ALTERNATE PATHWAYS OF FATTY ACID OXIDATION

目前的想法认为，高血脂在许多疾病中起着重要作用 现代工业文明中的主要健康问题。我们的研究所是 尤其关注糖尿病引起的新陈代谢紊乱， 越来越清楚的是，无序的碳水化合物 II型糖尿病患者的代谢可能在不小程度上是由 在这些患者中发现血脂升高。控制血脂水平，通过 饮食、锻炼、药物或荷尔蒙，反过来可以帮助改善 碳水化合物代谢紊乱。 这个项目涉及脂肪酸氧化的途径，它 这一过程有助于降低循环中的血脂水平。而在这个过程中 线粒体β氧化很早就被确立了，它有更多 最近发现，另一种细胞器--过氧化物酶体--在 在脂肪酸的氧化中。我们打算定量地衡量 过氧酶体和线粒体对总体的相对贡献 脂肪酸氧化，尤指肝脏和肾脏。的确有 目前，关于过氧酶体对 主要循环脂肪酸的氧化，如棕榈酸酯和 油酸盐。我们还将量化脂肪酸的另一种替代途径。 氧化，欧米伽氧化，在氧化过程中生成二元酸。 欧米伽氧化通常被认为是一个相当次要的途径， 但在某些遗传性疾病中显著的二元酸积聚 而在雷耶氏综合征中，它可能在 以前的工作。 我们的方法涉及到大量的合成和应用 氚和14C标记化合物，包括脂肪酸，具有 使用复杂的稳态模型测量代谢途径。 我们将特别观察像氯贝特这样的药物的效果 诱导过氧体脂肪酸氧化酶，试图了解 过氧化体代谢增强可能与其低脂血症有关。 行为。

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.