Oxidized Linoleic Acid, Aldosterone, and Obesity

氧化亚油酸、醛固酮和肥胖

• 批准号: 7062122
• 负责人: THEODORE L GOODFRIEND
• 金额: $ 28.04万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-05 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7062122
• 关键词: African American; adipose tissue; aldosterone; antioxidants; blood chemistry; blood pressure; cardiovascular disorder risk; caucasian American; clinical research; dietary lipid; dietary sodium; fatty acid metabolism; hormone biosynthesis; hormone regulation /control mechanism; human subject; hypertension; laboratory rat; linoleate; liquid chromatography mass spectrometry; liver cells; obesity; potassium; racial /ethnic difference; radioimmunoassay; renin; urinalysis

DESCRIPTION (provided by applicant): Linoleic acid is the most abundant polyunsaturated fatty acid in human adipose tissue, and it is readily oxidized by the liver and other organs. The applicant found that one oxidized derivative, 12,13-epoxy-9-keto-10-trans-octadecenoic acid, ("EKODE"), stimulates production of aldosterone by rat adrenal cells. EKODE circulates in mammalian blood, and plasma levels correlated with levels of aldosterone in 24 human subjects. In 12 African Americans in that cohort, EKODE levels also correlated with body mass index and systolic blood pressure. These observations suggest the hypothesis that EKODE is produced in the liver from linoleic acid, EKODE stimulates aldosterone secretion, and aldosterone and contributes to the hypertension and other sequelae of obesity. This pathogenesis may be particularly important in African Americans. Because its biosynthesis involves free radicals and oxygen, EKODE may be a product and hallmark of oxidative stress. The proposed experiments explore the relevance of EKODE in the regulation of aldosterone and blood pressure. The hypothesis will be addressed in three ways: by testing associations of EKODE with aldosterone and blood pressure in humans; by administering EKODE to animals and measuring their production of aldosterone and their blood pressure; and by devising ways to impair EKODE production. Two groups of 60 humans will be studied, both groups comprised of equal numbers of African Americans and Caucasians, males and females. Several measurements of body fat and blood pressure will be made, and blood and urine samples collected. All subjects will be studied while consuming carefully controlled diets. Measurements and sample collections will be done in clinical research units. Aldosterone and renin will be measured by radioimmunoassays, and EKODE by LC/MS. Statistical tests will be applied to see if EKODE levels correlate with aldosterone, obesity parameters, and/or blood pressure. One cohort will consume diets high and low in antioxidants to see if levels of EKODE, aldosterone, and blood pressure change together. EKODE will be administered to rats for two weeks by implanted osmotic minipumps. Urinary aldosterone will be measured. In rats receiving the optimum dose of EKODE, blood pressure will be measured by intraarterial catheterization. To identify non-toxic inhibitors of EKODE production, compounds will be screened in rat hepatocytes that convert labeled linoleic acid to EKODE. The proposed research is designed to explore the properties and relevance of the newly identified linoleic acid derivative EKODE with particular attention to aldosterone secretion and blood pressure. If dietary antioxidants reduce EKODE levels, or if non-toxic inhibitors of EKODE production are identified, it will be possible to test directly the role of EKODE in the hypertension of obesity and in other situations where aldosterone and oxidative stress are implicated.

描述（由申请人提供）：亚油酸是人脂肪组织中最丰富的多不饱和脂肪酸，它很容易被肝脏和其他器官氧化。申请人发现，一个氧化的衍生物，12,13-蛋白-9-酮-10--10- trans-octadecenoic Acid（“ Ekode”），刺激大鼠肾上腺细胞刺激醛固酮的产生。 Ekode在哺乳动物血液中循环，血浆水平与24受试者的醛固酮水平相关。在该队列中的12名非裔美国人中，Ekode水平也与体重指数和收缩压相关。这些观察结果表明，ekode是通过亚油酸在肝脏中产生的，Ekode刺激醛固酮的分泌和醛固酮，并有助于肥胖的高血压和其他后遗症。这种发病机理在非裔美国人中可能尤其重要。由于其生物合成涉及自由基和氧气，因此Ekode可能是氧化应激的产物和标志。 提出的实验探讨了Ekode在醛固酮和血压调节中的相关性。该假设将通过三种方式解决：通过测试Ekode与醛固酮和人类血压的关联；通过对动物进行Ekode并测量其醛固酮的产生及其血压；并设计方法来损害Ekode的生产。将研究两组60人，这两组由相等数量的非洲裔美国人和高加索人，男性和女性组成。将对体内脂肪和血压进行几种测量，并收集血液和尿液样本。所有受试者将在消费精心控制的饮食时进行研究。测量和样本收集将在临床研究单元中进行。醛固酮和肾素将通过放射免疫测定法和LC/MS测量Ekode。统计检验将用于查看Ekode水平是否与醛固酮，肥胖参数和/或血压相关。一个队列将消耗抗氧化剂高和低的饮食，以查看Ekode，醛固酮和血压的水平是否一起改变。 Ekode将通过植入的渗透微型植物对大鼠进行两周的施用。将测量尿醛固酮。在接受Ekode最佳剂量的大鼠中，血压将通过囊内导管插入术来测量。为了鉴定Ekode产生的无毒抑制剂，将在大鼠肝细胞中筛选化合物，以将标记的亚油酸转换为Ekode。 拟议的研究旨在探讨新确定的亚油酸衍生物Ekode的特性和相关性，并特别注意醛固酮分泌和血压。如果饮食抗氧化剂降低Ekode水平，或者确定了Ekode产生的无毒抑制剂，则可以直接测试Ekode在肥胖症高血压中的作用，以及在其他情况下，与醛固酮和氧化应激有关。