EPA AND HEPATIC SYNTHESIS AND SECRETION OF THE VLDL

我们建议调查这些机制 二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)的作用 降低血浆甘油三酯(TG)和 胆固醇(C)。我们解决这个问题的方法将是研究 肝脏脂肪酸的代谢，脂肪酸的形成和分泌 极低密度脂蛋白(VLDL)及其与 胆固醇生成及omega-3-多不饱和脂肪酸的作用 这些过程中的脂肪酸。实验将在#年进行。 以大鼠为实验动物的体外模型系统， 但将与补充的活体研究相关。vbl.使用 取自正常饲料喂养的大鼠的离体灌流肝。 将评估EPA和DHA的吸收，TG的输出，以及 氧化速度，与其他脂肪酸相比。总数 (U-14C)EPA和DHA在代谢途径中的分配 将会被确定。EPA和DHA可能会 改变常见哺乳动物脂肪的肝脏代谢 将对酸类进行调查。EPA/DHA对黄瓜产量的影响 极低密度脂蛋白，极低密度脂蛋白的脂类和载脂蛋白组成， 极低密度脂蛋白的合成和分泌，以及 带状超速离心机中极低密度脂蛋白的特征将是 在上述条件下进行了详细研究。既然是胖子 酸刺激肝脏分泌和C的从头合成 将研究EPA和DHA对这些参数的影响。 此外，EPA/DHA对配位的影响 脂肪酸对胆固醇生成酶(HMG-)的刺激作用 CoA还原酶、HMG-CoA合成酶、acac CoA硫解酶)将 研究，以及omega-3-脂肪的任何内在活性 酸。这些参数也将在获得的肝脏中进行评估 来自动物的高EPA饲料，与饲料相比 辅以猪油或橄榄油。此外，我们还将 将这些饮食研究与肝脏的评估联系起来 体内极低密度脂蛋白的分泌。作为我们主要研究的辅助工具 随着肝脏的灌注，我们将评估脂肪酸代谢， 重点研究了甘油三酯的合成，通过分离 肝细胞和微粒体制剂。这些比较 实验将帮助我们评估EPA/DHA的有效性 TG合成的底物，以及推定的竞争性 其他常见脂肪酸底物的抑制剂。这个 欧米茄-3-不饱和脂肪酸的特殊降血脂作用 血浆甘油三酯和C水平与临床的明显相关性 观察结果，以及他们通过监管采取行动的可能性 极低密度脂蛋白的合成和分泌构成了这一提议的基础。

We propose to investigate the mechanisms by which eicosopentaenoic acid (EPA) and docosohexaenoic acid (DHA) act to reduce plasma concentrations of triglyceride (TG) and cholesterol (C). Our approach to the problem will be to study the hepatic metabolism of fatty acids, the formation and secretion of the very low density lipoprotein (VLDL), its relationship to cholesterogenesis, and the effects of omega-3-polyunsaturated fatty acids on these processes. Experiments will be carried out in model systems in vitro using the rat as an experimental animal, but will be correlated with complementary in vivo studies. Using isolated perfused livers obtained from normal chow fed rats, we will evaluate the uptake of EPA and DHA, the output of TG, and rates of oxidation, compared to other fatty acids. The total disposition of (U-14C)EPA and DHA among metabolic pathways will be determined. The possibility that EPA and DHA might alter the hepatic metabolism of the common mammalian fatty acids will be investigated. The effects of EPA/DHA on output of VLDL lipids, the lipid and apoprotein composition of the VLDL, the synthesis and secretion of VLDL apoproteins, and the characterization of the VLDL in the zonal ultracentrifuge will be studied in detail under conditions described above. Since fatty acids stimulate hepatic secretion and denovo synthesis of C, the effects of EPA and DHA on these parameters will be investigated. Furthermore, the effects of EPA/DHA on the coordinate stimulation by fatty acids of enzymes of cholesterogenesis (HMG- CoA reductase, HMG-CoA synthase, AcAc CoA thiolase) will be investigated, as will any intrinsic activity of the omega-3-fatty acids. These parameters will also be evaluated in livers obtained from animals on diets high in EPA, compared with diets supplemented with lard or olive oil. Furthermore, we will correlate these dietary studies with estimation of hepatic secretion of VLDL in vivo. As adjuncts to our primary studies with the perfused liver, we will evaluate fatty acid metabolism, with emphasis on synthesis of triglyceride, by isolated hepatocytes and microsomal preparations. These comparative experiments will help us evaluate the efficacy of EPA/DHA as substrates for TG synthesis, as well as putative competitive inhibitors of other common fatty acid substrates. The extraordinary effects of omega-3-unsaturated fatty acids to lower plasma TG and C, the obvious clinical relevance of these observations, and the probability that they act through regulation of VLDL synthesis and secretion form the basis of this proposal.