HEPATIC FATTY ACID OXIDATION AND CARNITINE METABOLISM

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Project III: Hepatic Fatty Acid Oxidation and Carnitine Metabolism The long-term goals of this project are to determine the site(s) of defect in hepatic fatty acid oxidation in patients who present as Reye's syndrome on either an acquired or a genetic basis and to define the relationship of this defect to the clinical manifestations of the disorder. To accomplish these goals, the present project will examine the metabolic consequences of defects in fatty acid oxidation on the generation of abnormal patterns of plasma fatty acids and alterations in carnitine intermediates. Aim 1 is to identify and quantify urinary acyl-carnitine esters in patients with defects in fatty acid oxidation using high performance liquid chromatography. Aim 2 is to characterize the effects of enzymatic defects in fatty acid oxidation on carnitine content, acyl-carnitine production, and carnitine uptake and efflux in cultured fibroblasts grown in the presence fatty acid substrates. Aim 3 is to measure plasma medium- and long-chain mono- and dicarboxylic acids in patients with Reye's syndrome and other known and suspected defects in fatty acid oxidation. Aim 4 is to determine the origin of abnormalities in circullating fatty acid metabolites associated with defects in fatty acid oxidation using animal models treated with various inhibitors of the pathway. These studies will improve our ability to distinguish defects in fatty acid oxidation using clinical methods prior to assay of specific enzymes in-vitro and to understand the pathogenesis of these diseases.