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.

Project Start
Project End
Budget Start
Budget End
Support Year
29
Fiscal Year
2011
Total Cost
$790,699
Indirect Cost
Name
National Institute on Alcohol Abuse and Alcoholism
Department
Type
DUNS #
City
State
Country
Zip Code
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