ALTERNATE PATHWAYS OF FATTY ACID OXIDATION

目前的观点认为，血脂升高在许多癌症中起着重要作用。 现代工业文明的主要健康问题。我们的研究所是 特别关注糖尿病引起的代谢紊乱， 越来越清楚的是， II型糖尿病患者的代谢可能在不小程度上来自于 在这些患者中发现的高脂血症。控制血脂水平，通过 饮食、锻炼、药物或激素，反过来又有助于改善 碳水化合物代谢紊乱。 该项目涉及脂肪酸氧化的途径， 这一过程有助于降低循环脂质水平。虽然这条路 线粒体β氧化早已建立，它有更多的 最近发现，另一种细胞器，过氧化物酶体，发挥作用， 在脂肪酸的氧化中。我们打算定量测量 过氧化物酶体和线粒体的相对贡献， 脂肪酸氧化，特别是在肝脏和肾脏。有 目前，关于过氧化物酶体对 主要循环脂肪酸如棕榈酸和 油酸盐。我们还将定量脂肪酸的另一种替代途径 氧化，ω氧化，其中产生二羧酸。 欧米茄氧化通常被认为是一个很小的途径， 但在某些遗传疾病中， 在雷氏综合征中， 以前的工作。 我们的方法涉及大量的合成和应用， 氚和14C标记的化合物，包括脂肪酸， 使用复杂稳态模型测量代谢途径。 我们将特别关注像氯贝丁酯这样的药物的作用， 诱导过氧化物酶体脂肪酸氧化酶，试图了解如何 过氧化物酶体代谢的增加可能有助于他们的降血脂 行动

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.