Erucic acid, a nutritional PPARδ-ligand may influence Huntington's disease pathogenesis.

Increasing recent evidence suggests a key role of oligodendroglial injury and demyelination in the pathophysiology of Huntington's Disease (HD) and the transcription factor PPARδ is critical for oligodendroglial regeneration and myelination. PPARδ directly involves in the pathogenesis of HD and treatment with a brain-permeable PPARδ-agonist (KD3010) alleviates its severity in mice. Erucic acid (EA) is also a PPARδ-ligand ω9 fatty acid which is highly consumed in Asian countries through ingesting cruciferous vegetables such as rapeseed (Brassica napus) and indian mustard (Brassica juncea). EA is also an ingredient of Lorenzo's oil employed in the medical treatment of adrenoleukodystrophy and can be converted to nervonic acid, a component of myelin. HD pathogenesis also involves oxidative and inflammatory injury and EA exerts antioxidative and antiinflammatory efficacies including inhibition of thrombin and elastase. Consumption of rapeseed, indian mustard, and Canola oils (containing EA) improves cognitive parameters in animal models, as well as treatment with pure EA. Moreover, erucamide, an endogenous EA-amide derivative regulating angiogenesis and water balance, exerts antidepressive and anxiolytic effects in mice. Hitherto, no study has investigated the therapeutic potential of EA in HD and we believe that it strongly merits to be studied in animal models of HD as a potential therapeutic.

Dietary intake of specific fatty acids and breast cancer risk among postmenopausal women in the VITAL cohort.

Studies of dietary fat intake and breast cancer have been inconsistent and few have examined specific fatty acids. We examined the association between specific monounsaturated (MUFA), polyunsaturated (PUFA), saturated (SFA), and trans-fatty acids (TFA) and breast cancer risk. Participants, 50-76 yr, were female members of the VITamins And Lifestyle (VITAL) Cohort, who were postmenopausal at baseline. In 2000-2002, participants completed a food frequency questionnaire. Seven hundred seventy-two incident, primary breast cancer cases were identified using a population-based cancer registry. Cox proportional hazard models estimated hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between fatty acid intake and breast cancer risk. Intake of total MUFAs (highest vs. lowest quintile: HR = 1.61, 95% CI: 1.08-2.38, P trend = 0.02), particularly myristoleic and erucic acids, was associated with increased breast cancer risk. Whereas total SFA was suggestive of an increased risk (HR = 1.47, 95% CI: 1.00-2.15, P trend = 0.09), strong associations were observed for palmitic, margaric, and stearic acids. Total TFA and PUFA intake were not associated with breast cancer. However, among TFAs, linolelaidic acid was positively associated with risk; among PUFAs, intake of eicosapentaenoic and docosahexaenoic acids were inversely associated with risk. Our findings show that fatty acids are heterogeneous in their association with postmenopausal breast cancer risk.

Clinical aspects and adrenal functions in eleven Japanese children with X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is a genetic disease associated with demyelination of the central nervous system, adrenocortical insufficiency and accumulation of very long chain fatty acids. It is a clinically heterogeneous disorder ranging from a severe childhood cerebral form to an asymptomatic form. The incidence in Japan is estimated to be between 1:30,000 and 1:50,000 boys as determined by a nationwide retrospective survey between 1990 and 1999, which found no cases with Addison's form. We reviewed the medical records of eleven Japanese boys with X-ALD from 1990 to 2010 in our institute. Eight patients were detected by neuropsychological abnormalities, whereas a higher prevalence of unrecognized adrenocortical insufficiency (5/11: 45%) was observed than previously recognized. While no neurological abnormalities were demonstrated in two brothers, the elder brother had moderate Addison's disease at diagnosis and the presymptomatic younger brother progressed to Addison's disease six months after the diagnosis of X-ALD. Early detection of impaired adrenal function as well as early identification of neurologically presymptomatic patients by genetic analysis is essential for better prognosis. Addison's form might be overlooked in Japan; therefore, X-ALD should be suspected in patients with adrenocortical insufficiency.

Preventing neurodegeneration in the Drosophila mutant bubblegum.

The Drosophila melanogaster recessive mutant bubblegum (bgm) exhibits adult neurodegeneration, with marked dilation of photoreceptor axons. The bubblegum mutant shows elevated levels of very long chain fatty acids (VLCFAs), as seen in the human disease adrenoleukodystrophy (ALD). In ALD, the excess can be lowered by dietary treatment with "Lorenzo's oil," a mixture of unsaturated fatty acids. Feeding the fly mutant one of the components, glyceryl trioleate oil, blocked the accumulation of excess VLCFAs as well as development of the pathology. Mutant flies thus provide a potential model system for studying mechanisms of neurodegenerative disease and screening drugs for treatment.

Erucamide from Radish Leaves Has an Inhibitory Effect Against Acetylcholinesterase and Prevents Memory Deficit Induced by Trimethyltin.

In this study, we investigated a potent acetylcholinesterase inhibitor that was isolated from radish leaf (Raphanus sativus L.) extracts. Through sequential fractionation of radish leaf extract, the active constituent was identified as cis-13-docosenamide (erucamide). To validate the potency, erucamide derived from radish leaves was supplemented in diets and then fed to trimethyltin (TMT)-exposed mice. Specifically, mice had free access to a control diet or diets containing different concentrations of erucamide for 3 weeks, followed by an injection of TMT (2.5 mg/kg body weight). Our results showed that pretreatment of mice with erucamide (20 and 40 mg/kg body weight per day) significantly attenuated the TMT-induced learning and memory deficits that were assessed by Y-maze and passive avoidance tests. These findings suggest that radish leaves, and possibly its isolated erucamide, may have preventive effects against memory deficits related to Alzheimer's disease by modulation of cholinergic functions.

Metabolism of dietary cetoleic acid (22:1n-11) in mink (Mustela vison) and gray seals (Halichoerus grypus) studied using radiolabeled fatty acids.

Cetoleic acid (22:1n-11) is a good indicator of diet in marine predators and has proven to be an important fatty acid (FA) when using adipose tissue FA composition to study diet in marine mammals and seabirds. Feeding studies have shown that 22:1 isomers are predictably underrepresented in adipose tissue relative to diet, implying that metabolism within the predator strongly influences the relationship between the level of these FAs in diet and adipose tissue. Fully understanding such metabolic processes for individual FAs is important for the quantitative estimation of predator diets. We employed a dual-label radioisotope tracer technique to investigate the potential modification of 22:1n-11 and its recovery in the blubber of gray seals (Halichoerus grypus) and in the adipose tissue and liver of mink (Mustela vison), a smaller model carnivore also accustomed to fish-based diets. In both seals and mink, (3)H radioactivity was found in the chain-shortened products of 22:1n-11, with 18:1 being the dominant product. We also found (3)H radioactivity in saturated FAs. The distribution patterns of (3)H radioactivity across the FAs isolated from seal blubber and mink subcutaneous adipose tissue were comparable, indicating that mink are a good model for the investigation of lipid metabolism in marine carnivores.

Short communication: Eicosatrienoic acid and docosatrienoic acid do not promote vaccenic acid accumulation in mixed ruminal cultures.

Previous research found that docosahexaenoic acid (C22:6n-3) was a component of fish oil that promotes trans-C18:1 accumulation in ruminal cultures when incubated with linoleic acid. The objective of this study was to determine if eicosatrienoic acid (C20:3n-3) and docosatrienoic acid (C22:3n-3), n-3 fatty acids in fish oil, promote accumulation of trans-C18:1, vaccenic acid (VA) in particular, using cultures of mixed ruminal microorganisms. Treatments consisted of control, control plus 5 mg of C20:3n-3 (ETA), control plus 5 mg of C22:3n-3 (DTA), control plus 15 mg of linoleic acid (LA), control plus 5 mg of C20:3n-3 and 15 mg of linoleic acid (ETALA), and control plus 5 mg of C22:3n-3 and 15 mg of linoleic acid (DTALA). Treatments were incubated in triplicate in 125-mL flasks, and 5 mL of culture contents was taken at 0 and 24 h for fatty acid analysis by gas-liquid chromatography. After 24 h of incubation, the concentrations of trans-C18:1 (0.87, 0.88, and 0.99 mg/culture), and VA (0.52, 0.56, and 0.62 mg/culture) were similar for the control, ETA, and DTA cultures, respectively. The concentrations of trans-C18:1 (5.51, 5.41, and 5.36 mg/culture), and VA (4.78, 4.62, and 4.59 mg/culture) were also similar between LA, ETALA, and DTALA cultures, respectively. These data suggest that C20:3n-3 and C22:3n-3 are not the active components in fish oil that promote VA accumulation when incubated with linoleic acid.

Dietary erucic acid therapy for X-linked adrenoleukodystrophy.

We investigated the biochemical and clinical efficacy of dietary erucic acid (C22:1) therapy for X-linked adrenoleukodystrophy (ALD). In a double-blind crossover study of patients who were on chronic oleic acid (C18:1) therapy, addition of erucic acid to the diet led to a further reduction in plasma hexacosanoic acid (C26:0) concentration. We treated 12 newly diagnosed ALD patients with a diet enriched with erucic acid and oleic acid for 2 to 19 months. Mean plasma C26:0 concentration decreased to normal by 4 weeks, and the C26:0 composition of plasma sphingomyelin and phosphatidylcholine became normal by 4 months on therapy. Fatty acid analysis of postmortem tissues from 1 boy treated for 10 months suggested that dietary erucic acid entered the heart, liver, adrenal gland, and brain. Eight patients remained on treatment long enough (mean, 12 +/- 3 months) to evaluate their clinical response; 6 of these patients with moderate to advanced disease deteriorated neurologically or showed progression of white matter disease on brain magnetic resonance imaging whereas 2 mildly affected patients remained clinically stable after 10 and 19 months. No adverse effects of the diet occurred. We conclude that dietary erucic acid therapy is effective in lowering plasma C26:0 to normal in ALD patients, and may prevent further demyelination in some mildly affected boys.

Effects of diets enriched with two different plant stanol ester mixtures on plasma ubiquinol-10 and fat-soluble antioxidant concentrations.

Plant stanols lower intestinal cholesterol absorption. This causes a decrease in serum low-density lipoprotein (LDL)-cholesterol, despite a compensatory increase in cholesterol synthesis. We therefore hypothesized that plant stanols also change LDL-cholesterol-standardized concentrations of ubiquinol-10 (a side product of the cholesterol synthesis cascade) and of those fat-soluble antioxidants that are mainly carried by LDL. To examine this, 112 nonhypercholesterolemic subjects consumed low erucic acid rapeseed oil (LEAR)-based margarine and shortening for 4 weeks. For the next 8 weeks, 42 subjects consumed the same products, while the other subjects received products with vegetable oil-based stanols (2.6 g sitostanol plus 1.2 g campestanol daily, n = 36) or wood-based stanols (3.7 g sitostanol plus 0.3 g campestanol daily, n = 34). Consumption of both plant stanol ester mixtures increased cholesterol synthesis and lowered cholesterol absorption, as indicated by increased serum cholesterol-standardized lathosterol and decreased plant sterol concentrations, respectively. Compared with the control group, absolute plasma ubiquinol-10 concentrations were lowered by 12.3% +/- 18.9% (-0.14 microg/mL v. the control group; P =.004; 95% confidence interval [CI] for the difference in changes, -0.05 to -0.22 microg/mL) in the vegetable oil-based group and by 15.4% +/- 13.0% (-0.17 microg/mL v. the control group; P <.001; 95% CI for the difference, -0.08 to -0.27 microg/mL) in the wood-based group. Changes in LDL-cholesterol-standardized ubiquinol-10 concentrations were not significantly changed. The most lipophylic antioxidants, the hydrocarbon carotenoids (beta-carotene, alpha-carotene, and lycopene), decreased most, followed by the less lipophylic oxygenated carotenoids (lutein/zeaxanthin and beta-cryptoxanthin) and the tocopherols. These reductions were related to the reduction in LDL, which carry most of these antioxidants. The decrease in the hydrocarbon carotenoids, however, was also significantly associated with a decrease in cholesterol absorption. LDL-cholesterol-standardized antioxidant concentrations were not changed, except for beta-carotene, which was still, although not significantly, lowered by about 10%. We conclude that the increase in endogenous cholesterol synthesis during plant stanol ester consumption does not result in increased LDL-cholesterol-standardized concentrations of ubiquinol-10, a side product of the cholesterol synthesis cascade. Furthermore, decreases in absolute fat-soluble antioxidant concentrations are related to decreases in LDL-cholesterol. However, for the most lipophylic carotenoids, some of the reduction was also related to the decrease in cholesterol absorption.

Effects of plant and animal lipids rich in docosenoic acids on the myocardium of Cynomolgus monkeys.

Cynomolgus monkeys (Macaca fascicularis) were fed diets containing 25% rapeseed oil (RSO), partially-hydrogenated herring oil (PHHO) or a 3:1 mixture of lard/corn oil as control (CON) for 4 months. The RSO contained approximately 25% of the fatty acids as erucic acid (cis-docos-13-enoic, 22:1w9) while the PHHO contained a similar concentration of mainly cetoleic acid (cis-docos-11-enoic, 22:1w11). The CON contained no 22:1 acids. The monkeys developed the expected myocardial lipidosis, somewhat more pronounced in the RSO than the PHHO group, but small foci of mononuclear cell infiltration, while infrequent, occurred in all three groups. Significant intergroup differences in biochemical or hematologic measurements of serum constituents were an increase in serum cholesterol concentration in the RSO group and an increase in serum glutamicoxaloacetic transaminase activity in both RSO and PHHO groups at certain intervals. The shorter proportion of M. fascicularis life span represented by this experiment may account for the absence of clear intergroup differences such as are reported in rats used in similar studies.

[Effects of conjugates of linolenic acid and erucic acid on rat cardiac and liver lipids]. / Effets conjugés de l'acide linolénique et de l'acide érucique sur les lipides du foie et du myocarde du rat.

Cardiac and liver lipids (triglycerides and phospholipids) were analyzed in weanling rats fed for 8 days diets containing 15% by weight of four different lipid mixtures: trierucin and peanut oil (1/1), trierucin and linseed oil (1/1), triolein and peanut oil (1/1), triolein and linseed oil (1/1). Linolenic acid (8 cal% of the diet) does not influence the steatogenic effect of erucic acid (15 cal% of the diet) on the myocardium but seems to increase the hepatic conversion of erucic acid into shorter monoenes (C 18:1 mainly). The (n-6), (n-3) fatty acid spectra in heart and liver phospholipids are strongly affected when linolenic acid is added to the diet whereas erucic acid has little effect.

Hematological and lipid changes in newborn piglets fed milk-replacer diets containing erucic acid.

Canola oil is not presently permitted in infant formulations in the United States because of lack of information concerning the effects of feeding canola oil to the newborn. We have previously reported a transient decrease in platelet counts and an increase in platelet size in newborn piglets fed canola oil for 4 wk, and have confirmed this in the present study. In canola oil-fed piglets, changes in platelet size and number were overcome by adding either long-chain saturated fatty acids from cocoa butter (16:0 and 18:0), or shorter-chain saturates from coconut oil (12:0 and 14:0). Feeding a high erucic acid rape-seed (HEAR) oil, with 20% 22:1n-9, led to an even greater platelet reduction and increased platelet size throughout the 4-wk trial. Bleeding times were longer in piglets fed canola oil or HEAR oil compared to sow-reared and soybean oil-fed piglets. There were no other diet-related changes. Diet-induced platelet changes were not related to platelet lipid class composition, but there were fatty acid changes. The incorporation of 22:1n-9 into platelet phospholipids of piglets fed canola oil was low (0.2-1.2%), and even for the HEAR oil group ranged from only 0.2% in phosphatidylinositol to 2.4% in phosphatidylserine. A much greater change was observed in the concentration of 24:1n-9 and in the 24:1n-9/24:0 ratio in platelet sphingomyelin (SM). The 24:1n-9 increased to 49% in the HEAR oil group compared to about 12% in animals fed the control diets (sow-reared piglets and soybean oil-fed group), while the 24:1n-9/24:0 ratio increased from about 1 to 12. Even feeding canola oil, prepared to contain 2% 22:1n-9, led to a marked increase in 24:1n-9 to 29% and had a 24:1n-9/24:0 ratio of 5. The canola oil/cocoa butter group, which also contained 2% 22:1n-9, showed a lower level of 24:1n-9 (20%) and the 24:1n-9/24:0 ratio (3) compared to the canola oil group. The results suggest that the diet-related platelet changes in newborn piglets may be related to an increase in 24:1n-9 in platelet SM, resulting from chain elongation of 22:1n-9. The inclusion of canola oil as the sole source of fat in the milk-replacer diets of newborn piglets resulted in significant platelet and lipid changes.

Dietary effect of gamma-linolenic acid on the lipid profile of rat fed erucic acid rich oil.

This study evaluated the effects of dietary supplementation of gamma-Linolenic acid (18:3n-6, GLA) on the lipid profile of serum and other tissues of rats fed erucic acid (C22:1) rich oil like mustard oil. The rats were fed diet containing 20% mustard oil as erucic acid rich oil and 20% groundnut oil as dietary fat. These groups were kept as reference groups. Another group fed diet containing 20% fat to which evening primrose oil as a source of GLA was blended with mustard oil and groundnut oil at 5% level. The feeding experiment was done for 4 weeks. In another set mustard oil fed group was kept as control while the experimental group was fed evening primrose oil as a source of GLA blended with mustard oil at 2.5% level. The feeding experiment was carried out for 12 weeks. The other dietary components remained same for all the groups. After the scheduled feeding period, it was found that there was no significant change in weight gain, food intake and food efficiency ratio. It was found that dietary GLA resulted in significant decrease in serum triglyceride (TG) and very low density lipoprotein (VLDL) cholesterol and significant increase in high density lipoprotein (HDL) cholesterol in serum in the experimental group. In liver total cholesterol (TC) is significantly higher and in heart and liver TG is significantly lower in GLA fed group.

Metabolism of adrenic acid to vasodilatory 1alpha,1beta-dihomo-epoxyeicosatrienoic acids by bovine coronary arteries.

Adrenic acid (docosatetraenoic acid), an abundant fatty acid in the vasculature, is produced by a two-carbon chain elongation of arachidonic acid. Despite its abundance and similarity to arachidonic acid, little is known about its role in the regulation of vascular tone. Gas chromatography/mass spectrometric analysis of bovine coronary artery and endothelial cell lysates revealed arachidonic acid concentrations of 2.06 +/- 0.01 and 6.18 +/- 0.60 microg/mg protein and adrenic acid concentrations of 0.29 +/- 0.01 and 1.56 +/- 0.16 microg/mg protein, respectively. In bovine coronary arterial rings preconstricted with the thromboxane mimetic U-46619, adrenic acid (10(-9)-10(-5) M) induced concentration-related relaxations (maximal relaxation = 83 +/- 4%) that were similar to arachidonic acid relaxations. Adrenic acid relaxations were blocked by endothelium removal and the K(+) channel inhibitor, iberiotoxin (100 nM), and inhibited by the cyclooxygenase inhibitor, indomethacin (10 microM, maximal relaxation = 53 +/- 4%), and the cytochrome P-450 inhibitor, miconazole (10 microM, maximal relaxation = 52 +/- 5%). Reverse-phase HPLC and liquid chromatography/mass spectrometry isolated and identified numerous adrenic acid metabolites from coronary arteries including dihomo (DH)-epoxyeicosatrienoic acids (EETs) and DH-prostaglandins. DH-EET [16,17-, 13,14-, 10,11-, and 7,8- (10(-9)-10(-5) M)] induced similar concentration-related relaxations (maximal relaxations averaged 83 +/- 3%). Adrenic acid (10(-6) M) and DH-16,17-EET (10(-6) M) hyperpolarized coronary arterial smooth muscle. DH-16,17-EET (10(-8)-10(-6) M) activated iberiotoxin-sensitive, whole cell K(+) currents of isolated smooth muscle cells. Thus, in bovine coronary arteries, adrenic acid causes endothelium-dependent relaxations that are mediated by cyclooxygenase and cytochrome P-450 metabolites. The adrenic acid metabolite, DH-16,17-EET, activates smooth muscle K(+) channels to cause hyperpolarization and relaxation. Our results suggest a role of adrenic acid metabolites, specifically, DH-EETs as endothelium-derived hyperpolarizing factors in the coronary circulation.