EPA AND HEPATIC SYNTHESIS AND SECRETION OF THE VLDL

EPA 与肝脏 VLDL 的合成和分泌

• 批准号: 3355924
• 负责人: MURRAY HEIMBERG
• 金额: $ 11.08万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3355924
• 关键词: HMG coA reductases; antihyperlipoproteinemic agent; antiserum; apolipoproteins; blood lipid; blood lipoprotein biosynthesis; cholesterol; density gradient ultracentrifugation; diet therapy; dietary lipid; electrofocusing; enzyme mechanism; esterification; fatty acid metabolism; gas chromatography; gel electrophoresis; immunoprecipitation; ketones; laboratory rabbit; laboratory rat; lipid biosynthesis; liver cells; liver metabolism; microsomes; nutrition related tag; oleate; omega 3 fatty acid; oxidation; palmitates; perfusion; radioimmunoassay; radiotracer; saturated fatty acids; scintillation spectrometry; steroid biosynthesis; thin layer chromatography; triglycerides; vegetable oils; very low density lipoprotein

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.

我们建议调查其机制 二十碳五烯酸 (EPA) 和二十二碳六烯酸 (DHA) 作用 降低血浆甘油三酯 (TG) 浓度和 胆固醇（C）。 我们解决这个问题的方法是研究 脂肪酸的肝脏代谢、脂肪酸的形成和分泌 极低密度脂蛋白（VLDL），其与 胆固醇生成和 omega-3-多不饱和脂肪酸的影响 脂肪酸对这些过程的影响。 实验将在 使用大鼠作为实验动物进行体外模型系统， 但将与补充体内研究相关。 使用 从正常饲料喂养的大鼠中获得分离的灌注肝脏，我们 将评估 EPA 和 DHA 的吸收、TG 的输出以及 与其他脂肪酸相比，氧化速率。 总计 (U-14C)EPA 和 DHA 在代谢途径中的分布 将被确定。 EPA 和 DHA 可能 改变常见哺乳动物脂肪的肝脏代谢 酸将被研究。 EPA/DHA 对产量的影响 VLDL脂质，VLDL的脂质和脱辅基蛋白组成， VLDL 脱辅基蛋白的合成和分泌，以及 区带超速离心机中 VLDL 的表征将是 在上述条件下进行了详细研究。 既然胖了 酸刺激肝脏分泌和C的重新合成， 将研究 EPA 和 DHA 对这些参数的影响。 此外，EPA/DHA 对协调的影响 脂肪酸刺激胆固醇生成酶（HMG- CoA 还原酶、HMG-CoA 合酶、AcAc CoA 硫解酶） 研究了 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 与饮食相比，来自饮食中富含 EPA 的动物 补充猪油或橄榄油。 此外，我们将 将这些饮食研究与肝脏的估计相关联 体内VLDL的分泌。 作为我们初级研究的辅助手段 通过灌注的肝脏，我们将评估脂肪酸代谢， 重点是通过分离来合成甘油三酯 肝细胞和微粒体制剂。 这些比较 实验将帮助我们评估 EPA/DHA 的功效 TG 合成的底物，以及假定的竞争性底物 其他常见脂肪酸底物的抑制剂。 这 omega-3 不饱和脂肪酸对降低 血浆 TG 和 C，这些明显的临床相关性 观察结果，以及它们通过监管采取行动的概率 VLDL 合成和分泌的研究构成了该提案的基础。