EPA AND HEPATIC SYNTHESIS AND SECRETION OF THE VLDL

我们建议调查的机制， 二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）的作用 降低甘油三酯（TG）的血浆浓度， 胆固醇（C）。 我们解决这个问题的方法是研究 脂肪酸的形成和分泌 极低密度脂蛋白（VLDL），其与 胆固醇生成，以及omega-3-多不饱和脂肪酸的影响 脂肪酸在这些过程中。 实验将在 使用大鼠作为实验动物的体外模型系统， 但将与补充的体内研究相关联。 使用 从正常饲料喂养的大鼠获得的离体灌注肝脏，我们 将评估EPA和DHA的摄取，TG的输出， 氧化速率，与其他脂肪酸相比。 总 （U-14 C）EPA和DHA在代谢途径中的分布 将被确定。 EPA和DHA可能 改变哺乳动物脂肪肝的肝脏代谢 酸将被研究。 EPA/DHA对玉米产量的影响 VLDL脂质，VLDL的脂质和载脂蛋白组成， VLDL载脂蛋白的合成和分泌， VLDL在带状超离心中的表征将是 在上述条件下详细研究。 由于胖子 酸刺激肝分泌和C的从头合成， 将研究EPA和DHA对这些参数的影响。 此外，EPA/DHA对坐标的影响 脂肪酸对胆固醇生成酶（HMG- CoA还原酶、HMG-CoA合酶、AcAc CoA硫解酶）将被酶解。 研究，因为将任何内在的活性的ω-3-脂肪酸 acids. 还将在获得的肝脏中评价这些参数 从饮食中EPA含量高的动物， 添加猪油或橄榄油。 此外，我们将 将这些饮食研究与肝脏 VLDL在体内的分泌。 作为我们初步研究的补充 通过灌注的肝脏，我们将评估脂肪酸代谢， 重点是甘油三酯的合成，通过分离 肝细胞和微粒体制备物。 这些比较 实验将帮助我们评估EPA/DHA作为 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。 的 欧米茄-3-不饱和脂肪酸的特殊效果，以降低 血浆TG和C，这些明显的临床相关性 观察结果，以及它们通过调节作用的可能性 VLDL合成和分泌的基础上形成的这一建议。

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.