Dietary Polyunsaturated Fatty Acids Research Articles

The Role of Dietary and Microbial Fatty Acids in the Control of Inflammation in Neonatal Piglets.

Simple SummaryThe maturation of the gut is a specific and very dynamic process in new-born piglets. Consequently, piglet’s gut is very susceptible to disturbances, especially in stressful periods of life, such as weaning, when the gut lining often becomes inflamed and leaky. Dietary fatty acids (FA) do not only serve as source of energy and essential FA, but they are important precursors for bioactive lipid mediators, which modulate inflammatory signalling in the body. The current review summarizes results on dietary sources of FA for piglets, the signalling cascades, bioactivities, the necessity to consider the autoxidation potential of polyunsaturated FA and the area of microbially produced long-chain FA. That said, porcine milk is high in fat, whereby the milk FA composition partly depends on the dietary FA composition of the sow. Therefore, manipulation of the sow diet is an efficient tool to increase the piglet’s intake of specific FA, e.g., n-3 polyunsaturated FA which show anti-inflammatory activity and may support intestinal integrity and functioning in the growing animal.Excessive inflammation and a reduced gut mucosal barrier are major causes for gut dysfunction in piglets. The fatty acid (FA) composition of the membrane lipids is crucial for mediating inflammatory signalling and is largely determined by their dietary intake. Porcine colostrum and milk are the major sources of fat in neonatal piglets. Both are rich in fat, demonstrating the dependence of the young metabolism from fat and providing the young organism with the optimum profile of lipids for growth and development. The manipulation of sow’s dietary polyunsaturated FA (PUFA) intake has been shown to be an efficient strategy to increase the transfer of specific FAs to the piglet for incorporation in enteric tissues and cell membranes. n-3 PUFAs, especially seems to be beneficial for the immune response and gut epithelial barrier function, supporting the piglet’s enteric defences in situations of increased stress such as weaning. Little is known about microbial lipid mediators and their role in gut barrier function and inhibition of inflammation in neonatal piglets. The present review summarizes the current knowledge of lipid nutrition in new-born piglets, comparing the FA ingestion from milk and plant-based lipid sources and touching the areas of host lipid signalling, inflammatory signalling and microbially derived FAs.

Fish Intake, Dietary Polyunsaturated Fatty Acids, and Lung Cancer: Systematic Review and Dose–Response Meta-Analysis of 1.7 Million Men and Women

To determine the association between fish intake and dietary polyunsaturated fatty acids (PUFA) and incidence of lung cancer. We systematically reviewed and meta-analyzed all available studies to quantify the associations of fish and PUFA consumption with risk of lung cancer. Relative risk (RR) with 95% confidence interval (CI) was calculated. 13 population-based prospective cohort studies involving 1,785,000 participants and two randomized control trials were included. Our study demonstrated that dietary PUFA significant reduced risk of lung cancer for men (RR 0.99, 95%CI 0.98 to 1.00) and the U.S. population (RR 0.99, 95%CI 0.98 to 1.00). Dose-response analysis indicated that a 5 g/day increment of dietary PUFA was associated with 5% lower risk of lung cancer (RR 0.95, 95%CI 0.91 to 0.99). In addition, PUFA supplementation is significant improved overall survival in patients with lung cancer (RR 1.98, 95%CI 1.09 to 3.59). Our study showed an inverse association between dietary PUFA and risk of lung cancer in males and among the U.S. population. Although smoking cessation is the single biggest factor associated with lung cancer risk reduction, this study adds to a growing body of evidence that diet may have a role in modestly reducing lung cancer risk.

Taxonomic composition and lake bathymetry influence fatty acid export via emergent insects

Abstract The ecological role of emergent aquatic insects from lakes in exporting dietary polyunsaturated fatty acids (PUFA) across the freshwater‐land interface is still poorly understood. In this field study, we explored the seasonal biomass export of emergent insects from three subalpine lakes and investigated how lipids of emergent insects were related to lake bathymetry, lipids of organic matter in lake sediments (i.e., basal resources), and the taxonomic composition of insects. The total lipid and PUFA fluxes of emergent insects were strongly related to taxonomy and lake bathymetry, but weakly associated with the PUFA content of the uppermost lake sediment layers. PUFA flux estimates of the dominant taxon, Chironomidae, from the shallowest lake (3 m depth; 125 g PUFA m−2 season−1) were considerably higher than those from the deepest lake (33 m depth; 56 g PUFA m−2 season−1), due to the higher per area biomass of emergent insects from this shallow lake. Insect taxonomy also affected the composition of PUFA transfer to land: Chironomidae were richer in ω‐6 PUFA, such as linoleic acid (18:2n‐6) and arachidonic acid (20:4n‐6), whereas Ephemeroptera and Trichoptera contained more ω‐3 PUFA, especially α‐linolenic acid (18:3n‐3) and eicosapentaenoic acid (20:5n‐3). Our findings suggest that taxon‐specific differences in PUFA content and lake bathymetry jointly shape PUFA fluxes and thus the provisioning of emergent insects as dietary sources of physiologically important PUFA for riparian consumers.

Warming Decreases Bioconversion of Polyunsaturated Fatty Acids in Chironomid Larvae Maintained on Cyanobacterium Microcystis.

Cyanobacteria dominance and warming have been suggested to decrease the production of polyunsaturated fatty acids (PUFA) in freshwater ecosystems. Physiological adaptations of poikilothermic animals to higher temperatures may further decrease PUFA levels in aquatic food webs. We conducted diet manipulation experiments to investigate the combined effects of dietary PUFA and warming on the proportions of eicosapentaenoic acid (EPA) and arachidonic acid (ARA) in Chironomus riparius. The experimental diet consisted of a nontoxic cyanobacterium Microcystis, which contained C20 PUFA: 20:3n-3, 20:4n-3, and 20:3n-6, but no EPA or ARA. Additionally, we used TetraMin® fish flakes as a control treatment. A temperature increase from 20 °C to 25 °C decreased the proportion of n-3 C20 PUFA and the n-3/n-6 ratio in Microcystis. Diet manipulation experiments indicated that Chironomus desaturated dietary C20 precursors to EPA and ARA, but warming decreased this bioconversion and resulted in lower levels of EPA and ARA in Chironomus. Warming did not alter the proportions of EPA and ARA in Chironomus larvae if these PUFA were readily available in the diet (TetraMin® control treatment). In conclusion, warming and cyanobacteria dominance may decrease the production and trophic transfer of physiologically important PUFA in freshwaters by (1) decreasing the n-3/n-6 ratio and the abundance of n-3 C20 precursors in Microcystis, and (2) decreasing the bioconversion of n-3 and n-6 C20 precursors to EPA and ARA in chironomids. These changes may have cascading effects throughout the food web and decrease the content of EPA in fish, potentially affecting its availability to humans.

Dietary Intake of Linoleic Acid, Its Concentrations, and the Risk of Type 2 Diabetes: A Systematic Review and Dose-Response Meta-analysis of Prospective Cohort Studies.

Earlier evidence on the association between dietary polyunsaturated fatty acids and risk of diabetes has been conflicting. To quantitatively summarize previous studies on the association between dietary LA intake, its biomarkers, and the risk of type 2 diabetes mellitus (T2DM) in the general population. Our data sources included PubMed/MEDLINE, Scopus, and ISI Web of Science until 24 October 2020; reference lists of all related articles; and key journals. We included prospective cohort studies that examined the associations of linoleic acid (LA) with the risk of T2DM in adults. The inverse variance method was applied to calculate summary relative risk (RR) of LA intake and its biomarkers, and dose-response associations were modeled using restricted cubic splines. Twenty-three publications, covering a total of 31 prospective cohorts, were included; these studies included 297,685 participants (22,639 incident diabetes cases) with dietary intake assessment and 84,171 participants (18,458 incident diabetes cases) with biomarker measurements. High intake of LA was associated with a 6% lower risk of T2DM (summary relative risk [RR] 0.94, 95% CI 0.90, 0.99; I 2 = 48.5%). In the dose-response analysis, each 5% increment in energy from LA intake was associated with a 10% lower risk of T2DM. There was also evidence of a linear association between LA intake and diabetes, with the lowest risk at highest intakes. The summary RR for diabetes per SD increment in LA concentrations in adipose tissue/blood compartments was 0.85 (95% CI 0.80, 0.90; I2 = 66.2%). The certainty of the evidence was assessed as moderate. A limitation of our work was the observational design of studies included in the analyses. We found that a high intake of dietary LA and elevated concentrations of LA in the body were both significantly associated with a lower risk of T2DM. These findings support dietary recommendations to consume dietary LA.

Plant and algal lysophosphatidic acid acyltransferases increase docosahexaenoic acid accumulation at the sn-2 position of triacylglycerol in transgenic Arabidopsis seed oil.

Although docosahexaenoic acid (DHA), an important dietary omega-3 polyunsaturated fatty acid (PUFA), is at present primarily sourced from marine fish, bioengineered crops producing DHA may offer a more sustainable and cost-effective source. DHA has been produced in transgenic oilseed crops, however, DHA in seed oil primarily occupies the sn-1/3 positions of triacylglycerol (TAG) with relatively low amounts of DHA in the sn-2 position. To increase the amount of DHA in the sn-2 position of TAG and in seed oil, putative lysophosphatidic acid acyltransferases (LPAATs) were identified and characterized from the DHA-producing alga Schizochytrium sp. and from soybean (Glycine max). The affinity-purified proteins were confirmed to have LPAAT activity. Expression of the Schizochytrium or soybean LPAATs in DHA-producing Arabidopsis expressing the Schizochytrium PUFA synthase system significantly increased the total amount of DHA in seed oil. A novel sensitive band-selective heteronuclear single quantum coherence (HSQC) NMR method was developed to quantify DHA at the sn-2 position of glycerolipids. More than two-fold increases in sn-2 DHA were observed for Arabidopsis lines expressing Schizochytrium or soybean LPAATs, with one Schizochytrium LPAAT driving DHA accumulation in the sn-2 position to 61% of the total DHA. Furthermore, expression of a soybean LPAAT led to a redistribution of DHA-containing TAG species, with two new TAG species identified. Our results demonstrate that transgenic expression of Schizochytrium or soybean LPAATs can increase the proportion of DHA at the sn-2 position of TAG and the total amount of DHA in the seed oil of a DHA-accumulating oilseed plant. Additionally, the band-selective HSQC NMR method that we developed provides a sensitive and robust method for determining the regiochemistry of DHA in glycerolipids. These findings will benefit the advancement of sustainable sources of DHA via transgenic crops such as canola and soybean.

N-3 PUFA-Deficiency in Early Life Exhibits Aggravated MPTP-Induced Neurotoxicity in Old Age while Supplementation with DHA/EPA-Enriched Phospholipids Exerts a Neuroprotective Effect.

Malnutrition in early life affects the growth and development of fetus and children, which has a long-term impact on adult health. Previous studies reveal a relationship between dietary omega-3 polyunsaturated fatty acid (n-3 PUFA) content, brain development, and the prevalence of neurodevelopmental disorders and inflammation. However, it is unclear about the effect of n-3 PUFA-deficiency in early life on the development of Parkinson's disease (PD) in old age, as well as the neuroprotective effect of DHA- and EPA-enriched phospholipids (DHA/EPA-PLs) supplemented in old age in long-term n-3 PUFA-deficient mice. The PD mice induced by 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) in n-3 PUFA-adequate (N) and -deficient (DEF) group are supplemented with a DHA/EPA-PLs diet for 2 weeks (N+DPL, DEF+DPL). DHA/EPA-PLs supplementation significantly protects against MPTP-induced impairments. The DEF+DPL group shows poorer motor performance, the loss of dopaminergic neurons, mitochondrial dysfunction, and neurodevelopment delay than the N+DPL group, and still did not recover to the Control level. Dietary n-3 PUFA-deficiency in early life exhibits more aggravated MPTP-induced neurotoxicity in old age, than DHA/EPA-PLs supplementation recovers brain DHA levels and exerts neuroprotective effects in old age in long-term n-3 PUFA-deficient mice, which might provide a potential dietary guidance.

Elevated temperature and browning increase dietary methylmercury, but decrease essential fatty acids at the base of lake food webs

Climate change scenarios predict increases in temperature and organic matter supply from land to water, which affect trophic transfer of nutrients and contaminants in aquatic food webs. How essential nutrients, such as polyunsaturated fatty acids (PUFA), and potentially toxic contaminants, such as methylmercury (MeHg), at the base of aquatic food webs will be affected under climate change scenarios, remains unclear. The objective of this outdoor mesocosm study was to examine how increased water temperature and terrestrially-derived dissolved organic matter supply (tDOM; i.e., lake browning), and the interaction of both, will influence MeHg and PUFA in organisms at the base of food webs (i.e. seston; the most edible plankton size for zooplankton) in subalpine lake ecosystems. The interaction of higher temperature and tDOM increased the burden of MeHg in seston (< 40 μm) and larger sized plankton (microplankton; 40–200 μm), while the MeHg content per unit biomass remained stable. However, PUFA decreased in seston, but increased in microplankton, consisting mainly of filamentous algae, which are less readily bioavailable to zooplankton. We revealed elevated dietary exposure to MeHg, yet decreased supply of dietary PUFA to aquatic consumers with increasing temperature and tDOM supply. This experimental study provides evidence that the overall food quality at the base of aquatic food webs deteriorates during ongoing climate change scenarios by increasing the supply of toxic MeHg and lowering the dietary access to essential nutrients of consumers at higher trophic levels.

An abundant biliary fatty acid metabolite derived from dietary omega-3 polyunsaturated fatty acids regulates triglycerides

Background and Aims: Omega-3 fatty acids from fish oil reduce triglyceride levels in mammals, yet the mechanisms underlying this effect have not been fully clarified despite the clinical use of omega-3 ethyl esters to treat severe hypertriglyceridemia and reduce cardiovascular disease risk in humans. Here we identify in bile a class of hypotriglyceridemic omega-3 fatty acid-derived N-acyl taurines (NATs) that, after dietary omega-3 fatty acid supplementation, increase to concentrations similar to those of steroidal bile acids. We aimed to determine physiological function of this metabolite.

Eicosapentaenoic acid membrane incorporation stimulates ABCA1-mediated cholesterol efflux from human THP-1 macrophages

A high intake in polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acid (EPA) (C20:5 n-3), is cardioprotective. Dietary PUFAs incorporate into membrane phospholipids, which may modify the function of membrane proteins. We investigated the consequences of the membrane incorporation of several PUFAs on the key antiatherogenic ABCA1-mediated cholesterol efflux pathway. Human THP-1 macrophages were incubated with EPA, arachidonic acid (AA) (C20:4 n-6) or docosahexaenoic acid (DHA) (C22:6 n-3) for a long time to mimic a chronic exposure. EPA 70 μM, but not AA 50 μM or DHA 15 μM, increased ABCA1-mediated cholesterol efflux to apolipoprotein (apo) AI by 28% without altering aqueous diffusion. No variation in ABCA1 expression or localization was observed after EPA treatment. EPA incorporation did not affect the phenotype of THP-1 macrophages. The membrane phospholipids composition of EPA cells displayed higher levels of both EPA and its elongation product docosapentaenoic acid, which was associated with drastic lower levels of AA. Treatment by EPA increased the ATPase activity of the transporter, likely through a PKA-dependent mechanism. Eicosanoids were not involved in the stimulated ABCA1-mediated cholesterol efflux from EPA-enriched macrophages. In addition, EPA supplementation increased the apo AI binding capacity from macrophages by 38%. Moreover, the increased apo AI binding in EPA-enriched macrophages can be competed. In conclusion, EPA membrane incorporation increased ABCA1 functionality in cholesterol-normal human THP-1 macrophages, likely through a combination of different mechanisms. This beneficial in vitro effect may partly contribute to the cardioprotective effect of a diet enriched with EPA highlighted by several recent clinical trials.

Higher n-3 Polyunsaturated Fatty Acid Diet Improves Long-Term Neuropathological and Functional Outcome after Repeated Mild Traumatic Brain Injury.

Repeated mild traumatic brain injury (TBI) can cause persistent neuropathological effects and is a major risk factor for chronic traumatic encephalopathy. PUFAs (n-3 polyunsaturated fatty acids) were shown to improve acute TBI outcomes in single-injury models in most cases. In this study, we demonstrate positive effects of dietary n-3 PUFA on long-term neuropathological and functional outcome in a clinically relevant model of repeated mild TBI using the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA). Adult mice, reared on n-3 PUFA adequate (higher n-3 PUFA) or deficient (lower n-3 PUFA) diets, were given a mild CHIMERA daily for 3 consecutive days. At 2 months after injury, visual function and spatial memory were evaluated. Glia cell activation was assessed by immunostaining using antibodies of ionized calcium-binding adaptor molecule 1 and glial fibrillary acidic protein, and axonal damage was examined using silver staining. Repeated CHIMERA (rCHIMERA)-induced gliosis was significantly suppressed in the optic tract, corpus callosum, and hippocampus of mice fed the n-3 PUFA adequate diet compared to the deficient diet group. Considerable axonal damage was detected in the optic tract after rCHIMERA, but the adequate diet group displayed less axonal damage compared to the deficient diet group. rCHIMERA induced a drastic reduction in N1 amplitude of the visual evoked potential in both diet groups and the a-wave amplitude of the electroretinogram in the deficient diet group. However, reduction of N1 and a-wave amplitude were less severe in the adequate diet group. The Morris water maze probe test indicated a significant decrease in the number of platform crossings in the deficient diet group compared to the adequate group. In summary, dietary n-3 PUFA can attenuate persistent glial cell activation and axonal damage and improve deficits in visual function and spatial memory after repeated mild TBI. These data support the neuroprotective potential of a higher n-3 PUFA diet in ameliorating the adverse outcome of repeated mild TBI.

Dietary intake of fatty acids and risk of pancreatic cancer: Golestan cohort study

BackgroundAs pancreatic cancer (PC) is a malignancy with poor prognosis, finding strategies for its prevention became a notable priority. Among all the factors influencing the risk of PC, dietary items especially fats are considered as the most modifiable risk factors.This study is designed to assess the associations of dietary intake of fatty acids with the risk of PC incidence.MethodsA total of 50,045 adults between 40 and 75 years old participated in this cohort study in 2004–2008 and were followed up to the present. Intakes of fatty acids was evaluated by validated food-frequency questionnaire (FFQ). Cox proportional hazards regression model was used to estimate hazard ratio (HR) with 95 % confidence interval of differing levels of dietary intakes of fatty acids for incidence of PC.ResultsAt the end of follow-up period, 76 cases of PC were identified and 46,904 participants without history of cancer, acute kidney disorders, fibrosis and cirrhosis were included in the study. Dietary total saturated fatty acids (SFAS) was associated with PC risk (HR = 1.05 (1.01–1.09), Ptrend=0.01), whereas dietary total monounsaturated fatty acids (MUFAS) was inversely associated with the risk of PC (HR = 0.92 (0.86–0.99), Ptrend=0.04). Dietary total polyunsaturated fatty acids (PUFAS) did show a protective but not significant association with the risk of PC (HR = 0.91(0.84-1.00), Ptrend=0.05).ConclusionsThe amount of total fat intake is not a risk factor for PC in our study and focusing on the intake of specific fatty acids becomes more striking. Unsaturated fatty acids including PUFAS and especially MUFAS are considered as protective dietary factors in PC prevention. In contrast, total SFAS is positively associated with the increased risk of PC. However, very long chain and odd-chain saturated fatty acids intake may be protective against PC.

Dietary Polyunsaturated Fatty Acids (PUFAs): Uses and Potential Health Benefits.

Polyunsaturated fatty acids (PUFAs) are obtained from various sources, which can be incorporated in the routine diet to maintain the health. They provide protection from several diseases like osteoarthritis, cancer, and autoimmune disorders. Major focus is given to the PUFAs omega-3 (ω-3) and omega-6 (ω-6) fatty acids which are available in both terrestrial and in the marine environment. The main concern of this article is to review the key scientific reports in context with the human health consequences and advantages of the food sources of ω-3 and ω-6 fatty acids. ω-3 and ω-6 fatty acids are consumed by the population globally in the form of foods that are rich in fatty acids. Their nutritional effects have the capability to improve the physical functioning and metabolic rate of the body. These PUFAs contribute in various cellular activities like cell signaling, structural integrity and fluidity of cell membrane, the regulation of blood pressure, glucose level, the nervous system, inflammatory reactions, and hematic clotting. Animal and cell-based models represent that ω-3 and ω-6 PUFAs can regulate the skeletal muscle metabolism. The main concern of this article is to review the key scientific reports in context with the human health consequences and advantages of the food sources of ω-3 and ω-6 fatty acids.

Maternal omega-3 fatty acids maintained positive maternal lipids and cytokines profile, and improved pregnancy outcomes of C57BL/6 mice

Omega (n)-3 polyunsaturated fatty acids (PUFA) are known to regulate lipid metabolism and inflammation; however, the regulation of maternal lipid metabolism and cytokines profile by n-3 PUFA during different gestation stages, and its impact on fetal sustainability is not known. We investigated the effects of maternal diet varying in n-3 PUFA prior to, and during gestation, on maternal metabolic profile, placental inflammatory cytokines, and fetal outcomes. Female C57BL/6 mice were fed either a high, low or very low (9, 3 or 1% w/w n-3 PUFA) diet, containing n-6:n-3 PUFA of 5:1, 20:1 and 40:1, respectively for two weeks before mating, and throughout pregnancy. Animals were sacrificed prior to mating (NP), and during pregnancy at gestation days 6.5, 12.5 and 18.5. Maternal metabolic profile, placental cytokines and fetal outcomes were determined. Our results show for the first time that a maternal diet high in n-3 PUFA prevented dyslipidemia in NP mice, and maintained the expected lipid profile during pregnancy. However, females fed the very low n-3 PUFA diet became hyperlipidemic prior to pregnancy, and carried this profile into pregnancy. Maternal diet high in n-3 PUFA maintained maternal plasma progesterone and placental pro-inflammatory cytokines profile, and sustained fetal numbers throughout pregnancy, while females fed the low and very-low n-3 PUFA diet had fewer fetuses. Our findings demonstrate the importance of maternal diet before, and during pregnancy, to maintain maternal metabolic profile and fetus sustainability. These findings are important when designing dietary strategies to optimize maternal metabolism during pregnancy for successful pregnancy outcome.

Regulation of hepatic coenzyme Q biosynthesis by dietary omega-3 polyunsaturated fatty acids

Dietary fats are important for human health, yet it is not fully understood how different fats affect various health problems. Although polyunsaturated fatty acids (PUFAs) are generally considered as highly oxidizable, those of the n-3 series can ameliorate the risk of many age-related disorders. Coenzyme Q (CoQ) is both an essential component of the mitochondrial electron transport chain and the only lipid-soluble antioxidant that animal cells can synthesize. Previous work has documented the protective antioxidant properties of CoQ against the autoxidation products of PUFAs. Here, we have explored in vitro and in vivo models to better understand the regulation of CoQ biosynthesis by dietary fats. In mouse liver, PUFAs increased CoQ content, and PUFAs of the n-3 series increased preferentially CoQ10. This response was recapitulated in hepatic cells cultured in the presence of lipid emulsions, where we additionally demonstrated a role for n-3 PUFAs as regulators of CoQ biosynthesis via the upregulation of several COQ proteins and farnesyl pyrophosphate levels. In both models, n-3 PUFAs altered the mitochondrial network without changing the overall mitochondrial mass. Furthermore, in cellular systems, n-3 PUFAs favored the synthesis of CoQ10 over CoQ9, thus altering the ratio between CoQ isoforms through a mechanism that involved downregulation of farnesyl diphosphate synthase activity. This effect was recapitulated by both siRNA silencing and by pharmacological inhibition of farnesyl diphosphate synthase with zoledronic acid. We highlight here the ability of n-3 PUFAs to regulate CoQ biosynthesis, CoQ content, and the ratio between its isoforms, which might be relevant to better understand the health benefits associated with this type of fat. Additionally, we identify for the first time zoledronic acid as a drug that inhibits CoQ biosynthesis, which must be also considered with respect to its biological effects on patients.

Abstract 2581: Dietary fat influences pancreatic cancer progression by altering cell membrane lipid content to impact the PI3K/AKT pathway

Abstract Pancreatic cancer (PC) is one of the few cancers for which incidence and mortality continue to rise despite increasing knowledge of its etiology and risk factors. Amongst the latter, dietary patterns are significantly associated with PC risk. Due to its relatively slow progression, preventive strategies represent a simple means to improve outcomes. We are interested in understanding the influence of diet on PC prevention and have studied the effects of polyunsaturated fatty acids (PUFAs) in the progression of the disease both in vitro (via PC cell lines) and in vivo (via EL-KrasG12D and p48Cre/LSL-KrasG12D mouse models that recapitulate IPMN- and PanIN-like lesions, respectively). Our data demonstrate that dietary PUFAs are incorporated into plasma membrane phospholipids (PL) affecting signal transduction, particularly PI3K/AKT signaling, supporting the emergence of membrane-targeted therapies. We evaluated the effects of diets supplemented with omega-3 (ω-3) or omega-6 (ω-6) PUFAs on neoplastic lesion development. This work supports that ω-3 reduces while ω-6 accelerates lesion penetrance, tumor formation and proliferation associated with changes in pAKT. These results were also recapitulated in vitro to confirm that reduced activity of the PI3K/AKT pathway when incubated with Docosahexaenoic Acid (DHA), the primary component of the ω-3 enriched diet. This effect was abrogated by over-activation of the pathway when dosed with the main component of the ω-6 enriched diet, Linoleic Acid (LA). Since PI3K depends on its binding to PIP2 in the membrane for its activity, we next aimed to study if PUFAs were altering PL composition. By using IF and stably-transfected PC cells with a fluorescent translocation biosensor to monitor PIP2 and PIP3 lipids in the membrane, we discovered an effect of exogenous fatty acids expressed as a ratio of PIP2 to PIP3 in the plasma membrane. Enriched areas of membrane GFP staining (or PIP3) were observed in LA-treated Panc-1 cells. DHA treatment prevented PIP3 localization in the membrane of tumor cells, keeping the GFP signal diffuse in the cytoplasm. Using the PIP2 biosensor we sought to study the affinity of PI3K for PIP2 depending on the incorporation of DHA or LA in PIP2. DHA treatment reduced PI3K interaction (not total PI3K) with PIP2 resulting in lower levels of PIP3 in the membrane and reduced pAKT activation. Our results are encouraging because these PUFAs impinge on AKT, a downstream target of Kras which serves as a logical alternative to the elusive therapies for Kras and often toxic effects of PI3K/AKT pathway inhibition. Citation Format: Carolina Torres, Georgina Mancinelli, Emily Chen, Jose Cordoba-Chacon, Danielle Pins, Ronald McKinney, Sara Saeed, Karla Castellanos, Giulia Orsi, Megha Singhal, Sam Grimaldo, Poorna Chandra Rao Yalagala, Papasani Subbaiah, Cecilia Leal, Paul Grippo. Dietary fat influences pancreatic cancer progression by altering cell membrane lipid content to impact the PI3K/AKT pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2581.

Dietary intake and plasma levels of polyunsaturated fatty acids in early-stage Parkinson\u2019s disease

Polyunsaturated fatty acids (PUFA) are important for neuronal function and may contribute to the development of neurodegenerative diseases. Here, we investigated the correlation between dietary intake and plasma concentrations of PUFA and their associations with clinical severity in early-stage Parkinson’s disease (PD). In a case–control study with 38 patients with PD and 33 controls, we assessed dietary intake using food frequency questionnaires and simultaneously measured the plasma levels of five PUFA. No differences were observed in dietary total energy and lipid intake, including PUFA, between patients with PD and controls. However, α-linolenic acid (ALA), linoleic acid (LA), and arachidonic acid (AA) plasma levels were lower in patients with PD. The association between dietary intake and plasma PUFA concentrations was not significant in patients with PD. ALA and LA plasma levels were inversely correlated with motor severity in patients with PD, while docosahexaenoic acid and AA plasma levels were positively correlated with non-motor symptoms after controlling for age and sex.

Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects

Tumor acidosis promotes disease progression through a stimulation of fatty acid (FA) metabolism in cancer cells. Instead of blocking the use of FAs by acidic cancer cells, we examined whether excess uptake of specific FAs could lead to antitumor effects. We found that n-3 but also remarkably n-6 polyunsaturated FA (PUFA) selectively induced ferroptosis in cancer cells under ambient acidosis. Upon exceeding buffering capacity of triglyceride storage into lipid droplets, n-3 and n-6 PUFA peroxidation led to cytotoxic effects in proportion to the number of double bonds and even more so in the presence of diacylglycerol acyltransferase inhibitors (DGATi). Finally, an n-3 long-chain PUFA-rich diet significantly delayed mouse tumor growth when compared with a monounsaturated FA-rich diet, an effect further accentuated by administration of DGATi or ferroptosis inducers. These data point out dietary PUFA as a selective adjuvant antitumor modality that may efficiently complement pharmacological approaches.

Dietary Betaine and Polyunsaturated Fatty Acids Influence Circulating Fatty Acids and Tocopherols in Dogs

Abstract Objectives Evaluate the interaction of dietary betaine and two different sources of dietary polyunsaturated fatty acids (PUFA): alpha-linolenate (ALA) and combined eicosapentaenoate (EPA) and docosahexaenoate (DHA) on subsequent circulating single carbon metabolism and metabolomics. Methods This study was a complete factorial with or without added betaine and 3 levels of PUFA. Sixty four dogs with an average age of 5.9 years (range 1–12) were used in this study. All dogs were assigned to a prefeed period (14 days), then assigned to one of the six treatment foods: control (0.05% betaine, no measurable EPA or DHA, and 0.25% 18 : 3 omega 3), control with 0.81% ALA (flaxseed used to increase ALA), control with 0.47% betaine and 0.85% ALA (flax added to increase ALA), control with 0.28% EPA&amp;DHA combined (added fish oil as a source), control plus 0.55% betaine and 0.28% EPA&amp;DHA (fish oil added as a source), and control with 0.58% betaine. All treatment foods were fed for sixty days. Blood analysis (CBC, chem screen, fatty acid profile, and metabolome) was completed at the beginning of the feeding trial and at the end of the study. Statistical analysis used PUFA source, betaine and interaction with p ≤ 0.05 used as significant. Results Dietary betaine increased circulating betaine, dimethyl glycine and methionine while adding ALA or EPA&amp;DHA increased their respective circulating concentrations while decreasing circulating arachidonic acid. Adding betaine numerically increased circulating EPA and increased the concentration of total circulating n-3 fatty acids and total PUFA. There was a significant interaction of dietary betaine and PUFA on alpha-tocopherol, with dietary EPA&amp;DHA causing a decrease and the combination of betaine and EPA&amp;DHA resulting in an increased concentration, while in the absence of added PUFA dietary betaine alone had no effect. Similar results were observed with circulating beta and gamma tocopherol (combined). Conclusions Dietary betaine influences the circulating concentration of polyunsaturated fatty acids and the methyl donor pathway. It also counteracts the negative effect of EPA&amp;DHA on circulating tocopherols. Funding Sources This study was funded by Hill's Pet Nutrition, Inc.

Dietary Betaine and Polyunsaturated Fatty Acids Influence Circulating Fatty Acids and Alpha-Tocopherol in Cats

Abstract Objectives Evaluate the interaction of dietary betaine and two different sources of dietary polyunsaturated fatty acids (PUFA): alpha-linolenate (ALA) and combined eicosapentaenoate (EPA) and docosahexaenoate (DHA) on subsequent circulating single carbon metabolism and metabolomics. Methods This study was a complete factorial with or without added betaine and 3 levels of PUFA. Forty eight domestic short hair cats with an average age of 5.8 years (range 1–12) were used in this study. All cats were assigned to a pre-feed period (14 days) and then assigned to one of the six treatment foods: control, control plus 0.35% ALA (flaxseed used to increase ALA), control plus 0.27% EPA&amp;DHA combined (added fish oil as a source), control plus 0.5% betaine, control plus ALA and 0.5% betaine or control plus EPA&amp;DHA and 0.5% betaine. All treatment foods were fed for sixty days. Blood analysis (CBC, chem screens, fatty acid profiles, and metabolome) was completed at the beginning and at the end of the study. Statistical analysis used PUFA source or intake, betaine and interaction with p ≤ 0.05 used as significant. Results Dietary betaine increased circulating betaine, dimethyl glycine, sarcosine and methionine while adding ALA increased circulating ALA, and EPA&amp;DHA increased their respective circulating concentrations. Betaine increased circulating arachidonic acid when added alone or with ALA with no change when betaine and EPA&amp;DHA were added together. Dietary betaine increased the slope of the linear relationship between circulating EPA (or DHA) to dietary EPA (or DHA). Dietary betaine resulted in an increased concentration of alpha-tocopherol. Similar results were observed with circulating beta- and gamma-tocopherol (combined). Conclusions Dietary betaine influences the circulating concentration of polyunsaturated fatty acids and the methyl donor pathway. It also increases circulating tocopherols. Funding Sources This study was funded by Hill's Pet Nutrition, Inc.