Dietary Linoleic Acid Research Articles

Abstract 2557: 15-lipoxygenase-1 suppresses linoleic acid promotion of colorectal tumorigenesis through oxidative metabolism of PI3P_linoleic acid to inhibit membranous LRP5 recycling and WNT/β-catenin signaling activation

Abstract Western-type diets have been increasingly enriched with linoleic acid (LA). The impact of excess dietary LA on cancer risk remains poorly understood although some studies suggest that high LA diets promote chemically-induced colorectal carcinogenesis (CRC) in rodent models. 15-lipoxygenase-1 (15-LOX-1), the main metabolizing enzyme of LA, is transcriptionally silenced during the early stages of CRC. Whether 15-LOX-1 impacts the effects of excess LA on CRC is unknown. Herein, we report that high dietary LA promoted CRC in intestinally targeted APC mutation (ApcΔ580) and azoxymethane-induced CRC mouse models by upregulating expression of LRP5, a Wnt receptor, and aberrant β-catenin activation. These effects were negatively regulated by 15-LOX-1 when this enzyme was transgenically expressed in intestinal epithelial cells. Complementary genetic deletion studies of 15-LOX-1 in mice further supported 15-LOX-1's suppressive effects on these events. Mechanistic studies showed that 15-LOX-1 peroxidation of LA in phosphatidylinositol-3-phosphates (PI3P_LA) into PI3P_13-HODE decreased PI3P binding to SNX17 and LRP5, which inhibited LRP5 recycling from endosomes to the plasma membrane, thereby leading to an increase of LRP5 lysosomal degradation. Our findings demonstrate for the first time the importance of linoleic acid metabolism by 15-LOX-1 within complex lipids such as PI3P in regulating LRP5 membranous abundance and subsequently Wnt/β-catenin aberrant signaling activation and CRC risk. These results strongly support the need to carefully consider the potential of increasing CRC risk by enriching the diets with LA especially for individuals with low 15-LOX-1 expression. Citation Format: Fuyao Liu, Xiangsheng Zuo, Yi Liu, Yasunori Deguchi, Micheline J. Moussalli, Weidong Chen, Peiying Yang, Bo Wei, Lin Tan, Philip L. Lorenzi, Shen Gao, Jonathan C. Jaoude, Amir Mehdizadeh, Lovie A. Valentin, Daoyan Wei, Imad Shureiqi. 15-lipoxygenase-1 suppresses linoleic acid promotion of colorectal tumorigenesis through oxidative metabolism of PI3P_linoleic acid to inhibit membranous LRP5 recycling and WNT/β-catenin signaling activation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2557.

Suppression of Membranous LRP5 Recycling, Wnt/β-Catenin Signaling, and Colon Carcinogenesis by 15-LOX-1 Peroxidation of Linoleic Acid in PI3P

APC mutation activation of Wnt/β-catenin drives initiation of colorectal carcinogenesis (CRC). Additional factors potentiate β-catenin activation to promote CRC. Western diets are enriched in linoleic acid (LA); LA-enriched diets promote chemically induced CRC in rodents. 15-Lipoxygenase-1 (15-LOX-1), the main LA-metabolizing enzyme, is transcriptionally silenced during CRC. Whether LA and 15-LOX-1 affect Wnt/β-catenin signaling is unclear. We report that high dietary LA promotes CRC in mice treated with azoxymethane or with an intestinally targeted Apc mutation (ApcΔ580) by upregulating Wnt receptor LRP5 protein expression and β-catenin activation. 15-LOX-1 transgenic expression in mouse intestinal epithelial cells suppresses LRP5 protein expression, β-catenin activation, and CRC. 15-LOX-1 peroxidation of LA in phosphatidylinositol-3-phosphates (PI3P_LA) leads to PI3P_13-HODE formation, which decreases PI3P binding to SNX17 and LRP5 and inhibits LRP5 recycling from endosomes to the plasma membrane, thereby increasing LRP5 lysosomal degradation. This regulatory mechanism of LRP5/Wnt/β-catenin signaling could be therapeutically targeted to suppress CRC.

Biomarker of dietary linoleic acid and risk for stroke: A systematic review and meta-analysis.

Previous observational studiíes provided conflicting findings on the relationship between linoleic acid (LA) and the risk for stroke. The aim of this study was to evaluate the association of LA levels in blood or adipose tissue samples with risk for stroke. PubMed, Web of Science, and Embase databases were searched until February 29, 2020 to identify eligible observational studies, including cohort studies, nested case-control studies, case-cohort studies, and case-control studies, reporting the association of LA with the risk for stroke and its subtypes. We pooled hazard ratio (HR) estimates with 95% confidence intervals (CIs) and conducted heterogeneity test. Sensitivity analysis and publication bias test were also carried out. Twelve studies from 11 observational articles involving 47 836 individuals were included in the meta-analysis. We observed an inverse association between biomarkers of dietary LA and risk for total stroke (HR, 0.88; 95% CI, 0.83-0.94; P < 0.001). Meta-regression analysis suggested that ethnicity (P=0.029) and study design (P=0.049) contributed to between-study heterogeneity. Subgroup analysis showed that the association was statistically significant among studies conducted in white (P < 0.001) and Asian (P=0.032) populations, and those with cohort (P=0.001) and case-cohort design (P=0.007). Moreover, we found that higher LA levels were associated with a reduced risk for ischemic stroke (HR, 0.87; 95% CI, 0.80-0.95; P=0.001), although no statistically significant association was found between LA levels and the risk for hemorrhagic stroke. The present study supported an inverse association of LA levels with the risk for stroke, particularly ischemic stroke. Racial disparity exists in the association between LA and the risk for stroke, which deserves further studies.

Maternal High Linoleic Acid Alters Placental Fatty Acid Composition.

Fetal development is modulated by maternal nutrition during pregnancy. The dietary intake of linoleic acid (LA), an essential dietary n-6 polyunsaturated fatty acid (PUFA), has increased. We previously published that increased LA consumption during pregnancy does not alter offspring or placental weight but fetal plasma fatty acid composition; the developing fetus obtains their required PUFA from the maternal circulation. However, it is unknown if increased maternal linoleic acid alters placental fatty acid storage, metabolism, transport, and general placental function. Female Wistar-Kyoto rats were fed either a low LA diet (LLA; 1.44% of energy from LA) or high LA diet (HLA; 6.21% of energy from LA) for 10 weeks before pregnancy and during gestation. Rats were sacrificed at embryonic day 20 (E20, term = 22 days) and placentae collected. The labyrinth of placentae from one male and one female fetus from each litter were analyzed. High maternal LA consumption increased placental total n-6 and LA concentrations, and decreased total n-3 PUFA, alpha-linolenic acid (ALA), and docosahexaenoic acid (DHA). Fatty acid desaturase 1 (Fads1), angiopoietin-like 4 (Angptl4), and diacylglycerol lipase beta (Daglb) mRNA were downregulated in placentae from offspring from HLA dams. Maternal high LA downregulated the fatty acid transport protein 4 (Fatp4) and glucose transporter 1 (Slc2a1) mRNA in placentae. IL-7 and IL-10 protein were decreased in placentae from offspring from HLA dams. In conclusion, a high maternal LA diet alters the placental fatty acid composition, inflammatory proteins, and expressions of nutrient transporters, which may program deleterious outcomes in offspring.

Dietary intake and biomarkers of linoleic acid and mortality: systematic review and meta-analysis of prospective cohort studies

Current evidence on associations between intakes of linoleic acid (LA), the predominant n-6 (ω-6) fatty acid, and mortality is inconsistent and has not been summarized by a systematic review and meta-analysis. The aim was to perform a systematic review and meta-analysis of prospective cohort studies to examine associations between LA intake and mortality. We conducted a comprehensive search of MEDLINE and EMBASE databases through 31 July 2019 for prospective cohort studies reporting associations of LA (assessed by dietary surveys and/or LA concentrations in adipose tissue or blood compartments) with mortality from all causes, cardiovascular disease (CVD), and cancer. Multivariable-adjusted RRs were pooled using random-effects meta-analysis. Thirty-eight studies reporting 44 prospective cohorts were identified; these included 811,069 participants with dietary intake assessment (170,076 all-cause, 50,786 CVD, and 59,684 cancer deaths) and 65,411 participants with biomarker measurements (9758 all-cause, 6492 CVD, and 1719 cancer deaths). Pooled RRs comparing extreme categories of dietary LA intake (high vs low) were 0.87 (95% CI: 0.81, 0.94; I2=67.9%) for total mortality, 0.87 (95% CI: 0.82, 0.92; I2=3.7%) for CVD mortality, and 0.89 (95% CI: 0.85, 0.93; I2=0%) for cancer mortality. Pooled RRs for each SD increment in LA concentrations in adipose tissue/blood compartments were 0.91 (95% CI: 0.87, 0.95; I2=64.1%) for total mortality, 0.89 (95% CI: 0.85, 0.94; I2=28.9%) for CVD mortality, and 0.91 (95% CI: 0.84, 0.98; I2=26.3%) for cancer mortality. Meta-regressions suggested baseline age and dietary assessment methods as potential sources of heterogeneity for the association between LA and total mortality. In prospective cohort studies, higher LA intake, assessed by dietary surveys or biomarkers, was associated with a modestly lower risk of mortality from all causes, CVD, and cancer. These data support the potential long-term benefits of PUFA intake in lowering the risk of CVD and premature death.

Effects of dietary essential fatty acid requirements on growth performance, fatty acid composition, biochemical parameters, antioxidant response and lipid related genes expression in juvenile Onychostoma macrolepis

This study was conducted to elucidate effects of dietary essential fatty acid requirements on the growth, physiological characteristics and expressions of some lipid-related genes in juvenile Onychostoma macrolepis. Seven isonitrogenous and isoenergetic purified diets containing tristearin (control group), 2% linoleic acid (LA), 2% α-linolenic acid (LNA), 1% LA + 1% LNA, 1% eicosapentaenoic acid (EPA), 1% docosahexaenoic acid (DHA) and 0.5% EPA + 0.5% DHA were formulated to feed juvenile O.macrolepis (initial body weight:1.51 ± 0.05 g) for eight weeks. The weight gain (WG), specific growth rate (SGR) and feed efficiency (FE) of the fish were significantly higher in the LNA group and the EPA + DHA group than in the control group (P < .05). The growth and feed utilization of the fish in the LNA group were similar to those in the EPA + DHA group. The highest levels of 18:2n-6, 18:3n-3, 20:5n-3and 22:6n-3 in muscle and liver were found in the LA group, the LNA group, the EPA group and the DHA group, respectively. The highest concentrations of serum cholesterol (CHOL) and triglyceride (TG) were observed in the fish fed on the LA diet, and there were no significant differences in serum CHOL and TG between the LA group and the LA + LNA group. Serum malondialdehyde (MDA) content was observed to be the highest in the EPA group, DHA group and EPA + DHA group, and significantly higher in the these groups than in the other groups (P < .05). In liver, the superoxide dismutase (SOD) activities and the malondialdehyde (MDA) content were found to be significantly the lowest and the highest in the EPA, DHA and EPA + DHA groups (P < .05). The body fat content of the fish fed on the LA diet was significantly higher than those of the control ones (P < .05). The fatty acid synthetase (FAS), acetyl-CoA carboxylase 1(ACC1) and sterol regulatory element binding protein-1 (SREBP-1) genes involved in the anabolic pathway had the highest expression levels in the LA group. The adipose triglyceride lipase (ATGL), carnitine palmitoyl transferase 1 (CPT1) and peroxisome proliferators-activated receptor α (PPARα) genes involved in the catabolic pathway had the lowest expression levels in the control group. These results showed that the increase in fish body fat content induced by the LA diet was related to the up-regulation of some lipid biosynthesis metabolism genes. This study recommended that the dietary requirement of fatty acids for the optimal growth and health of juvenile O.macrolepis be 2% LNA or 0.5% EPA + 0.5% DHA (approximately 9% dietary fat). Its results might be conducive to optimizing fish diets while designing optimum dietary fatty acid profiles and proportions.

The Ratio of Linoleic and Linolenic Acid in the Pre-hibernation Diet Influences NFκB Signaling in Garden Dormice During Torpor.

The fatty acid composition of a pre-hibernation diet can influence the depth and duration of metabolic suppression achieved by hibernators. More specifically, a diet high in n−6 polyunsaturated fatty acids (PUFAs) relative to n−3 PUFAs is essential to maximize torpor expression. However, few studies have investigated how diets with different n−6/n−3 PUFA ratios change stress-inducible cell signaling. Garden dormice (Eliomys quercinus) were fed one of three diets designed with different ratios of n−6 PUFA linoleic acid (LA) and n−3 PUFA linolenic acid (ALA). Then, NFκB signaling was assessed in the white adipose, brown adipose, and liver tissues of euthermic and hibernating dormice via multiplex and RT-qPCR analyses of relative protein and transcript levels, respectively. Dormice fed a high LA diet regulated NFκB signaling in a protective manner in all tissues. NFκB signaling was generally decreased in the high LA group, with significant decreases in the protein levels of NFκB mediators IKKα/β, IκBα, and downstream pro-apoptotic protein FADD. Liver and white adipose from torpid dormice fed a high LA diet increased sod2 expression relative to the other diets or relative to euthermic controls, indicating protection against ROS generated from potentially increased β-oxidation of n−6 PUFAs. The low LA diet increased biomarkers for apoptosis relative to other diets and relative to euthermia, suggesting low LA diets may be detrimental to hibernator health. Overall, this study suggests that changes in the ratio of n−6/ n−3 PUFAs in the diet influences apoptotic and antioxidant responses in white adipose, brown adipose, and liver of hibernating garden dormice.

Preventive as well as therapeutic significances of linoleic acid in the containment of Leishmania donovani infection

People suffering from malnutrition show compromised levels of ω-6 fatty acid and malnutrition is frequently observed among visceral leishmaniasis (VL) patients as disease inflicts primarily the socioeconomic destitute communities. Dietary linoleic acid (LA, 18:2; ω-6 fatty acid) is the principal source of essential fatty acid and its derivatives i.e. eicosanoids possess immune-modulatory activities. However, its role in VL is not yet established. LA was measured in VL human subjects (serum) as well as in Leishmania(L.)donovani infected hamsters (serum and visceral organs). Organ-specific mRNA expressions of various enzymes of the LA metabolic pathway were measured in visceral organs of infected hamsters. Our findings showed a decrease in the concentrations of LA in the serum samples of VL patients, suggesting malnutrition among these patients. However, in L. donovani infected hamsters, its level was not altered in the early infection (15 days) and then increased at late infection (60 days). Importantly, the supplementation of LA restored the Th-1 type of immune response and significantly reduced the parasite load within infected macrophages in vitro. This protective response of LA was mediated through 5-lipoxygenase pathway not via the cyclooxygenase pathway. Preventive usage of LA to mϕ followed by L. donovani infection also showed the strengthening of Th-1 immune response and significantly fewer parasite loads. Our findings demonstrate the protective role of LA in the containment of the parasite load. Incorporating LA rich oils in daily food habits across highly inflicted regions may be a significant advancement towards the eradication of the disease.

The effects of dietary linolenic acid to linoleic acid ratio on growth performance, tissues fatty acid profile and sex steroid hormone synthesis of yellow catfish Pelteobagrus fulvidraco

The effects of different linolenic acid (LNA)/linoleic acid (LA) on tissues fatty acid composition and steroid hormone secretion of the female yellow catfish Pelteobagrus fulvidraco were evaluated after an 8-week feeding trial. Four isonitrogenous and isolipidic formulated diets were designed to contain different LNA/LA ratios of D0.27, D0.82, D1.71 and D2.63, respectively. The result showed that there were no significant effects on the weight gain (WG), gonadosomatic index (GSI), condition factor (CF) of yellow catfish among different diet treatments (P > 0.05). The relative fecundity was greatest in the D2.63 group (P < 0.05). The muscle and hepatic fatty acids profiles reflected corresponding dietary fatty acid profiles treatments, but not ovary. Eicosapentaenoic acid (EPA), arachidonic acid (ARA) and n–3 polyunsaturated fatty acid (PUFA) concentrations were significantly increased with increasing dietary LNA/LA ratios, in both muscle and liver (P < 0.05). ARA and highly unsaturated fatty acid (HUFA) concentrations in the egg were higher than that in liver and muscle, ARA was preferentially accumulated in yellow catfish gonad, which was not influenced by the dietary LNA/LA ratios. The levels of serum testosterone (T) decreased with increasing diet ratios of LNA to LA (P < 0.05), and the mRNA levels of steroidogenesis-related genes (CYP17a1, CYP19a and erβ) were significantly down-regulated with increasing dietary LNA/LA ratios in ovary of female (P < 0.05). In parallel with the changes of plasma follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the mRNA levels of 20 β-hydroxysteroid dehydrogenase (20β-HSD) upregulated with increasing LNA/LA ratios (P < 0.05). In conclusion, the present results suggest that dietary LNA/LA ratios regulated steroid hormone synthesis during ovarian development of yellow catfish. Higher-level dietary LNA/LA ratios are beneficial for HUFA -rich gonadal development and steroid synthesis of yellow catfish.

Impact of a high-fat diet on the fatty acid composition of the retina

Structure and function of the retina mainly rely on its fatty acid (FA) composition. Evidence from epidemiological studies and from animal experiments indicates that FA composition of the retina is influenced by the diet. Mice under chronic high-fat diet (HFD) develop metabolic syndrome, a risk factor for diabetes that is associated with structural and functional alterations of the retina. Here, we studied the impact of chronic exposure of mice to HFD on retinal FA composition.C57BL/6 J male mice were fed either a chow diet or a HFD for 11 weeks. As expected, HFD induced weight gain, adiposity, hyperglycemia and dyslipidemia. The retinal FA composition was determined by gas chromatography coupled to flame ionization detection. No significant change in the relative abundance of total saturated FAs (SFAs), total monounsaturated FAs (MUFAs) or total polyunsaturated FAs (PUFAs) was observed. However, retinas of HFD-fed mice displayed decreased amounts of C24:0 (p = 0.0231), C16:1n-7 (p < 0.0001), C18:1n-7 (p < 0.0001), C20:3n-9 (p = 0.0425) and C20:3n-6 (p = 0.0008), and an increased amount of C20:2n-6 (p < 0.0001). In addition, the ratio of linoleic acid (C18:2n-6) to alpha-linolenic acid (C18:3n-3) was increased in the retinas of HFD-fed mice (15.0 ± 0.8 versus 11.8 ± 0.6 in HFD and CD, respectively, p = 0.0045). No modification in the contents of arachidonic acid (C20:4n-6, AA) and docosahexaenoic acid (C22:6n-3, DHA) were observed. Analysis of dimethylacetals (DMA), which are residues of plasmalogens (Pls), revealed that the amount of Pls containing octadecanal-aldehydes (DMA C18:0) was significantly increased in HFD-fed mice (p = 0.0447). This increase was, at least in part, balanced by a decrease in Pls containing 7-octadecanal-aldehydes (DMA C18:1n-7) (p = 0.0007).In conclusion, HFD had an impact on the relative proportion of essential dietary fatty acids linoleic acid and alpha-linolenic acid that are incorporated in the retina. However, this imbalance in PUFA precursors did not alter the content of the two major retinal long-chain PUFAs, AA and DHA. HFD consumption also led to alterations in the retinal SFAs, MUFAs and Pls profiles.

4‐HNE Unfavorably Alters Muscle Mitochondrial Bioenergetics and Cell Viability

Linoleic acid consumption has increased by orders of magnitude over the past century, eliciting an increasing awareness of and appreciation for its metabolites, particularly 4‐hydroxynonenal (4‐HNE). Elevated 4‐HNE formation is causally implicated in myriad neurodegenerative, cardiovascular, autoimmune, and metabolic disorders. The purpose of this project was to identify the effect of 4‐HNE on muscle cell mitochondrial bioenergetics. Our primary observation was that physiological levels of 4‐HNE compromised muscle cell mitochondrial oxygen consumption, leading to reduced oxygen flux despite a substantial production of reactive oxygen species (ROS). Indeed, when viewed in light of the reduced oxygen consumption, the relative production of ROS with 4‐HNE was even more pronounced. These findings could explain the significant reduction of cell viability demonstrated. In conclusion, this work joins the growing body of evidence suggesting a need to scrutinize dietary linoleic acid consumption.

Role of a Maternal Diet High in Linoleic Acid on the Plasma Fatty Acid Composition in Rat Offspring

Linoleic acid (LA) is a major omega‐6 polyunsaturated fatty acid (PUFA) which is essential in our diet. LA is an important fatty acid for fetal growth and development and is transported from mother to fetus through the placenta. Dietary intake of LA has increased significantly in western societies primarily due to increased consumption of vegetable oils. Conversely, the consumption of alpha‐linolenic acid (ALA), an omega‐3 PUFA, has remained similar or decreased due to limited consumption of fish. Metabolites of omega‐3 PUFAs such as docosahexaenoic (DHA) and eicosapentaenoic (EPA) have critical roles in fetal neural development and may influence brain function in later in life. The aim of this study is to investigate the effect of a maternal diet high in LA on offspring fatty acid composition at 40 days of age (adolescence). Female rats were fed with either low LA diet (LLA; 1.44% of energy from LA) or high LA (HLA; 6.21% of energy from LA) with matched ALA (0.3% of energy) for 10 weeks before pregnancy and during gestation. The pups were weaned at postnatal day 25 (PN25) and fed with either LLA or HLA diet (Four groups ‐ LL, LH, HL, HH; first letter denotes maternal diet and second letter denotes post‐weaning diet). The offspring were sacrificed at postnatal day 40 and biological samples were collected and stored at −80°C. The concentration of fatty acids in plasma was quantified using gas chromatography. Total omega‐6 fatty acid (FA) and LA levels in plasma were significantly elevated in the offspring fed with HLA diet at weaning and offspring from dams fed with HLA (LH, HL, HH) compared to offspring from LLA dams fed with LLA at weaning (LL) both in male and female offspring. Total omega‐3 FA was significantly decreased in offspring from HLA dams fed with HLA diet (HH) at weaning in comparison to offspring from LLA dams fed with LLA at weaning (LL). The concentration of ALA was significantly decreased in male offspring from HLA dams fed with HLA diet (HH) compared to HL offspring; however, there was no difference in female offspring. In addition, the plasma level of EPA was significantly decreased in male offspring fed with HLA diet at weaning (LH and HH) compared with LL offspring; however, there was no difference in female offspring. Moreover, DHA, an important omega‐3 FA for brain development, was significantly decreased in HH offspring compared to LL offspring. Hence, the findings from the current study suggest that elevated LA in both maternal diet and weaning diet influence the plasma fatty acid composition in adolescent offspring in a rat model.Support or Funding InformationThis work was supported by the Allen Foundation (D.H.H., A.J.M.), and through the Australian Government's Collaborative Research Networks (CRN) programme (A.J.M.). Scholarship funding is provided by Griffith University International Postgraduate Research Scholarship (GUIPRS; N.S.), Griffith University Postgraduate Research Scholarship (GUPRS, N.S.) and Griffith Health Top Up Scholarship (N.S.). B.S.M. is supported by a National Health and Medical Research Council of Australia Career Development Award (Level 2) (APP1083009).

Elevated maternal linoleic acid alters placental fatty acids, nutrient transporters and inflammatory proteins

Linoleic acid (LA) is the major omega‐6 fatty acid which is obtained from our diet. During pregnancy, LA is required for adequate fetal growth and development. For the growing fetus LA can only be obtained from the maternal diet, and is transferred from the maternal to fetal circulations by the placenta. At this time, in Western societies, we are overconsuming LA during pregnancy. Omega‐6 is metabolised by FADS1 and FADS2, which also metabiolise omega‐3. The ratio of omega‐6 to omega‐3 is important for human health, as they are proinflammatory and anti‐inflammatory, respectively. Therefore, the aim of this study is to determine if elevated maternal LA during pregnancy is alters placental fatty acids, nutrient transporter gene expression and inflammatory proteins.Female Wistar Kyoto rats were fed a diet low in LA (LLA‐1.44% of energy) or diet high in LA (HLA‐6.21% of energy) for 10 weeks before and during gestation. Following mating with a male consuming normal chow, offspring and maternal rats were sacrificed at embryonic day (E)20, and placenta were collected for analysis of placental fatty acids, nutrient transporters and inflammatory markers.In isolated placenta from pregnancies where mothers consumed an elevated LA diet, the concentration of LA was increased and the concentration of the omega‐3 fatty acid a‐linoleinic acid was decreased. Of interest, the downstream metabolite of LA, arachidonic acid was not altered in placenta from mothers consuming an elevated LA diet. mRNA expression of slc27a1 (fatty acid trasnport protein 1) was significantly downregulated in the male placenta from the dams fed with HLA, but not females. The mRNA expression of slc2a1 (glucose trasnporter 1) was significantly decreased in both male and female placenta from mothers fed the HLA diet. Further, the protein concentration of interleukin‐7 (IL‐7) was significantly decreased in both male and female placenta (labyrinth) from the dams fed with HLA, however there were no changes in protein expression of IL‐6 and TNF‐α in the labyrinth.In conclusion, a maternal diet high in LA alters fatty acid concentrations, nutrient transporters and inflammatory cytokines in the placenta. The consequences of this on offspring development, and therefore long term health require further investigation.Support or Funding InformationAllen Foundation (USA)

Effects of parental dietary linoleic acid on growth performance, antioxidant capacity, and lipid metabolism in domestic pigeons (Columba livia)

The objective of this study was to evaluate the effects of dietary linoleic acid (LA) on growth performance, antioxidant capacity, and lipid metabolism in pigeon squabs by supplementing LA in their parental diets. A completely randomized design that consisted of a control group, 1% dietary LA addition group (LA1%), 2% dietary LA addition group (LA2%), and 4% dietary LA addition group (LA4%) was used. Six squabs from each treatment were randomly sampled at the day of hatch and days 7, 14, and 21 after hatch. The results showed that parental dietary LA had no significant influence (P > 0.05) on body weight (BW) gain or relative organ weights (% of BW) in squabs. The activities of superoxide dismutase, catalase, and glutathione peroxidase in the LA1% were significantly increased (P < 0.05) compared with those in the control group. The malondialdehyde content in the LA1% was significantly lower (P < 0.05) than that in the control group. The levels of serum triglyceride in the LA1% and LA2% were significantly decreased (P < 0.05) compared with those in the control group, whereas the serum high-density lipoprotein cholesterol level in the LA1% and LA2% and the free fatty acid level in the LA4% were significantly higher (P < 0.05) than those of the control group. The activities of lipoprotein lipase, hepatic lipase, and hormone-sensitive lipase in the LA1% were significantly higher (P < 0.05) than those in the control group. The 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in the LA1% and the hormone-sensitive lipase activity in the LA4% were significantly decreased (P < 0.05) compared with those in the control group. The mRNA expression of carnitine palmitoyltransferase 1, acyl-CoA 1, and peroxisome proliferator-activated receptor α was significantly upregulated (P < 0.05) in the LA1% compared with that in the control group. The Oil Red O staining area in the LA1% and LA2% was significantly reduced compared with that in the control group. The results indicated that although supplemental LA had negligible effects on growth and development in pigeon squabs, parental dietary LA at a concentration of 1% could have beneficial effects on maintaining squabs healthy as reflected by improved antioxidant capacity and lipid metabolism.

The effects of dietary linoleic acid and hydrophilic antioxidants on basal, peak, and sustained metabolism in flight-trained European starlings.

Dietary micronutrients have the ability to strongly influence animal physiology and ecology. For songbirds, dietary polyunsaturated fatty acids (PUFAs) and antioxidants are hypothesized to be particularly important micronutrients because of their influence on an individual's capacity for aerobic metabolism and recovery from extended bouts of exercise. However, the influence of specific fatty acids and hydrophilic antioxidants on whole‐animal performance remains largely untested. We used diet manipulations to directly test the effects of dietary PUFA, specifically linoleic acid (18:2n6), and anthocyanins, a hydrophilic antioxidant, on basal metabolic rate (BMR), peak metabolic rate (PMR), and rates of fat catabolism, lean catabolism, and energy expenditure during sustained flight in a wind tunnel in European starlings (Sturnus vulgaris). BMR, PMR, energy expenditure, and fat metabolism decreased and lean catabolism increased over the course of the experiment in birds fed a high (32%) 18:2n6 diet, while birds fed a low (13%) 18:2n6 diet exhibited the reverse pattern. Additionally, energy expenditure, fat catabolism, and flight duration were all subject to diet‐specific effects of whole‐body fat content. Dietary antioxidants and diet‐related differences in tissue fatty acid composition were not directly related to any measure of whole‐animal performance. Together, these results suggest that the effect of dietary 18:2n6 on performance was most likely the result of the signaling properties of 18:2n6. This implies that dietary PUFA influence the energetic capabilities of songbirds and could strongly influence songbird ecology, given their availability in terrestrial systems.

Pregnancy and diet-related changes in the maternal gut microbiota following exposure to an elevated linoleic acid diet.

Dietary intakes of linoleic acid (LA) have increased, including in women of reproductive age. Changes in maternal gut microbiome have been implicated in the metabolic adaptions that occur during pregnancy. We aimed to investigate whether consumption of a diet with elevated LA altered fecal microbiome diversity before and during pregnancy. Female Wistar-Kyoto rats consumed a high-LA diet (HLA: 6.21% of energy) or a low-LA diet (LLA: 1.44% of energy) for 10 wk before mating and during pregnancy. DNA was isolated from fecal samples before pregnancy [embryonic day 0 (E0)], or during pregnancy at E10 and E20. The microbiome composition was assessed with 16S rRNA sequencing. At E0, the beta-diversity of LLA and HLA groups differed with HLA rats having significantly lower abundance of the genera Akkermansia, Peptococcus, Sutterella, and Xo2d06 but higher abundance of Butyricimonas and Coprococcus. Over gestation, in LLA but not HLA rats, there was a reduction in alpha-diversity and an increase in beta-diversity. In the LLA group, the abundance of Akkermansia, Blautia, rc4.4, and Streptococcus decreased over gestation, whereas Coprococcus increased. In the HLA group; only the abundance of Butyricimonas decreased. At E20, there were no differences in alpha- and beta-diversity, and the abundance of Roseburia was significantly increased in the HLA group. In conclusion, consumption of a HLA diet alters gut microbiota composition, as does pregnancy in rats consuming a LLA diet. In pregnancy, consumption of a HLA diet does not alter gut microbiota composition.

The effect of high maternal linoleic acid on endocannabinoid signalling in rodent hearts.

The endocannabinoid system (ECS), modulated by metabolites of linoleic acid (LA), is important in regulating cardiovascular function. In pregnancy, LA is vital for foetal development. We investigated the effects of elevated LA in H9c2 cardiomyoblasts in vitro and of a high linoleic acid (HLA, 6.21%) or low linoleic acid (LLA, 1.44%) diet during pregnancy in maternal and offspring hearts. H9c2 cell viability was reduced following LA exposure at concentrations between 300 and 1000 µM. HLA diet decreased cannabinoid receptor type 2 (CB2) mRNA expression in foetal hearts from both sexes. However, HLA diet increased CB2 expression in maternal hearts. The mRNA expression of fatty acid amide hydrolase (FAAH) in foetal hearts was higher in females than in males irrespective of diet and N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) mRNA expression showed an interaction between diet and sex. Data indicate that a high LA diet alters cell viability and CB2 expression, potentially influencing cardiac function during pregnancy and development of the offspring's heart.

Plasma and Dietary Linoleic Acid and 3-Year Risk of Type 2 Diabetes After Myocardial Infarction: A Prospective Analysis in the Alpha Omega Cohort.

To study plasma and dietary linoleic acid (LA) in relation to type 2 diabetes risk in post-myocardial infarction (MI) patients. We included 3,257 patients aged 60-80 years (80% male) with a median time since MI of 3.5 years from the Alpha Omega Cohort and who were initially free of type 2 diabetes. At baseline (2002-2006), plasma LA was measured in cholesteryl esters, and dietary LA was estimated with a 203-item food-frequency questionnaire. Incident type 2 diabetes was ascertained through self-reported physician diagnosis and medication use. Hazard ratios (with 95% CIs) were calculated by Cox regressions, in which dietary LA isocalorically replaced the sum of saturated (SFA) and trans fatty acids (TFA). Mean ± SD circulating and dietary LA was 50.1 ± 4.9% and 5.9 ± 2.1% energy, respectively. Plasma and dietary LA were weakly correlated (Spearman r = 0.13, P < 0.001). During a median follow-up of 41 months, 171 patients developed type 2 diabetes. Plasma LA was inversely associated with type 2 diabetes risk (quintile [Q]5 vs. Q1: 0.44 [0.26, 0.75]; per 5%: 0.73 [0.62, 0.86]). Substitution of dietary LA for SFA+TFA showed no association with type 2 diabetes risk (Q5 vs. Q1: 0.78 [0.36, 1.72]; per 5% energy: 1.18 [0.59, 2.35]). Adjustment for markers of de novo lipogenesis attenuated plasma LA associations. In our cohort of post-MI patients, plasma LA was inversely related to type 2 diabetes risk, whereas dietary LA was not related. Further research is needed to assess whether plasma LA indicates metabolic state rather than dietary LA in these patients.

The catadromous teleost Anguilla japonica has a complete enzymatic repertoire for the biosynthesis of docosahexaenoic acid from α-linolenic acid: Cloning and functional characterization of an Elovl2 elongase.

The Japanese eel Anguilla japonica is a catadromous fish species with considerable farming scale. Previous studies showed that dietary α-linolenic acid (18:3n-3) and linoleic acid (18:2n-6) satisfied essential fatty acid requirements in eel, which suggested that Japanese eel should have a complete pathway for the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFA). However, existing knowledge was insufficient to explain the molecular basis of LC-PUFA biosynthetic capacity in eel. In order to further characterize this pathway in eel, a full-length cDNA of a putative fatty acyl elongase was isolated, with the ORF encoding a protein with 294 amino acids. The putative elongase displayed high homology to Elovl2 of other teleosts. Functional characterization by heterologous expression in yeast showed the protein product of the cDNA had high activity towards C20 and C22 PUFA substrates and low activity towards C18 PUFA substrates, characteristic of Elovl2 elongases. Tissue distribution of the elovl2 mRNA showed highest expression in brain and eyes, which was different from freshwater and anadromous species. This may reflect an important role for this enzyme in the in situ endogenous biosynthesis of docosahexaenoic acid (DHA) in neural tissues in eel. This is the first report of an Elovl2 in a catadromous teleost and demonstrates that Japanese eel has a complete enzyme repertoire required for the endogenous biosynthesis of DHA via the Sprecher pathway. These data have increased our knowledge of the diversity of LC-PUFA biosynthesis in vertebrates, and provided further insight into the regulatory mechanisms of LC-PUFA biosynthesis in teleost fish.

Linoleic acid improves assembly of the CII subunit and CIII2/CIV complex of the mitochondrial oxidative phosphorylation system in heart failure

BackgroundLinoleic acid is the major fatty acid moiety of cardiolipin, which is central to the assembly of components involved in mitochondrial oxidative phosphorylation (OXPHOS). Although linoleic acid is an essential nutrient, its excess intake is harmful to health. On the other hand, linoleic acid has been shown to prevent the reduction in cardiolipin content and to improve mitochondrial function in aged rats with spontaneous hypertensive heart failure (HF). In this study, we found that lower dietary intake of linoleic acid in HF patients statistically correlates with greater severity of HF, and we investigated the mechanisms therein involved.MethodsHF patients, who were classified as New York Heart Association (NYHA) functional class I (n = 45), II (n = 93), and III (n = 15), were analyzed regarding their dietary intakes of different fatty acids during the one month prior to the study. Then, using a mouse model of HF, we confirmed reduced cardiolipin levels in their cardiac myocytes, and then analyzed the mechanisms by which dietary supplementation of linoleic acid improves cardiac malfunction of mitochondria.ResultsThe dietary intake of linoleic acid was significantly lower in NYHA III patients, as compared to NYHA II patients. In HF model mice, both CI-based and CII-based OXPHOS activities were affected together with reduced cardiolipin levels. Silencing of CRLS1, which encodes cardiolipin synthetase, in cultured cardiomyocytes phenocopied these events. Feeding HF mice with linoleic acid improved both CI-based and CII-based respiration as well as left ventricular function, together with an increase in cardiolipin levels. However, although assembly of the respirasome (i.e., CI/CIII2/CIV complex), as well as assembly of CII subunits and the CIII2/CIV complex statistically correlated with cardiolipin levels in cultured cardiomyocytes, respirasome assembly was not notably restored by dietary linoleic acid in HF mice. Therefore, although linoleic acid may significantly improve both CI-based and CII-based respiration of cardiomyocytes, respirasomes impaired by HF were not easily repaired by the dietary intake of linoleic acid.ConclusionsDietary supplement of linoleic acid is beneficial for improving cardiac malfunction in HF, but is unable to completely cure HF.