondrial transport at the tissue level In this project we will investigate both aspects of fatty acid oxidation. We will use new tracer methodology to quantify for the first time the relative contributions of plasma free fatty acids (FFA), plasma VLDL-TG, and intramuscular TG to the intramuscular fatty acylcarnitine pool, and to fatty acid oxidation. We will use this methodology to investigate the following hypotheses: 1) The hydrolysis of intramuscular triglyceride (TG) is regulated independently of the availability of plasma FFA. 2) The uptake of plasma FFA by muscle is determined by the arterial concentration and is not affected by the intracellular fate of fatty acids. (Malonyl-CoA inhibits muscle CPT-I activity. 4) For any activity of CPT-I, fatty acid oxidation is a function of fatty acid availability and 5) Changes in intracellular fatty acid availability will have more effect on fatty acid oxidation when CPT-I activity is stimulated when it is low. We will use tracer infusion of stable isotopically labeled substrates and the A-V balance technique, coupled with muscle biopsies, to quantify intramuscular kinetics and oxidation of triglyceride, fatty acids and pyruvate. Kinetic parameters will be related to the measurement of factors thought to control CPT-I activity, including activities of AMP-activated protein kinase (AMPK), and acetyl-CoA carboxylase (ACC), and malonyl- CoA concentration.

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