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; 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研究表明，酗酒导致神经系统中主要多不饱和的二十六烯酸酯（DHA）丧失。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。在跟踪这项工作时，重要的是确定生理功能的损失是由各种器官系统中DHA丢失造成的。 在吸烟者和非吸烟者中，研究了必需的脂肪酸代谢，作为吸烟酗酒者的参考点。 单一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，雌性吸烟者的血浆中剂量的百分之二高，而从D5-22：5N-3组成D5-22：6N-3的分数率更高。 雄性吸烟者的总血浆N-3脂肪酸水平升高，更快地转移了18：3n-3，D5-20：5N-3的消失率既延迟又慢，而D5-20：5N-3的百分比更高，而D5-22：5N-3的比例是D5-22：5N-3的形成。 吸烟通常增加了血浆N-3脂肪酸的生物利用度，加速的分数合成速率，并增加了一些长链N-3多不饱和脂肪酸的形成百分比。 在2001 - 2002年的横截面国家健康和营养检查调查中，研究了4168名成年人，研究了饮食中酒精和必需脂肪酸摄入量的关系。 我们的结果表明，在男性中，饱和，单不饱和，多不饱和，亚油酸和α-烯酚酸的营养密度降低与饮酒有关。 暴饮暴食的男性的饱和，单不饱和，多不饱和和亚油果，α-中苯酚，二糖蛋白烯酸酯和二十二碳六烯酸的摄入量显着降低。 因此，饮酒似乎通过改变脂肪酸的代谢以及通过改变食物选择和饮食习惯来降低组织中高度不饱和的脂肪酸。 在另一项主要研究中，我们评估了降低omega-6脂肪酸亚油酸饮食摄入量对升高长链omega-3脂肪酸eicosapentaenoic eicososapentaenoic and docosahecahecahecaheenoic的饮食摄入量的影响。 在三代实验中，均等的饮食在其中α-三酚酸（N-3多不饱和脂肪酸的饮食前体）被亚油酸取代。 与标准饮食喂养的小鼠相比，我们发现整个生命的体重显着增加。在低N-3脂肪酸小鼠中观察到的脂肪生成伴随着静脉凝胶酶A除饱和酶1（SCD1）的6倍上调，其活性与等离子甘油三酸酯水平相关。在总肝脏脂质和磷脂提取物中，N-3脂肪酸和个体较长的碳链酸的总和，eicosapentaenoic（20：5n3），docosapentaenoic acid（22：5n3）和cotosahecahecahecainoic酸（22：6n3）显着降低了酸（22：6n3），而酸会显着降低。此外，低N-3脂肪酸喂养的小鼠具有肝脏脂肪变性，心脏和肾脏肥大。因此，将饮食中的α-烯醇酸从1.02能量％降低到0.16能量％，加上升高的亚油酸摄入量会导致肥胖，并对器官功能产生不利影响。 在两项人类临床试验中，正在评估降低omega-6脂肪酸。 在患有慢性每日头痛的受试者中，选择性降低亚油酸以及与EPA和DHA摄入量升高的亚油酸降低，磷脂中的蛛网膜酸减少，血清中的EPA和DHA升高。 这些变化导致头痛的严重程度和持续时间降低了50％。 最近已批准了第二种人类方案，以评估选择性linoleate降低对降低超重女性肥胖的影响。 该协议将选择性地将Linoleate的摄入量降至约1 en％。 Omega-3α亚麻酸（D5）对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消耗至少5％至10％的能源作为Omega-6 PUFA，基于将N-3/N-6 PUFA混合的随机对照试验（RCT）和其CHD结果的荟萃分析的随机对照试验（RCT）。 为了更好地评估这些研究：1）进行了广泛的文献搜索，并提取了详细的饮食和结果数据，从而对所有增加了PUFA的RCT进行了批判性检查并报告了相关的CHD结果； 2）确定饮食干预措施是否特别增加了N-6 PUFA，或者增加了N-3和N-6 PUFA（即混合N-3/N-6 PUFA饮食）； 3）将N-3/N-6 PUFA与N-6特异性PUFA饮食进行了比较，以荟萃分析中的相关CHD结局； 4）评估了反式脂肪酸在这些试验中的潜在混杂作用。 在8个数据集中的4个中，Omega-3 PUFA摄入量显着增加，并且在4个数据集中以特异性提高了N-6 PUFA亚油酸； N-3和N-6 PUFA代替了所有8个数据集中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为22％（RR = 0.78 95％CI 0.65-0.93），而N-6特定PUFA饮食的风险增加了13％（RR = 1.13 95％CI 0.84-1.53​​）。 与混合N-3/N-6饮食相比，N-6特异性PUFA中非致命MI + CHD死亡的风险明显更高（Q-Statistic = 5.44，DF = 1，P = 0.02）。 将N-6 PUFA代替反式和饱和脂肪酸而不同时增加N-3 PUFA的RCT产生的死亡风险增加了统计学意义（RR = 1.16 95％CI 0.95-1.42）。 我们发现，基于混合N-3/N-6 RCT数据，特别增加N-6 PUFA摄入量的建议可能会增加CHD风险。 在高吞吐量脂肪酸分析方面，已经完成了一种方法论发展，促进了脂质组和代谢组方法。劳动密集型跨甲基化程序被简化，然后采用给机器人技术。已经开发了一个机器人程序和程序，以及定制硬件，并为血浆样品进行了验证，这些样品每天可能会产生400甲基样品。 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。已经开发了一个程序来处理GC数据以进行峰值分配和量化。 该系统目前正在进行大型临床研究。 FADS 1-2基因复合物中的遗传变异被认为会影响其各自产物AA和EPA/DHA的18个碳脂肪，ALA和LA的能力。 Caspi等人的一项研究表明，FADS2基因内的RS174575 rs174575调节了这种效果，因此在次要等位基因（GG基因型）中纯合子（GG基因型）具有相似的智商，而与乳腺癌或喂养方法无关。母乳含有预先形成的DHA，因为婴儿配方奶粉没有。 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，使母乳喂养的GG儿童的表现要比其配方奶粉喂的更好的对应物的5.8点1.4、10.1（相互作用p 0.0091）。调整了7个因素后，相互作用的结果减弱了约10％。