ALTERNATE PATHWAYS OF FATTY ACID OXIDATION

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Current thinking ascribes a major role for elevated lipids in many of the major health problems in modern industrial civilizations. Our Institute is especially concerned with the metabolic derangements caused by diabetes, and it is becoming increasingly clear that the disordered carbohydrate metabolism of Type II diabetics may result to no small degree from the elevated lipids found in these patients. Control of lipid levels, through diet, exercise, drugs or hormones, in turn can help to ameliorate the disorders of carbohydrate metabolism. This project is concerned with pathways of fatty acid oxidation, which process helps to lower circulating lipid levels. While the pathway of mitochondrial beta oxidation has long been established, it has more recently been found that another organelle, the peroxisome, plays a role in the oxidation of fatty acids. We intend to quantitatively measure the relative contributions of the peroxisomes and the mitochondria to overall fatty acid oxidation, especially in the liver and kidney. There is presently a good deal of controversy about the peroxisomal contribution to the oxidation of the major circulating fatty acids, such as palmitate and oleate. We will also quantitate another alternate pathway of fatty acid oxidation, omega oxidation, in which dicarboxylic acids are generated. Omega oxidation has usually been considered to be quite a minor pathway, but the marked dicarboxylic acid accumulation in certain genetic disorders and in Reye's syndrome suggests that it may have been underestimated in previous work. Our approach involves the synthesis and application of a large number of tritium and 14C labelled compounds, including fatty acids, with measurement of the metabolic pathways using complex steady state models. We especially will look at the effect of drugs like clofibrate which induce peroxisomal fatty acid oxidizing enzymes, in an attempt to see how the increased peroxisomal metabolism may contribute to their hypolipidemic actions.