Nutritional Effects On Essential Fatty Acid Composition

营养对必需脂肪酸组成的影响

基本信息

批准号：
7732109
负责人：
Joseph Hibbeln
金额：
$ 84.66万
依托单位：
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7732109
关键词：
7 year old Adopted Adult Aging Alcohol abuse Alcohol consumption Alcohol-Related Neurodevelopmental Disorder Animal Feed Animals Anxiety Arachidonic Acids Be++ element Behavioral Beryllium Biological Assay Biological Availability Biological Process Bottle feeding Brain Carbon Clinical Research Collaborations Condition Cues Custom Daily Data Development Diet Diet Habits Dietary Alcohol Dietary Supplementation Dietary intake Disease model Docosahexaenoate Docosahexaenoic Acids Dose Erythrocytes Essential Fatty Acids Esters Fatty Acids Female Fetal Alcohol Syndrome Folate Food Selections Head Health Benefit Individual Infant Intake Isotopes Lead Life Light Measures Memory Mercury Metabolism Milk Modeling Mothers Motor Activity Mus National Health and Nutrition Examination Survey Nervous System Physiology Nervous system structure Neurophysiology - biologic function Neurotoxins Newborn Infant Noise Nutrient Nutritional Nutritional Study Omega-3 Fatty Acids Oral Organ Pathology Physiological Placenta Plasma Polyunsaturated Fatty Acids Pregnancy Procedures Process Rate Rattus Relative (related person)Research Research Personnel Reversal Learning Risk Robotics Sampling Short-Term Memory Smoker Smoking Supplementation System Task Performances Techniques Testing Time Tissues Trace metal Umbilical cord structure Universities Unsaturated Fatty Acids Upper arm Venous Visit Vitamins Week Work alcoholism/alcohol abuse alpha-Linolenic Acid binge drinking body system cohort day density drinking fatty acid metabolism feeding fetal follow-up functional loss in vivo interest latent nuclear antigen male maternal cigarette smoking memory retention men metabolomics neurodevelopment non-smoker prenatal prepulse inhibition prevent problem drinker programs pup research study transmethylation

项目摘要

Our past studies as well as those of others have indicated that alcohol abuse leads to a loss of docosahexaenoate (DHA), the major polyunsaturate in the nervous system. Nutritional inadequacies, particularly during early development, may also lead to such losses in this essential fatty acid. In following up this work, it is important to establish what losses in physiological functions are caused by the loss of DHA in various organ systems. In a collaboration with several investigators at Wayne State University, the relationships of alcohol intake during pregnancy is related to the mother's and newborn infant's essential fatty acid and vitamin status. Dietary intake of DHA throughout the study was estimated at 68 mg/day and might not support optimal fetal DHA accretion and subsequent neural development. The proportion of drinking days at the first prenatal visit is associated with decreased DHA in plasma and erythrocytes throughout the study and is the strongest at 24 weeks of gestation. In daily drinkers, high intakes of alcohol are associated with decreased DHA and arachidonic acid (AA) concentrations in plasma. The present findings indicate that maternal DHA deficiency is associated with high risk for fetal alcohol syndrome and may contribute to the mechanism(s) of alcohol-related neurodevelopmental disorders. Maternal folate was positively correlated with alcohol intake per drinking day, while infant venous plasma folate was negatively correlated with maternal smoking. It appears that concentrative transport of folate across the placenta occurs during pregnancy that smoking may negatively impact. Essential fatty acid metabolism was studied in male and female adults, both smokers and non-smokers, as a reference point for smoking alcoholics. Metabolism of D5-18:2n-6 and D5-18:3n-3 was studied in vivo after a single oral dose of the isotope mixture. Our results indicated that female smokers had a two-fold greater percent of the dose in their plasma, and a higher fractional rate for formation of D5-22:6n-3 from D5-22:5n-3 compared with non-smokers. Male smokers had elevated levels of total plasma n-3 fatty acids, more rapid turn over of 18:3n-3, a disappearance rate for D5-20:5n-3 that was both delayed and slower, and a greater percentage of D5-20:5n-3 that was directed towards D5-22:5n-3 formation relative to non-smokers. Smoking generally increased the bioavailability of plasma n-3 fatty acids, accelerated fractional synthetic rates, and increased the percent formation of some long chain n-3 polyunsaturated fatty acids. The relationship of dietary alcohol and essential fatty acid intakes were studied in 4168 adults taken from the cross-sectional National Health and Nutrition Examination Survey 2001-2002. Our results indicated that among men, decreased nutrient densities of saturated, monounsaturated, polyunsaturated, linoleic and alpha-linolenic acid were associated with alcohol consumption. Binge drinking men had significantly decreased intakes of saturated, monounsaturated, polyunsaturated and linoleic, alpha-linolenic, eicosapentaenoic and docosahexaenoic acids. Thus it appears that drinking alcohol lowers highly unsaturated fatty acids in tissues thru altered fatty acid metabolism but also thru altered food selection and dietary habits. Great progress was made in the successful rearing of pups from the second day of life using feeding bottles developed by Prof. J. Hoshiba. Rats and mice were raised on n-3 supplemeented or deficient milks to adulthood and tested in several behavioral tasks. There was no difference in motor activity or in the plus maze but escape latency and memory retention were poorer in the n-3 deficient rats. This technique now makes possible many experiments where control of individual fatty acids or other nutrients in the diet and thus in tissue composition is required. In the first such application, a major expperiment was performed where DPAn6 was compared to DHA feeding for the first 10 weeks of life. It was shown that the DPAn6-fed rats had the same deficit in spatial task performance as did the LA-fed group, i.e., that DPAn6 conferred none of the benefit that adding DHA did. Mice were also raised on similar diets by artificial rearing and a 50% loss of brain DHA was observed at adulthood in the n-3 deficient group. In the open field test, habituation was slower and decreases in the general level of activity were observed in the n-3 deficient group. Under usual conditions, no differences could be seen in the plus maze between these dietary fgroups. However, under stressful conditions, when a bright light and a loud noise were given during the testing, the n-3 deficient group spent less time in the open arms and made fewer entries and had fewer head dips, indicating a higher level of anxiety. The low DHA mice also performed less well in another spatial task, the reference memory version of the Barnes maze, but there were no differences observed in either the cued or the working memory versions. These experiments have established that the nervous sytem has a requirement for the 22-carbon n-3 highly unsaturated fatty acids for optimal function. In another major line of research, a two generational model of DHA deficiency in rats was used in order to characterize the loss in nervous system function. A deficit in spatial task peformance was observed in n-3 deficient rats using the Barnes circular maze along with a 58% loss of brain DHA. No differnces were observed in memory retention for this task but the n-3 adequate rats perfomed better in a reversal learning task. There was no difference in locomotor activity but slower habituation was observed in the open field apparatus. No differences between groups were observed in the plus maze. This two generational dietary model has been employed to produce mice on four different diets varying LNA and DHA so that four different levels of brain DHA are obtained. At adulthood, the animals were tested for prepulse inhibition (PPI), a measure of neuromotor gating. It was observed that four different levels of PPI was obtained in the four dietary groups with the most PPI being obtained in those with the highest DHA level, ie., those fed preformed DHA. A significantly lower PPI was observed in animals fed a high level of LNA but without preformed DHA even though it resulted in only about a 10% loss of brain DHA. This was the first experiment where it could be shown that there was a brain functional loss in animals fed LNA but without preformed DHA. A methodological development has been completed facilitating lipidomic and metabolomic approaches has been made with regard to high throughput fatty acid analysis. Labor intensive transmethylation procedures were simplified and then adopted to robotics. A robotic program and procedures, together with custom hardware have been developed and validated for plasma samples that can potentially produce 400 methyl ester samples per day. GCs have been converted to fast GC mode and analyses can now be completed within about 15 minutes. A program has been developed to process GC data for peak assignment and quantification. Large clinical studies are currently underway with this system. Umbilical cord samples from 2,500 subjects in the ALSPAC longitudinal cohort will be assayed. Additionally, 4,500 samples from 7 year olds will be assayed. In this cohort, trace metal analyses for methyl mercury and other elements is progressing. The benificial levels of essential fatty acids will be compared to the risks of these neurotoxicants.

我们过去的研究以及其他人的研究表明，酗酒会导致二十二碳六烯酸 (DHA) 的损失，二十二碳六烯酸 (DHA) 是神经系统中主要的多不饱和脂肪酸。营养不足，特别是在早期发育期间，也可能导致这种必需脂肪酸的损失。在后续工作中，重要的是要确定不同器官系统中 DHA 的损失会导致哪些生理功能的损失。与韦恩州立大学的几位研究人员合作，怀孕期间的酒精摄入量与母亲和新生儿的必需脂肪酸和维生素状况有关。整个研究期间 DHA 的膳食摄入量估计为 68 毫克/天，可能不支持胎儿 DHA 的最佳积累和随后的神经发育。在整个研究过程中，第一次产前检查时饮酒天数的比例与血浆和红细胞中 DHA 的减少有关，并且在妊娠 24 周时最强。对于日常饮酒者来说，大量饮酒会导致血浆中 DHA 和花生四烯酸 (AA) 浓度降低。目前的研究结果表明，母亲 DHA 缺乏与胎儿酒精综合症的高风险相关，并可能导致酒精相关神经发育障碍的机制。母亲叶酸与每天饮酒量的酒精摄入量呈正相关，而婴儿静脉血浆叶酸与母亲吸烟呈负相关。叶酸在怀孕期间通过胎盘集中运输，吸烟可能会产生负面影响。研究了男性和女性成年人（吸烟者和非吸烟者）的必需脂肪酸代谢，作为吸烟酗酒者的参考点。在单次口服同位素混合物后，在体内研究了 D5-18:2n-6 和 D5-18:3n-3 的代谢。我们的结果表明，与非吸烟者相比，女性吸烟者血浆中的剂量百分比高出两倍，并且从 D5-22:5n-3 形成 D5-22:6n-3 的分数率更高。男性吸烟者的血浆总 n-3 脂肪酸水平升高，18:3n-3 的周转速度更快，D5-20:5n-3 的消失率既延迟又缓慢，并且 D5-20 的消失率更高。相对于非吸烟者而言，20:5n-3 旨在形成 D5-22:5n-3。吸烟通常会增加血浆 n-3 脂肪酸的生物利用度，加速部分合成速率，并增加某些长链 n-3 多不饱和脂肪酸的形成百分比。研究人员对 2001-2002 年国家健康和营养横断面调查中的 4168 名成年人进行了研究，研究了膳食酒精和必需脂肪酸摄入量的关系。我们的研究结果表明，在男性中，饱和、单不饱和、多不饱和、亚油酸和α-亚麻酸的营养密度降低与饮酒有关。酗酒的男性饱和、单不饱和、多不饱和和亚油酸、α-亚麻酸、二十碳五烯酸和二十二碳六烯酸的摄入量显着减少。因此，饮酒似乎可以通过改变脂肪酸代谢以及改变食物选择和饮食习惯来降低组织中的高度不饱和脂肪酸。使用 J. Hoshiba 教授开发的奶瓶，从出生第二天开始成功饲养幼崽，取得了巨大进展。大鼠和小鼠在添加或缺乏 n-3 的牛奶中长大直至成年，并进行多项行为任务测试。 n-3 缺陷大鼠的运动活动或十字迷宫没有差异，但逃避潜伏期和记忆保留较差。现在，这项技术使得许多实验成为可能，其中需要控制饮食中的单个脂肪酸或其他营养物质，从而控制组织成分。在第一个此类应用中，进行了一项主要实验，将 DPAn6 与 DHA 喂养在生命的前 10 周进行比较。结果表明，喂食 DPAn6 的大鼠与喂食 LA 的大鼠在空间任务表现方面存在相同的缺陷，即 DPAn6 没有带来添加 DHA 所带来的任何好处。小鼠也通过人工饲养以类似的饮食饲养，在 n-3 缺陷组中，成年后观察到大脑 DHA 损失 50%。在旷场测试中，n-3 缺陷组的适应速度较慢，总体活动水平下降。在通常情况下，这些饮食 f 组之间的十字迷宫没有差异。然而，在压力条件下，当测试过程中出现强光和大声噪音时，n-3缺陷组张开双臂的时间更少，进入的次数也更少，低头的次数也更少，这表明焦虑程度更高。低 DHA 小鼠在另一项空间任务（巴恩斯迷宫的参考记忆版本）中也表现较差，但在提示记忆版本或工作记忆版本中没有观察到差异。这些实验已经证实，神经系统需要 22 碳 n-3 高度不饱和脂肪酸才能发挥最佳功能。在另一项主要研究中，使用了大鼠 DHA 缺乏的两代模型来表征神经系统功能的丧失。使用 Barnes 圆形迷宫观察到 n-3 缺陷大鼠的空间任务表现存在缺陷，并且大脑 DHA 损失 58%。在这项任务的记忆保留方面没有观察到差异，但 n-3 只足够的大鼠在逆转学习任务中表现更好。运动活动没有差异，但在旷场仪器中观察到较慢的习惯化。在十字迷宫中没有观察到组间差异。这种两代饮食模型已被用来生产四种不同 LNA 和 DHA 不同饮食的小鼠，从而获得四种不同水平的大脑 DHA。成年后，对动物进行前脉冲抑制（PPI）测试，这是一种神经运动门控的测量方法。据观察，在四个饮食组中获得了四种不同水平的PPI，其中在DHA水平最高的组中获得最多的PPI，即那些喂食预制DHA的组。在喂食高水平 LNA 但不喂食预先形成的 DHA 的动物中，观察到 PPI 显着降低，尽管这仅导致大脑 DHA 损失约 10%。这是第一个实验表明，喂食 LNA 但未预先形成 DHA 的动物会出现脑功能丧失。方法学开发已经完成，促进了高通量脂肪酸分析方面的脂质组学和代谢组学方法。劳动密集型转甲基化程序被简化，然后采用机器人技术。已经针对血浆样品开发并验证了机器人程序和程序以及定制硬件，每天可以生产 400 个甲酯样品。 GC 已转换为快速 GC 模式，现在可以在大约 15 分钟内完成分析。已开发出一个程序来处理 GC 数据以进行峰分配和定量。目前正在对该系统进行大型临床研究。将对 ASPAC 纵向队列中 2,500 名受试者的脐带样本进行分析。此外，还将对 4,500 个 7 岁儿童的样本进行分析。在这个队列中，甲基汞和其他元素的痕量金属分析正在取得进展。必需脂肪酸的有益水平将与这些神经毒物的风险进行比较。

项目成果

期刊论文数量（51）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Validation of an equation predicting highly unsaturated fatty acid (HUFA) compositions of human blood fractions from dietary intakes of both HUFAs and their precursors.

验证从膳食摄入的 HUFA 及其前体中预测人类血液部分的高度不饱和脂肪酸 (HUFA) 组成的方程。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Strandjord, Sarah E;Lands, Bill;Hibbeln, Joseph R
通讯作者：
Hibbeln, Joseph R

An extraordinary degree of structural specificity is required in neural phospholipids for optimal brain function: n-6 docosapentaenoic acid substitution for docosahexaenoic acid leads to a loss in spatial task performance.

为了实现最佳的大脑功能，神经磷脂需要极高的结构特异性：用 n-6 二十二碳五烯酸替代二十二碳六烯酸会导致空间任务表现的损失。

DOI：
发表时间：
2005-11
期刊：
影响因子：
4.7
作者：
Lim, Sun;Hoshiba, Junji;Salem Jr, Norman
通讯作者：
Salem Jr, Norman

Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease.

单倍体不足并不是 STGD3 疾病杂合 Elovl4 敲除小鼠模型发病机制的关键机制。

DOI：
发表时间：
2006-08
期刊：
影响因子：
4.4
作者：
Raz;Ayyagari, Radha;Fariss, Robert N;Mandal, Md Nawajes A;Vasireddy, Vidyullatha;Majchrzak, Sharon;Webber, Andrea L;Bush, Ronald A;Salem Jr, Norman;Petrukhin, Konstantin;Sieving, Paul A
通讯作者：
Sieving, Paul A

Nutritional deprivation of alpha-linolenic acid decreases but does not abolish turnover and availability of unacylated docosahexaenoic acid and docosahexaenoyl-CoA in rat brain.

α-亚麻酸的营养缺乏会降低但不会消除大鼠脑中未酰化二十二碳六烯酸和二十二碳六烯酰辅酶A的周转和可用性。