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Kentz S Willis1, Derek T Smith2, Kenneth S Broughton3, D Enette Larson-Meyer2,31Extension, 2Division of Kinesiology and Health, 3Department of Family and Consumer Sciences (Human Nutrition), University of Wyoming, Laramie, WY, USABackground and purpose: The extra-skeletal functions of vitamin D – including its role in inflammatory modulation – are now well recognized but have not yet been investigated in an athletic population. Thus, the purpose of this study was to investigate the relationship between vitamin D status and pro- and anti-inflammatory cytokines (as markers of inflammation and immune system function) in endurance athletes.Patients and methods: We analyzed fasting blood samples from 19 healthy, endurance-trained male and female runners (following a standardized diet and exercise regimen) for vitamin D status (serum 25-hydroxyvitamin D [25(OH)D)] and specific plasma cytokine concentrations (tumor necrosis factor alpha [TNF-α], interferon-gamma [IFN-γ], interleukin [IL]-4, and IL-10). Serum/plasma concentrations were log-transformed and simple regression analysis was used to determine significant associations between 25(OH)D and cytokine concentrations.Results: Forty-two percent of participants had insufficient vitamin D status [25(OH)D < 32 ng/mL], whereas 11% were deficient [25(OH)D , 20 ng/mL]. TNF-α and IL-4 were variable, ranging from 2.9 to 36.4 pg/mL and 0 to 252.1 pg/mL, respectively. Concentrations of IFN-γ and IL-10 were minimal, with means of 6.7 ± 7.0 pg/mL and 4.8 ± 5.1 pg/mL, respectively. Regression analysis revealed a significant inverse association between 25(OH)D and TNF-α concentrations (R2 = 56.5, P < 0.001) but not between 25(OH)D and the remaining cytokines, IFN-γ, IL-4, and IL-10 (P = 0.477, 0.694, and 0.673, respectively).Conclusion: These results call further attention to the epidemic of vitamin D insufficiency, even in outdoor athletes, and support a possible link between decreased vitamin D status and one particular marker of inflammation. Future investigations are necessary to determine whether increased inflammation in athletes with reduced vitamin D status could increase risk for inflammation-related injury.Keywords: health, exercise training, tumor necrosis factor alpha, cytokines, injury risk

Background: Tree nuts are nutrient dense, and their consumption has been associated with improvements in health outcomes., Objective: To estimate the usual tree nut intake and examine the association between tree nut consumption and cardiometabolic (CM) health outcomes in a nationally representative sample of US adults., Methods: Cross-sectional data were analyzed from a sample of 18,150 adults aged ≥ 20y who provided at least one reliable 24-h dietary recall and had complete data for the variables of interest in the NHANES 2011-2018. Tree nut consumers were defined as those consuming ≥ ¼ ounce/d (7.09 g). The National Cancer Institute Method was used to estimate the usual tree nut intake among consumers. Measurement error calibrated regression models were used to assess the association between tree nut consumption and each health outcome of interest., Results: Approximately 8% of all participants ( n = 1238) consumed tree nuts and had a mean ± SE usual intake of 39.5 ± 1.8 g/d. Tree nut consumers were less likely to have obesity (31% vs. 40%, P < 0.001) and low high-density lipoprotein cholesterol (22% vs. 30%, P < 0.001 ) compared with nonconsumers. Moreover, tree nut consumers had a lower mean waist circumference (WC) (97.1 ± 0.7 vs. 100.5 ± 0.3 cm, P < 0.001) and apolipoprotein B (87.5 ± 1.2 vs. 91.8 ± 0.5 mg/dL, P = 0.004) than nonconsumers. After adjusting models for demographics and lifestyle covariates, the difference in WC between average intake (33.7 g/d) and low threshold intake (7.09/g) of tree nuts was -1.42 ± 0.58 cm ( P = 0.005)., Conclusions: Most US adults do not consume tree nuts, yet modest consumption was associated with decreased prevalence of cardiovascular disease and CM risk factors and improvement for some health outcome measures., (© 2023 The Authors.)

This study estimated the prevalence of cardiovascular disease (CVD) risk factors, cardiometabolic (CM) risk factors, and cardiovascular health metrics (CVHMs) among US adults and across race/ethnicity groups. The study comprised 8370 US adults aged ≥ 20 years from the National Health and Nutrition Examination Survey (NHANES) 2011-2018, free of coronary heart disease/heart failure, angina/angina pectoris, heart attack, and stroke, who provided complete data for the outcome variables of interest. Age-adjusted prevalence of CVD and CM risk factors, and CVHMs were computed for all adults and across race/ethnicity groups. All analyses accounted for the complex, multi-stage survey sampling design of the NHANES. Hypertension (45.0%), obesity (40.0%), fasting plasma glucose ≥ 100 mg/dL or hypoglycemic medication (51.0%), ideal physical activity (59.2%) and ideal smoking status (56.9%) were most prevalent for the whole sample. Mexican Americans and non-Hispanic Blacks had elevated risk for some, but not all, CVD and CM risk factors compared to non-Hispanic Whites and non-Hispanic Asians. Reducing further health disparities and persisting differences among racial and ethnic groups is vital to achieving the American Heart Association vision of all people having ideal cardiovascular health, living healthier and longer., (© 2022. The Author(s).)

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. The article is a duplicate of a paper that has already been published in Nutrients: (Nutrients 2021, 13(7), 2451. https://doi.org/10.3390/nu13072451. Redundant publications overweigh the relative importance of published findings and distort the academic record of the authors. One of the conditions of submission of a paper for publication is therefore that authors declare explicitly that the paper has not been previously published and is not under consideration for publication elsewhere. As such this article represents a misuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process., (Copyright © 2021. Published by Elsevier Inc.)

Polycystic ovary syndrome (PCOS) increases type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) with insulin resistance. We hypothesized that a 35 g whey preload would improve insulin sensitivity and glucose handling while reducing biomarkers associated with NAFLD. Twenty-nine age-matched women (CON = 15, PCOS = 14) completed oral glycemic tolerance tests following baseline (Day 0) as well as an acute (Day 1) and short-term whey supplementation (Day 7). Whey had an interaction effect on glucose ( p = 0.02) and insulin ( p = 0.03), with glucose remaining stable and insulin increasing with whey supplementation. Insulin sensitivity ( p < 0.01) improved with whey associated with increased glucagon secretion ( p < 0.01). Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) remained unchanged, but "day" had an effect on the AST:ALT ratio ( p = 0.04), whereas triglycerides and sex hormone binding globulin overall were greater in the PCOS group ( p < 0.05). Total cholesterol decreased in PCOS (by 13%) and CON (by 8%) (NS). HepG2 cells treated with plasma from participants before and after whey decreased lipid accumulation in the PCOS group after whey ( p < 0.05). Whey provided an insulinogenic and glycemic homeostatic effect in women with PCOS with the potential to combat NAFLD-consequences.

Background: The insulinotropic effect of whey protein is not fully understood and has clinical implications in the regulation of chronic and acute hyperglycemia., Summary: This review describes the composition of whey protein and potential mechanisms through which whey exerts an insulinotropic effect, including increasing the gastric emptying rate, effect on incretin hormones particularly gastric inhibitory peptide and glucagon-like polypeptide-1, and whey's role as a dipeptidyl peptidase IV inhibitor. Recent clinical evidence on the use of whey protein concentrate, isolate and hydrolysate in the management of type 2 diabetes and in the acute care adult population is reviewed., Key Messages: The mechanism through which whey protein exerts its insulinotropic effect is multifactorial. Increasing evidence supports the potential use of whey protein in medical/nutritional therapy to manage glycemia; however, additional research is needed to determine the most appropriate dose, form and delivery method for whey supplementation., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

Many view bison as a healthful alternative to other red meat sources, and as a way to decrease health risks, they associate it with meat consumption. Using mice as a model for immune function, we hypothesized that consumption of meat from range-fed bison would decrease prostaglandin (PG) E₂ and alter prostacyclin (PGI₂) release upon immune challenge when compared with mice fed meat from grain-finished bison, range-fed beef, feedlot steers, free-ranging elk, or chicken breast. After 2 weeks on an experimental diet and inflammatory stimulation, mouse peritoneal macrophage was isolated and analyzed in 12 animals per diet. Peritoneal cell arachidonic acid increased in response to a chicken-based diet (P < .05), which was likely attributable to higher arachidonic acid intake. Release of PGE₂ was lowest in mice consuming meat of range-fed beef, range-fed bison, and elk but was highest with meat of grain-finished beef and intermediate in mice fed chicken (P < .05). Mice fed elk meat had the greatest PGI₂, whereas PGI₂ was decreased in mice fed meat of either range bison, range beef, or chicken (P < .05) and intermediate in mice fed meat of steers or bison finished in a feedlot. We conclude that consumption of meats characteristic of range-fed ruminants or wild ungulates supports reduced PGE₂ and greater PGI₂ synthesis, indicating potentially greater immune health and lower blood clotting potential than meat from grain-finished cattle or bison in this model system., (Published by Elsevier Inc.)

Prostaglandins (PG) have a regulatory influence on ovulation. α-Linolenic acid (ALA) vs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) differently influence PG biosynthesis. Whereas high EPA/DHA reduces PGE₂, enhancing ovulation, we hypothesized that ALA would not affect ovulation. Our objective was to determine the effect of low and high ALA intake vs EPA/DHA on ovarian phospholipids, ovulation, and PG synthesis in rats. Following 27 days on diet and ovulation induction, ovaries were isolated and analyzed in 22 pups per diet. Ovarian phospholipid (n-3) polyunsaturated fatty acid (PUFA) incorporation increased with EPA/DHA ingestion. With significant ovarian (n-3) PUFA or EPA (P < .05) enrichment in the high-n-3 PUFA diets, ova release increased. Although high ALA did not enrich total (n-3), it increased ova release and tissue EPA over low ALA or control. Dietary EPA/DHA more effectively reduced ovarian arachidonic acid levels than dietary ALA. Dietary ALA increased PGF and very high intake reduced PGE, whereas EPA/DHA did not alter PGE or PGF. Enhanced ova release with high (n-3) PUFA intake may be induced via multiple mechanisms including reduced ovarian arachidonic acid. Significant ovarian retention of EPA and DHA enhanced ovulation with unchanged total PGE and PGF. Lack of change in PGE may have resulted from reduced PGE₂ combined with increased PGE₃. When EPA alone was elevated, PGE was reduced, whereas PGF was increased. Results indicate that very high ALA intake enhances ovulation similar to very high EPA/DHA ingestion, an effect potentially mediated via similar patterns of PGF₂α and PGE₂ synthesis., (Published by Elsevier Inc.)

Prostaglandins (PGs) play a key role in the regulation of ovulation. Typically, ingestion of the long-chain n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) has been found to decrease, whereas arachidonic acid (ARA) increases PG biosynthesis in most systems. We hypothesized that DHA and EPA would decrease ovarian PGE(2), enhancing ovulation, with combined EPA and DHA having the greatest effect, whereas ARA would increase PGE(2), suppressing ovulation. Our objective was to determine how 0.3-g/100-g diet DHA and EPA alone or combined, or ARA would affect tissue composition, ovulation, and PG synthesis in rats. After 27 days on diet and ovulation induction, ovaries were isolated and analyzed from 22 pups per diet. Eicosapentaenoic acid alone reduced ovarian n-6 PUFA attributable to reduced ARA incorporation. Arachidonic acid ingestion reduced and EPA enhanced ovarian n-3 PUFA to levels above what was seen with DHA or DHA/EPA combinations. Docosahexaenoic acid alone increased total PGE 1.5-fold over control, whereas neither differed from the remaining treatments. Increased total PGE with DHA was attributable to elevated PGE(3) with PGE(2) unchanged by diet, and PGE(3) only increased with DHA ingestion alone. Total PGF differed from control with the highest DHA intake, alone or combined with EPA, or with ARA ingestion (P < .05). Increased PGF with DHA was attributable to increased PGF(3alpha). Experimental diets did not alter ovulation from control. Results indicate that DHA and EPA consumption at human achievable doses differently alters ovarian phospholipids and PGs associated with ovulation with potential for significant 3-series PG without significantly perturbing ovulation.

Ovulation is a prostaglandin (PG)-dependent process. Although n-3 polyunsaturated fatty acids (PUFA) and conjugated linoleic acid (CLA) have differing effects in the body, both reduce PG synthesis. We hypothesized that dietary n-3 fatty acids and CLA would differentially alter ovarian PG profiles through reductions in expression of enzymes involved in PG biosynthesis resulting in enhanced ovulation. Our objectives were to determine how dietary stearidonic acid and eicosapentaenoic acid (EPA) at 0.3 g/100 g diet and mixed isomers of CLA at 0.7 g/100 g diet, human achievable levels with daily consumption of fish or beef and dairy products, respectively, would influence ovulation and ovarian cyclooxygenase-1 (COX-1) and COX-2 expression in ovulation-induced rats. After 27 days on diet and ovulation induction, ovaries were isolated and analyzed from 22 pups per diet. Eicosapentaenoic acid ingestion reduced ova release by 16% while increasing PGE(2) and PGF(2alpha) release without altering COX-1 or COX-2 expression. Conversely, ovarian COX-1 expression was increased 135% with stearidonic acid ingestion associated with increased PGF(2alpha) without altering PGE(2) or ova release. Conjugated linoleic acid ingestion reduced COX-2 expression to 65% of that in rats consuming control and EPA diets; however, without affecting ovulation or PGs. Although it is generally believed that the COX-2 is the primary COX involved in ovulation, these results demonstrated that the n-3 PUFA differently affect ovarian COX-1 expression and that this effect differs from CLA, which reduced COX-2 expression. Further, although ovarian PGF(2alpha) is the primary PG altered by dietary n-3 PUFA, n-3 PUFA differentially influence ovarian PG biosynthesis and can decrease ova release, possibly induced through constitutive COX-1 enzyme expression.

The objective of this study was to compare fatty acid weight percentages and cholesterol concentrations of longissimus dorsi (LD), semitendinosus (ST), and supraspinatus (SS) muscles (n = 10 for each) of range bison (31 mo of age), feedlot-finished bison (18 mo of age), range beef cows (4 to 7 yr of age), feedlot steers (18 mo of age), free-ranging cow elk (3 to 5 yr of age), and chicken breast. Lipids were analyzed by capillary GLC. Total saturated fatty acids (SFA) were greater (P < 0.01) in range bison than in feedlot bison and were greater (P < 0.01) in SS of range beef cattle than in feedlot steers. Muscles of elk and range bison were similar (P > 0.05) in SAT. In LD, polyunsaturated fatty acids (PUFA) were highest (P < 0.01) for elk and range bison and lowest (P < 0.01) for feedlot steers within each muscle. Range bison and range beef cows had greater (P < 0.01) PUFA in LD and ST than feedlot bison or steers, respectively. Range-fed animals had higher (P < 0.01) n-3 fatty acids than feedlot-fed animals or chicken breast. Chicken breast n-6 fatty acids were greater (P < 0.01) than for muscles from bison, beef, or elk. Elk had higher (P < 0.01) n-6 fatty acids than bison or beef cattle; however, range-fed animals had higher (P < 0.01) n-6 fatty acids than feedlot-fed animals in ST. Conjugated linoleic acid (CLA, 18:2cis-9, trans-11) in LD was greatest (P < 0.01) for range beef cows (0.4%), and lowest for chicken breast and elk (mean = 0.1%). In ST, CLA was greatest (P < 0.01) for range and feedlot bison and range beef cows (mean = 0.4%) and lowest for elk and chicken breast (mean = 0.1%). Also, SS CLA was greatest (P < 0.01) for range beef cows (0.5%) and lowest for chicken breast (0.1%). Mean total fatty acid concentration (g/100 g tissue) for all muscles was highest (P < 0.01) for feedlot bison and feedlot cattle and lowest (P < 0.01) for range bison, range beef cows, elk, and chicken. Chicken breast cholesterol (mg/100 g tissue) was higher (P < 0.01) than LD and ST cholesterol, which were lowest (P < 0.01; 43.8) for range bison and intermediate for the other species. Cholesterol in SS was highest (P < 0.01) for feedlot bison and steers, which were similar to chicken breast (mean = 61.2 vs 52.8 for the mean of the other species). We conclude that lipid composition of bison muscle varies with feeding regimen, and range-fed bison had muscle lipid composition similar to that of forage-fed beef cows and wild elk.

Previous studies have not addressed the effect of differing fat intake on the effectiveness of varying (n-3) polyunsaturated fatty acid (PUFA) ingestion in altering tissue composition and eicosanoid production. This study examined (n-3):(n-6) PUFA ratios of 0, 0.1:1, 0.2:1, 0.4:1, and 1:1 with total fat at 5, 10, 15, and 20 g/100 g of diet and (n-6) PUFA fixed at 1.5 g/100 g of diet on tissue composition and peritoneal cell eicosanoid response to an in vivo inflammatory stimulus in 240 mice. Both (n-3) PUFA and total fat intake influenced tissue composition and eicosanoid biosynthesis. Increased (n-3) PUFA intake was associated with an increase in tissue (n-3) PUFA and a decrease in long-chain (n-6) PUFA. Although hepatic tissue linoleic acid (LA) was not altered by (n-3) PUFA intake or changes in total fat, peritoneal cell LA increased in response to increasing total fat but was unaffected by changes in dietary (n-3) PUFA. Four-series leukotrienes (LT) decreased progressively with increased (n-3) PUFA at all fat intake levels. In addition, four-series LT decreased with increased total fat at low (n-3):(n-6) ratios (0 and 0.1). At high (n-3):(n-6) ratios (0.4 and 1.0) increasing dietary fat between the 5 and 15 g/100 g diets increased four-series LT synthesis, which reached a plateau between 15 and 20 g fat/100 g diets. Five-series LT production generally rose with increased (n-3) PUFA intake; this effect was most evident in mice fed the 5 g fat/100 g diet. Increasing total dietary fat at the three highest (n-3):(n-6) ratios (0.2, 0.4, 1.0) decreased five-series LT production. Elevated (n-3) PUFA and total fat intake exerted an additive effect with respect to prostacyclin (PGI(2)) production because it was reduced with increasing intakes of both. Compared with the mice consuming the no (n-3) 5 g/100 g diets, PGI(2) levels were reduced by 88% in mice consuming the highest total fat and (n-3) PUFA diets. At low fat intake (5 and 10 g/100 g diet), increasing the (n-3) PUFA intake was associated with a decrease in PGE(2) synthesis. However, unlike PGI(2), high fat intake reduced PGE(2) to basal levels with no further reduction induced by increased (n-3) PUFA intake.

Previously, we reported differences in arachidonic acid metabolism in elicited chicken peritoneal macrophages when compared with murine resident and elicited peritoneal macrophages. We now describe leukotriene (LT) production in the same systems, using resident (murine) and inflammatory macrophages (from both species). Inflammatory (4- or 42-g Sephadex-elicited) peritoneal macrophages from chickens lacked the capacity to produce LT in vivo (following opsonized zymosan [OZ] stimulation) or in vitro, in response to A23187. In addition, chicken macrophages were unable to metabolize exogenously added LTC4 or LTD4 in vitro. In contrast, resident murine peritoneal macrophages produced measurable quantities of LTs (in vivo) within 5 min with an 8-fold increase after 45 min. LTC4 was effectively converted to LTE4 in vivo in a time-dependent manner (65% LTC4/35% LTE4 after 5 min stimulation with OZ and 6% LTC4/94% LTE4 after 60 min stimulation), but no in vitro. The lack of LTC4 metabolism to LTE4 in vitro could not be explained by cell-cell interaction between adherent and nonadherent cells. LTD4 was not detected under any experimental condition. Murine peritoneal cells incubated with LTD4 (with or without agonist) produced LTE4 in a time-dependent fashion. Addition of L-cysteine (a dipeptidase inhibitor) did not explain the lack of detectable levels of LTD4 following intraperitoneal stimulation with OZ. These results suggest that elicited chicken peritoneal macrophages are incapable of producing LTs compared to murine peritoneal macrophages. In addition, these studies fail to explain the different product profiles with in vivo stimulation of murine peritoneal macrophages as compared to in vitro stimulation.

The effects of different ratios of dietary (n-3):(n-6) polyunsaturated fatty acids on prostaglandin E, prostaglandin F2 alpha and ovulation in rats were assessed. Dietary (n-3) polyunsaturated fatty acids were incorporated, by ovarian phospholipids with ovarian tissue enrichment, with (n-3) polyunsaturated fatty acids enhancing, and (n-6) polyunsaturated fatty acids reducing, the number of ova released in immature rats primed with pregnant mares' serum gonadotrophin and human chorionic gonadotrophin. Incorporation of (n-3) polyunsaturated fatty acids appeared to enhance ovulation by altering total prostaglandin E production. This effect may be induced by changes in the prostaglandin E3:E2 ratio and the synthesis of less biologically active prostaglandin E3, or by dilution of the anti-ovulatory properties attributable to prostaglandin E2. High incorporation of dietary (n-6) polyunsaturated fatty acids may lead to reduced ovulation through excessive production of prostaglandin E2. Prostaglandin E or F2 alpha and alterations in tissue phospholipid composition inhibited progesterone release, and inhibition was independent of the series of prostaglandin produced. This study provides evidence that dietary lipids affect ovulation in rats with possible implications for reproduction in other vertebrates.

Effects of aspirin and fish-oil ingestion on caffeine-induced hypercalciuria and renal prostaglandins (PG) were investigated in 12 healthy women. The 11-wk study consisted of 7-d baseline, 5-d aspirin (1000 mg/d), 11-d washout, and two 24-d fish-oil periods (FO-1 and FO-2, respectively, providing 1.5 vs 3.0 g n-3 fatty acids/d) separated by a 4-d washout period. Caffeine-load (CL) tests providing 5 mg caffeine/kg body wt were administered after baseline and each experimental period. Timed urine samples were collected precaffeine (basal) and at 1, 2, and 3 h post-caffeine. PGE2 excretion decreased during tests after aspirin and FO-2. There were significant increases in PGF2 alpha from baseline during each CL test. Hypercalciuria was observed during each CL test and the magnitude of this response was not altered by the experimental treatments. The finding that concentrations of post-caffeine urinary PGF2 alpha paralleled concentrations of urinary calcium supports the possibility that this prostaglandin plays a role in caffeine-induced hypercalciuria.

This study assessed the effect of frequency of consumption of a diet containing 10 g fat/100 g, with a (n-3):(n-6) polyunsaturated fatty acid (PUFA) ratio of 0.5, on tissue fatty acid composition and eicosanoid synthesis in CD-1 mice. With greater (n-3) PUFA consumption frequency, hepatic and peritoneal cell (n-3) PUFA levels changed to 14.4 +/- 1.3 and 12.4 +/- 0.9 mol/100 mol, respectively, from 2.4 +/- 0.3 and 1.9 +/- 0.3 mol/100 mol in control animals consuming a diet without (n-3) PUFA. Hepatic and peritoneal cell (n-6) PUFA levels were reduced to 6.4 +/- 0.5 and 7.6 +/- 0.5 mol/100 mol, respectively, with daily (n-3) PUFA consumption, compared with 23.6 +/- 0.7 and 17.9 +/- 0.7 mol/100 mol in control animals. Prostaglandin E, 6-keto-prostaglandin F1 alpha, and 4-series sulfidopeptide leukotriene biosyntheses reflected frequency of (n-3) PUFA consumption, with daily (n-3) PUFA consumption reducing prostaglandin E, consumption of (n-3) PUFA every other day reducing 6-keto-prostaglandin F1 alpha, and (n-3) PUFA consumption every 3 d reducing leukotriene C4 and leukotriene E4. Leukotriene C5 and leukotriene E5 changed from undetectable in animals consuming the control diet to > 40% of total leukotriene production in animals consuming (n-3) PUFA daily. Daily to biweekly consumption of fish or fish oil [1.26-0.63 g/wk of (n-3) PUFA, 6-3% of energy] may be a means for changing eicosanoid production. Consumption of (n-3) PUFA less often than twice a week may not change eicosanoid synthesis.

Ingestion of modest amounts of n-3 polyunsaturated fatty acids (PUFA) (2.8% w/w) decreased plasma triglyceride levels in Syrian hamsters by 49%. This was associated with a 45% increase in hepatic carnitine palmitoyl transferase activity. Significantly, at this low level of n-3 PUFA intake, hepatic peroxisomal oxidation measured as CN- insensitive palmitoyl-CoA dependent NAD reduction was unaffected. Consumption of increasing amounts of dietary n-3 PUFA up to 2% (w/w) in hamster diets containing 15% fat, gradually decreased plasma triglycerides to 56% of the control levels. The diet induced changes in plasma triglyceride levels were highly correlated (r = -0.97, P less than 0.01) with changes in hepatic carnitine palmitoyl transferase activity. A gradual decrease up to 59% in hepatic phosphatidate phosphohydrolase activity with n-3 fatty acid consumption was also observed. The hypotriglyceridemic effects of moderate intakes of n-3 fatty acids are, therefore, associated with changes in key enzymes in hepatic triglyceride synthesis and mitochondrial oxidation, but not peroxisomal oxidation.

The effects of preformed dietary arachidonic acid (AA, 20:4n-6) on murine phospholipid fatty acid composition in tissues capable (liver) and incapable (peritoneal exudate cells, PEC) of desaturating and elongating linoleic acid (LA, 18:2n-6) to AA were investigated. The results were compared with those obtained on matched animals on LA diets by either substituting or supplementing dietary LA with AA. Modest amounts of AA ethyl ester (0.5 wt%) included in the diet significantly increased tissue phospholipid AA levels by 39% and 57% in the liver and in PEC, respectively. The changes were further enhanced when dietary LA and AA intakes were equivalent, i.e., 57% and 68% in liver and PEC, respectively. This enrichment was observed in all phospholipid classes analyzed, with the greatest impact on phosphatidylcholine. In addition, the doubling of dietary LA had little effect on tissue phospholipid AA levels. The data suggest that while the level of n-6 PUFA may have an important effect on tissue fatty acid composition, the type of n-6 PUFA in the diet could be of greater significance.

The comparative effects of dietary alpha-linolenic acid and fish oil on eicosanoid metabolism was studied in vivo. Resident murine peritoneal cells were stimulated in vivo with opsonized zymosan in animals maintained on diets containing increasing amounts of alpha-linolenic acid or fish oil concentrate with projected n-3/n-6 ratios of 0.2, 0.4 and 1.0. While fish oil feeding resulted in significant changes in eicosapentaenoate tissue levels, alpha-linolenic acid was preferentially metabolized to docosahexaenoate. High performance liquid chromatographic analysis revealed the formation of leukotriene E5 (LTE5) in all the fish oil groups (19.8 +/- 3.5 ng/mouse to 83.3 +/- 13 ng/mouse), but only in the highest linolenic acid group (6.0 +/- 3.2 ng/mouse). Concomitantly, the 4-series sulfidopeptide leukotrienes and PGI2 were significantly reduced in the two highest fish oil containing dietary groups. Similar reductions were observed in the highest linolenic acid group, but the changes were not statistically different from the control values. In summary, this paper reports the de novo synthesis of 5-series sulfidopeptide leukotrienes in animals consuming alpha-linolenic acid. It also reveals that dietary fish oil is 2.5 to 5 times more effective than alpha-linolenic acid in modulating eicosanoid metabolism and altering tissue phospholipid fatty acid composition.

An incremental increase in the dietary (n-3):(n-6) polyunsaturated fatty acid (PUFA) ratio from 0 to 1.93 in diets containing 15% fat (wt/wt) decreased the total (n-6) PUFA content of phospholipids of the liver and peritoneal cells (macrophage) in mice from 43.1 and 33.6 mol/100 mol to 16.0 and 12.3 mol/100 mol with a concomitant increase of 27.6 and 16.1 mol/100 mol in (n-3) PUFA, respectively. Consumption of (n-3) PUFA increased hepatic (n-3) PUFA levels without changing total PUFA (46.35 vs. 46.87 mol/100 mol), whereas macrophage PUFA levels were decreased. The synthesis of sulfidopeptide leukotrienes (SP-LT) (LTC4 and LTE4) was progressively reduced by increasing dietary (n-3) PUFA, i.e., there was a reduction of 76% in mice fed a diet containing a (n-3):(n-6) PUFA ratio of 1.93 compared with the control diet. The 5-series SP-LT (LTC5 and LTF5) were produced in all animals consuming (n-3) PUFA and accounted for 62% of all SP-LT synthesized in mice fed the diet containing a 1.93 (n-3):(n-6) PUFA ratio. Synthesis of 6-keto-prostaglandin F1 alpha decreased 81% in mice fed a diet containing a (n-3):(n-6) PUFA ratio of 1.93 whereas prostaglandin E2 synthesis decreased 44% in mice fed diets with (n-3):(n-6) ratios ranging from 0.41 to 1.93.

Resident mouse peritoneal cells, stimulated in vivo with opsonized zymosan, produced leukotriene C4 and E4, with LTE4 being the major (80-90%) product. When mice were placed on diets containing increasing amounts of fish oil, four additional sulfidopeptide leukotrienes (SP-LT), LTC5, LTE5, 11-trans LTC5 and 11-trans LTE5, were identified. The identity of LTE5 was confirmed by spectrophotometric, chromatographic and enzymatic methods. When equivalent amounts of n-6 and n-3 polyunsaturated fatty acids (PUFA) were included in the diet, the stimulated peritoneal cells (in vivo) produced higher quantities of LTE5 (30.2 +/- 5.4 ng/10(6) cells) than LTE4 (22.8 +/- 7.3 ng/10(6) cells). In addition, in vitro studies demonstrated a 60% reduction in LTC4 (42.0 +/- 10.8 ng/10(6) cells to 16.7 +/- 6.2 ng/10(6) cells) and the appearance of LTC5 (2.1 +/- 0.9 ng/10(6) cells) in resident macrophages (stimulated with A23187) from mice maintained on a fish oil diet compared to mice fed the control diet. This study demonstrated that formation of the pentaenyl SP-LT in vivo, in particular LTE5, by peritoneal cells can significantly contribute to the endogenous SP-LT pool in response to an inflammatory stimulus following a dietary regimen containing fish oil.

In addition to providing energy and essential fatty acids, dietary fatty acids can affect numerous biochemical and physiologic reactions related to secretory, cardiovascular, and immune functions. The major dietary unsaturated fatty acid, linoleic acid, affects tissue arachidonic acid and can influence eicosanoid-mediated reactions. Chronic, excess, or imbalanced eicosanoid synthesis may be conductive to excessive inflammation, thrombotic tendencies, atherosclerosis, and immune suppression. Dietary n-3 polyunsaturated fatty acids (PUFAs) may ameliorate eicosanoid-related phenomena by reducing tissue arachidonic acid and by inhibiting eicosanoid synthesis. This review summarizes information concerning the metabolism of unsaturated fatty acids, with emphasis on tissue arachidonic acid levels and eicosanoids, and discusses the need for data concerning the appropriate intake of dietary n-6 and n-3 PUFAs to modulate arachidonic acid and eicosanoid synthesis and to minimize possible adverse reactions.