Nutritional Effects On Essential Fatty Acid Composition

营养对必需脂肪酸组成的影响

• 批准号: 8344671
• 负责人: Joseph Hibbeln
• 金额: $ 79.07万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 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/8344671
• 关键词: 8 year old; Acids; Adopted; Adult; Aging; Alcohol abuse; Alcohol consumption; Alcoholism; Alleles; American Heart Association; Animals; Arachidonic Acids; Attenuated; Biological Availability; Biological Process; Brain; Breast; Breast Feeding; Carbon; Cessation of life; Child; Chronic Daily Headaches; Clinical Research; Clinical Trials; Coenzyme A; Complex; Consumption; Custom; Data; Data Set; Development; Diet; Diet Habits; Dietary Alcohol; Dietary Intervention; Dietary Supplementation; Dietary intake; Disease model; Docosahexaenoate; Docosahexaenoic Acids; Dose; Eicosapentaenoic Acid; Essential Fatty Acids; Esters; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Feeding Methods; Female; Food Selections; Genes; Genetic Polymorphism; Genotype; Headache; Health; Health Benefit; Heart; Human; Human Milk; Individual; Infant formula; Infusion procedures; Intake; Isotopes; Lead; Life; Linoleic Acids; Lipids; Liver; Meta-Analysis; Metabolism; Minor; Mothers; Mus; Myocardial Infarction; N-3 polyunsaturated fatty acid; National Health and Nutrition Examination Survey; Nervous system structure; Neurophysiology - biologic function; Nutrient; Nutritional; Nutritional Study; Obesity; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Oral; Organ; Outcome; Overweight; Pathology; Phospholipids; Physiological; Plasma; Polyunsaturated Fatty Acids; Procedures; Process; Production; Protocols documentation; Randomized Controlled Trials; Relative (related person); Reporting; Research; Risk; Risk Reduction; Robotics; Role; Sampling; Saturated Fatty Acids; Serum; Severities; Smoker; Smoking; Specificity; Sum; Supplementation; System; Tissues; Trans Fatty Acids; Triglycerides; Unsaturated Fatty Acids; Up-Regulation; Weight Gain; Woman; Work; alpha-Linolenic Acid; base; binge drinking; body system; density; desaturase; docosapentaenoic acid; fatty acid metabolism; feeding; genetic variant; in vivo; interest; kidney hypertrophy; lipid biosynthesis; male; men; metabolomics; non-smoker; offspring; prevent; problem drinker; programs; research study; statistics; text searching; transmethylation

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. 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 through altered fatty acid metabolism but also through altered food selection and dietary habits. In another major line of research, we evaluated the effects of lowering dietary intakes of the omega-6 fatty acid linoleic acid on elevating endogenous production of the long chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid. In a three generational experiment an equicaloric diet in which alpha-linolenic acid, the dietary precursor of n-3 polyunsaturated fatty acids, was substituted by linoleic acid. We found significantly increased body weight throughout life when compared with standard diet-fed mice. Adipogenesis observed in the low n-3 fatty acid mice was accompanied by a 6-fold upregulation of stearyl-coenzyme A desaturase 1 (Scd1), whose activity is correlated to plasma triglyceride levels. In total liver lipid and phospholipid extracts, the sum of n-3 fatty acids and the individual longer carbon chain acids, eicosapentaenoic acid (20:5n3), docosapentaenoic acid (22:5n3), and docosahexaenoic acid (22:6n3) were significantly decreased whereas arachidonic acid (20:4n6) was significantly increased. In addition, low n-3 fatty acid-fed mice had liver steatosis, heart, and kidney hypertrophy. Hence, reducing dietary alpha-linolenic acid, from 1.02 energy % to 0.16 energy % combined with raising linoleic acid intake resulted in obesity and had detrimental consequences on organ function. Lowering the omega-6 fatty acid is being evaluated in two human clinical trials. Among subjects with chronic daily headache, selective lowering of linoleic acid, and linoleic acid lowering in conjunction with elevating EPA and DHA intakes, reduced arachidonic acid in phospholipids and elevated EPA and DHA in serum. These changes caused a 50% reduction in headache severity and duration. A second human protocol has recently been approved to evaluate the effects of selective linoleate lowering on reducing adiposity among overweight women. The protocol will selectively lowe linoleate intake to approximately 1 en%. Elongation and desaturation of the omega-3 alpha linolenic acid (d5) to EPA and DHA will be quantified using steady state infusion and GC- MS/MS/MS quantification. The American Heart Association has specifically advised consumption of at least 5 to 10% of energy as omega-6 PUFAs substantially based on randomized controlled trials (RCTs) of mixed n-3/n-6 PUFAs and meta-analyses of their CHD outcomes. To better evaluate these studies we: 1) performed an extensive literature search and extracted detailed dietary and outcome data enabling a critical examination of all RCTs that increased PUFAs and reported relevant CHD outcomes; 2) determined if dietary interventions increased n-6 PUFAs specifically, or increased both n-3 and n-6 PUFAs (i.e. mixed n-3/n-6 PUFA diets); 3) compared mixed n-3/n-6 PUFA to n-6 specific PUFA diets on relevant CHD outcomes in meta-analyses; and 4) evaluated the potential confounding role of trans fatty acids in these trials. Omega-3 PUFA intakes were increased substantially in 4 of 8 datasets and the n-6 PUFA linoleic acid was raised with specificity in 4 datasets; n-3 and n-6 PUFAs replaced a combination of trans and saturated fatty acids in all 8 datasets. For non-fatal myocardial infarction (MI) + CHD death, the pooled risk reduction for mixed n-3/n-6 PUFA diets was 22% (RR=0.78 95%CI 0.65-0.93), compared to an increased risk of 13% for n-6 specific PUFA diets (RR=1.13 95%CI 0.84-1.53). Risk of non-fatal MI + CHD death was significantly higher in n-6 specific PUFA compared to mixed n-3/n-6 diets (Q-statistic=5.44, df =1, p=0.02). RCTs that substituted n-6 PUFAs for trans and saturated fatty acids without simultaneously increasing n-3 PUFAs produced an increase in risk of death that approached statistical significance (RR=1.16 95%CI 0.95-1.42). We found that advice to specifically increase n-6 PUFA intake, based on mixed n-3/n-6 RCT data, is likely to increase CHD risk. 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. Genetic variants in the FADS 1-2 gene complex are thought to influence the ability to desaturate 18 carbon fats, ALA and LA to their respective products AA,and EPA/DHA. A study by Caspi et al has suggested that rs174575 within the FADS2 gene moderates this effect so that children homozygous in the minor allele (GG genotype) have similar IQs irrespective of breast or feeding method. Breast milk contains preformed DHA where as infant formula did not. In our study of 5934 children aged 8 years, an interaction with this polymorphism was observed such that breastfed GG children performed better than their formula fed counterparts by an additional 5.8 points 1.4, 10.1 (interaction p 0.0091). Interaction results were attenuated by about 10% after adjustment for 7 factors.

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。 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。 在另一项主要研究中，我们评估了降低 omega-6 脂肪酸亚油酸的膳食摄入量对提高长链 omega-3 脂肪酸二十碳五烯酸和二十二碳六烯酸内源性产生的影响。 在一项三代实验中，采用等热量饮食，其中 α-亚麻酸（n-3 多不饱和脂肪酸的饮食前体）被亚油酸取代。 我们发现与标准饮食喂养的小鼠相比，其一生中体重显着增加。在低 n-3 脂肪酸小鼠中观察到的脂肪形成伴随着硬脂酰辅酶 A 去饱和酶 1 (Scd1) 的 6 倍上调，其活性与血浆甘油三酯水平相关。在总肝脂质和磷脂提取物中，n-3 脂肪酸和单个较长碳链酸、二十碳五烯酸 (20:5n3)、二十二碳五烯酸 (22:5n3) 和二十二碳六烯酸 (22:6n3) 的总和显着减少，而花生四烯酸 (20:4n6) 显着增加。此外，低n-3脂肪酸喂养的小鼠出现肝脏脂肪变性、心脏和肾脏肥大。因此，将膳食α-亚麻酸从1.02能量%减少到0.16能量%，同时增加亚油酸摄入量会导致肥胖，并对器官功能产生不利影响。 两项人体临床试验正在评估降低 omega-6 脂肪酸的效果。 在患有慢性日常头痛的受试者中，选择性降低亚油酸，以及降低亚油酸与增加 EPA 和 DHA 摄入量相结合，会导致磷脂中花生四烯酸减少，血清中 EPA 和 DHA 升高。 这些变化使头痛的严重程度和持续时间减少了 50%。 最近批准了第二个人类方案，用于评估选择性降低亚油酸对减少超重女性肥胖的影响。 该方案将选择性地将亚油酸摄入量降低至大约 1 en%。 omega-3 α 亚麻酸 (d5) 向 EPA 和 DHA 的伸长和去饱和将使用稳态输注和 GC-MS/MS/MS 定量进行定量。 美国心脏协会特别建议摄入至少 5% 至 10% 的 omega-6 PUFA 能量，主要基于混合 n-3/n-6 PUFA 的随机对照试验 (RCT) 及其 CHD 结局的荟萃分析。 为了更好地评估这些研究，我们：1）进行了广泛的文献检索并提取了详细的饮食和结果数据，从而能够对所有增加 PUFA 并报告相关 CHD 结果的随机对照试验进行严格检查； 2) 确定饮食干预是否专门增加 n-6 PUFA，或同时增加 n-3 和 n-6 PUFA（即混合 n-3/n-6 PUFA 饮食）； 3) 在荟萃分析中比较混合 n-3/n-6 PUFA 与 n-6 特定 PUFA 饮食对相关 CHD 结局的影响； 4) 评估了反式脂肪酸在这些试验中的潜在混杂作用。 8 个数据集中的 4 个数据集中，Omega-3 PUFA 摄入量大幅增加，n-6 PUFA 亚油酸在 4 个数据集中特异性升高；在所有 8 个数据集中，n-3 和 n-6 PUFA 取代了反式脂肪酸和饱和脂肪酸的组合。 对于非致命性心肌梗死 (MI) + CHD 死亡，混合 n-3/n-6 PUFA 饮食的汇总风险降低了 22% (RR=0.78 95%CI 0.65-0.93)，而风险增加了 13% n-6 特定 PUFA 饮食的百分比 (RR=1.13 95%CI 0.84-1.53​​)。 与混合 n-3/n-6 饮食相比，n-6 特定 PUFA 的非致命性 MI + CHD 死亡风险显着更高（Q 统计量 = 5.44，df = 1，p = 0.02）。 用 n-6 PUFA 替代反式和饱和脂肪酸而不同时增加 n-3 PUFA 的随机对照试验导致死亡风险增加，达到统计学显着性 (RR=1.16 95%CI 0.95-1.42)。 我们发现，根据混合 n-3/n-6 RCT 数据，专门增加 n-6 PUFA 摄入量的建议可能会增加冠心病风险。 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。 FADS 1-2 基因复合体中的遗传变异被认为影响将 18 碳脂肪、ALA 和 LA 去饱和为其各自产物 AA 和 EPA/DHA 的能力。 Caspi 等人的一项研究表明，FADS2 基因内的 rs174575 可以缓和这种效应，因此，无论母乳或喂养方式如何，次要等位基因（GG 基因型）纯合子的儿童都具有相似的智商。母乳含有预成型 DHA，而婴儿配方奶粉则不含。 在我们对 5934 名 8 岁儿童的研究中，观察到与这种多态性的相互作用，使得母乳喂养的 GG 儿童的表现比配方奶喂养的儿童多出 5.8 分 1.4, 10.1（交互作用 p = 0.0091）。调整7个因素后，交互结果衰减了约10%。