MECHANISMS OF ACTIONS OF ALCOHOL AND OMEGA3 FATTY ACIDS

酒精和 OMEGA3 脂肪酸的作用机制

• 批准号: 2748427
• 负责人: RAJ M LAKSHMAN
• 金额: $ 13.6万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-12-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2748427
• 关键词: alcoholism /alcohol abuse; apolipoprotein E; apolipoproteins; blood lipoprotein metabolism; chylomicrons; dietary lipid; enzyme activity; fatty acid biosynthesis; fatty liver; gel electrophoresis; high density lipoproteins; human subject; hyperlipidemia; ion exchange chromatography; laboratory rat; lipid metabolism; messenger RNA; nutrition related tag; omega 3 fatty acid; posttranslational modifications; sialyltransferases; toxicology; triglycerides; very low density lipoprotein

APPLICANT'S ABSTRACT: Plasma apolipoprotein E (apoE) is a glycoprotein which plays important roles in "Reverse Cholesterol Transport" (RCT) functions of HDL, viz., (i) cholesterol removal from peripheral tissues and/or (ii) its delivery to the liver. Significantly, ethanol decreased plasma HDL apoE, whereas omega3-fatty acids prevented this decrease. Our preliminary work shows that plasma HDL apoE is also reduced in human alcoholics. We have further shown that chronic ethanol inhibits hepatic sialation of apoE. Sialic acid deficiency in apoE may affect its association with HDL. In turn, the loss of apoE from HDL may impair its RCT functions. Therefore, it is important to confirm whether apoE concentration in HDL and sialic acid content of apoE are reduced in alcoholics and then show how these changes affect HDL metabolism and functions. 90% of the study will utilize humans and only the remainder will use rats:Human Study: ApoE and HDL will be from sera of human alcoholics and non-alcoholics and non-alcoholics. The specific questions are: Does the degree of sialic acid deficiency in apoE affect (I) the association of apoE with HDL and (II) dissociation of apoE from HDL & association of HDL- apoE with cholesterol. III. does the loss of apoE from HDL affect its ability to remove cholesterol from peripheral tissues? Do human alcoholics compared to non-alcoholics have decreased: IV. concentration of apoE in HDL? V. sialic acid content of HDL-apoE? VI. HDL ability to remove cholesterol from the peripheral tissues using human macrophages?VII. HDL ability to deliver cholesterol to liver using the human HepG2 liver cells?Rat Study: If apoE sialation is crucial in the above important aspects of HDL it is equally important to determine the post-translational modifications of apoE in the liver. This can only be done in experimental animals like rats.Similarly, if omega3- fatty acids do correct the above defects caused by ethanol it is simpler and less time consuming to test their effects on HDL-apoE functions in rats than in humans. Thus, the questions asked are what are the influences of ethanol and omega3-fatty acids on: VIII. the posttranslational modifications of apoE at the subcellular level? IX. the mechanism of inhibition of hepatic sialyltransferase activity? Specifically, does ethanol inhibit the synthesis of sialyltransferase and by down regulation of its hepatic mRNA levels?

申请人的摘要：血浆载脂蛋白E（APOE）是糖蛋白 在“反向胆固醇运输”（RCT）中起着重要作用 HDL的功能，即（i）从外周组织中去除胆固醇的功能 和/或（ii）将其传递到肝脏。 值得注意的是，乙醇减少 等离子体HDL APOE，而Omega3-Fatty酸阻止了这种减少。 我们的初步工作表明，血浆HDL APOE也减少了人类 酗酒者。 我们进一步表明，慢性乙醇抑制了肝 apoe的唾液。 ApoE中的唾液酸缺乏可能会影响其 与HDL的关联。 反过，HDL失去APOE可能会损害其 RCT功能。 因此，重要的是要确认APOE是否 HDL中的浓度和APOE的唾液酸含量降低 酗酒者，然后展示这些变化如何影响HDL代谢和 功能。 90％的研究将利用人类，只有其余的 将使用老鼠：人类研究：APOE和HDL将来自人类的血清 酒精中毒，非酒精和非酒精饮料。 具体问题 是：apoE中的唾液酸缺乏程度会影响（i） APOE与HDL的关联和（ii）APOE从HDL＆解离 HDL-APOE与胆固醇的关联。 iii。失去了apoe吗 来自HDL会影响其从外围去除胆固醇的能力 组织？ 与非酒精饮料相比，人类酗酒者是否有所减少： iv。 HDL中APOE的浓度？ V. HDL-APOE的唾液酸含量？ vi。 HDL能够使用外周组织去除胆固醇 人类巨噬细胞？vii。 HDL能够使用胆固醇向肝脏输送胆固醇 人hepg2肝细胞？大鼠研究：如果apoe唾液在 HDL的上述重要方面，确定同样重要 肝脏中APOE的翻译后修饰。 这可以 仅在实验动物（例如大鼠）中完成。 脂肪酸确实纠正了乙醇引起的上述缺陷，这更简单 更少的时间来测试其对HDL-APOE功能的影响 老鼠比人类。 因此，问的问题是 乙醇和omega3脂肪酸的影响：VIII。 这 亚细胞水平的APOE的翻译后修饰？ ix。 抑制肝转移酶活性的机制？ 具体而言，乙醇是否抑制乙醇的合成 并通过调节其肝mRNA水平？