Oocyte signals derived from polyunsaturated fatty acids control sperm recruitment in vivo

A fundamental question in animal development is how motile cells find their correct target destinations. During mating in the nematode Caenorhabditis elegans, males inject sperm through the hermaphrodite vulva into the uterus. Amoeboid sperm crawl around fertilized eggs to the spermatheca--a convoluted tube where fertilization occurs. Here, we show that polyunsaturated fatty acids (PUFAs), the precursors of eicosanoid signalling molecules, function in oocytes to control directional sperm motility within the uterus. PUFAs are transported from the intestine, the site of fat metabolism, to the oocytes yolk, which is a lipoprotein complex. Loss of the RME-2 low-density lipoprotein (LDL) receptor, which mediates yolk endocytosis and fatty acid transport into oocytes, causes severe defects in sperm targeting. We used an RNAi screen to identify lipid regulators required for directional sperm motility. Our results support the hypothesis that PUFAs function in oocytes as precursors of signals that control sperm recruitment to the spermatheca. A common property of PUFAs in mammals and C. elegans is that these fats control local recruitment of motile cells to their target tissues.     

Folate and long-chain polyunsaturated fatty acids in psychiatric disease

Schizophrenia, autism and depression do not inherit by Mendel's law, and the search for a genetic basis seems unsuccessful. Schizophrenia and autism relate to low birth weight and pregnancy complications, which are associated with developmental adaptations by "programming". Epigenetics might constitute the basis of programming and depend on folate status and one-carbon metabolism in general. Early folate status of patients with schizophrenia might be compromised as suggested by (i) coinciding incidences of schizophrenia and neural tube defects (NTDs) in the Dutch hunger winter, (ii) coinciding seasonal fluctuations in birth of patients with schizophrenia and NTDs, (iii) higher schizophrenia incidence in immigrants and (iv) higher incidence in methylene tetrahydrofolate reductase 677C-->T homozygotes. Recent studies in schizophrenia and autism point at epigenetic silencing of critical genes or chromosomal loci. The long-chain polyunsaturated fatty acids (LCPUFA), arachidonic acid (AA, from meat) and docosahexaenoic acid (fish) are components of brain phospholipids and modulators of signal transduction and gene expression. Patients with schizophrenia and, possibly, autism exhibit abnormal phospholipid metabolism that might cause local AA depletion and impaired eicosanoid-mediated signal transduction. National fish intakes relate inversely with major and postpartum depressions. Five out of six randomized controlled trials with eicosapentaenoic acid (fish) have shown positive effects in schizophrenia, and 4 of 6 were favorable in depression and bipolar disorders. We conclude that folate and LCPUFA might be important in both the etiology and severity of at least some psychiatric diseases.     

Selective toxic effects of polyunsaturated fatty acids derived from Ulva fasciata on red tide phyotoplankter species

Alpha-linolenic acid and linoleic acid isolated from Ulva fasciata showed toxic effects on red tide phytoplankters in a concentration-dependent manner. Among six species tested, raphidophycean flagellate Heterosigma akashiwo was the most susceptible to these fatty acids, and 50% lethal concentrations (LC50) of alpha-linolenic acid and linoleic acid were estimated to be 0.58 and 1.91 microg/ml respectively, whereas dinoflagellate Gymnodinium impudicum and Heterocapsa circularisquama were highly resistant and no significant toxic effects were observed up to 1,000 microg/ml. Both fatty acids were less toxic to fish (devil stinger), zooplankters (brine shrimp and rotifer), and mammalian cell lines (U937, HeLa, Vero, and CHO cells) than H. akashiwo.     

Docosahexaenoic acid synthesis from n-3 polyunsaturated fatty acids in differentiated rat brain astrocytes

DHA, the main n-3 PUFA in the brain, is synthesized from n-3 PUFA precursors by astrocytes. To assess the potential of this process to supply DHA for the brain, we investigated whether the synthesis in astrocytes is dependent on DHA availability. Rat brain astrocytes differentiated with dibutyryl cAMP and incubated in media containing 10% fetal bovine serum synthesized DHA from alpha-linolenic acid ([1-(14)C]18:3n-3), docosapentaenoic acid ([3-(14)C]22:5n-3), tetracosapentaenoic acid ([3-(14)C]24:5n-3), and tetracosahexaenoic acid ([3-(14)C]24:6n-3). When DHA was added to media containing a 5 microM concentration of these (14)C-labeled n-3 PUFA, radiolabeled DHA synthesis was reduced but not completely suppressed even when the DHA concentration was increased to 15 microM. Radiolabeled DHA synthesis also was reduced but not completely suppressed when the astrocytes were treated with 30 microM DHA for 24 h before incubation with 5 microM [1-(14)C]18:3n-3.These findings indicate that although the DHA synthesis in astrocytes is dependent on DHA availability, some synthesis continues even when the cells have access to substantial amounts of DHA. This suggests that DHA synthesis from n-3 PUFA precursors is a constitutive process in the brain and, therefore, is likely to have an essential function.     

Functional lipidomics of oxidized products from polyunsaturated fatty acids

Because of their high degree of unsaturation, polyunsaturated fatty acids (PUFA) in mammals, with mainly 18, 20 and 22 carbons, can easily be autooxidized, and converted into many oxidized derivatives and degradation products. This short review reports on some of those relevant to the evaluation of oxidative stress in situ. In addition, the enzyme-dependent oxygenation by both dioxygenases and monooxygenases is briefly reviewed by functional and/or metabolic categories, pointing out the structure variety and the analytical approaches.     

Dietary polyunsaturated fatty acids improve cholinergic transmission in the aged brain

The cholinergic theory of aging states that dysfunction of cholinergic neurons arising from the basal forebrain and terminating in the cortex and hippocampus may be involved in the cognitive decline that occurs during aging and Alzheimer’s disease. Despite years of research, pharmacological interventions to treat or forestall the development of Alzheimer’s disease have primarily focused on enhancing cholinergic transmission, either through increasing acetylcholine (ACh) synthesis or inhibition of the acetylcholinesterase enzyme responsible for ACh hydrolysis. However, recent studies have indicated that dietary supplementation can impact the cholinergic system, particularly during aging. The purpose of the present review is to examine the relevant research suggesting that cholinergic functioning may be maintained during aging via consuming a diet containing polyunsaturated fatty acids (PUFAs). The data reviewed herein indicate that, at least in animal studies, inclusion of PUFAs in the diet can improve cholinergic transmission in the brain, possibly leading to improvements in cognitive functioning.     

Metabolic pathway that produces essential fatty acids from polymethylene-interrupted polyunsaturated fatty acids in animal cells

Sciadonic acid (20:3 Delta-5,11,14) and juniperonic acid (20:4 Delta-5,11,14,17) are polyunsaturated fatty acids (PUFAs) that lack the Delta-8 double bond of arachidonic acid (20:4 Delta-5,8,11,14) and eicosapentaenoic acid (20:5 Delta-5,8,11,14,17), respectively. Here, we demonstrate that these conifer oil-derived PUFAs are metabolized to essential fatty acids in animal cells. When Swiss 3T3 cells were cultured with sciadonic acid, linoleic acid (18:2 Delta-9,12) accumulated in the cells to an extent dependent on the concentration of sciadonic acid. At the same time, a small amount of 16:2 Delta-7,10 appeared in the cellular lipids. Both 16:2 Delta-7,10 and linoleic acid accumulated in sciadonic acid-supplemented CHO cells, but not in peroxisome-deficient CHO cells. We confirmed that 16:2 Delta-7,10 was effectively elongated to linoleic acid in rat liver microsomes. These results indicate that sciadonic acid was partially degraded to 16:2 Delta-7,10 by two cycles of beta-oxidation in peroxisomes, then elongated to linoleic acid in microsomes. Supplementation of Swiss 3T3 cells with juniperonic acid, an n-3 analogue of sciadonic acid, induced accumulation of alpha-linolenic acid (18:3 Delta-9,12,15) in cellular lipids, suggesting that juniperonic acid was metabolized in a similar manner to sciadonic acid. This PUFA remodeling is thought to be a process that converts unsuitable fatty acids into essential fatty acids required by animals.     

Apple pomace: An enzyme system for producing aroma compounds from polyunsaturated fatty acids

Summary This paper reports on the possibility of obtaining C-6 (hexanal) and C-10 (2,4-dedadienal) volatile aldehydes by degradation of linoleic acid (C182 9–12) under the action of the intrinsic enzyme systems found in apple pomace. More aroma compounds are produced by micronization of the pomace and by adding SO2 (60 ppm) and vitamin C (500 ppm), thereby synergistically counteracting oxidation of phenolic compounds, which is a limiting factor in bioconversion.     

Free radicals, polyunsaturated fatty acids, cell death, brain aging

Neuronal death generally involves, directly or indirectly, free radical attack and peroxidation. Targets are nucleic acids, proteins, the cytoskeleton, the extracellular matrix and especially membrane polyunsaturated fatty acids. a) One example for the fundamental role of fatty acids. Dietary fatty acids, and more particularly essential polyunsaturated fatty acids, have a direct influence on the composition of cerebral membranes, and hence on their functioning. Each of the two series of polyunsaturated fatty acids plays a particular role. In animals, a deficiency in linolenic acid causes serious perturbations in the nervous system. In fact, feeding animals with oils that have a low n-3 content leads to severe abnormalities in the composition of membranes, both of the brain and other organs. The rate of recovery from these anomalies is extremely slow in the brain, but rapid in the liver. Compared to certain other organs, the nervous system is neither protected against deficiency nor has it priority in the satisfaction if its needs. A decrease in acids of the linolenic series in the membranes results in a 40% reduction of Na-K-ATPase in nerve endings and a 20% reduction in 5'-nucleotidase. It also leads to anomalies in the electroretinogram which disappear with age. This deficiency in linolenic acid has little effect on motor function and disturbes activity and emotivity only slightly, but it seriously affects learning tasks. The presence of linolenic acid in the diet confers greater resistance to certain neurotoxic substances (triethyl lead, for example). Fatty acids essential for the brain could be those with very long chains. They are probably synthesized in the liver from linolenic and linoleic acids. They can also be supplied directly by food. However, if the diet contains a large proportion of very long chain fatty acids (fish oils), the lipid composition of all organs, including the brain, is altered. During the period of brain development there is a linear relation between the polyunsaturated fatty acid content of the brain and that of the diet. The requirement in linolenic acid is 200 mg/100 g of diet (0.4% of calories). That of linoleic acid is 1,200 mg/100 g of diet (2.4% of calories). b) Peroxidation of polyunsaturated fatty acids. Arachidonic acid is released by lysis of phospholipids (it is directly toxic), its peroxidized derivatives are extremely toxic. Peroxidation of membrane lipids alters enzymatic activity, the relationship between receptor and ligand, transport, and the symmetry of the lipid bilayer.(ABSTRACT TRUNCATED AT 400 WORDS)     

Enzymes for transgenic biosynthesis of long-chain polyunsaturated fatty acids

Polyunsaturated fatty acids (PUFAs) are important for the normal development and function of all organisms, and are essential in maintaining human health. Impaired PUFA metabolism is thought to be associated with pathogenesis of many chronic diseases. Dietary supplementation of PUFAs, such as gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, which bypass the defective or dysfunctional steps of the biosynthetic pathway has been found to significantly alleviate the symptoms of the disease. These findings have drawn a great deal of interest from general public and food manufacturers. As the demand of these beneficial PUFAs has drastically increased in recent years, there are also increasing efforts in finding the alternate sources of PUFAs that are more economical and sustainable. One option is to modify the oil-seed crops to produce PUFAs through genetic engineering technique. This review examines the isolation, identification and expression of genes encoding the enzymes required for the biosynthesis of the above mentioned PUFAs in plants.     

Elongation of polyunsaturated fatty acids in trypanosomatids

Leishmania major synthesizes polyunsaturated fatty acids by using Delta6, Delta5 and Delta4 front-end desaturases, which have recently been characterized [Tripodi KE, Buttigliero LV, Altabe SG & Uttaro AD (2006) FEBS J273, 271-280], and two predicted elongases specific for C18 Delta6 and C20 Delta5 polyunsaturated fatty acids, respectively. Trypanosoma brucei and Trypanosoma cruzi lack Delta6 and Delta5 desaturases but contain Delta4 desaturases, implying that trypanosomes use exogenous polyunsaturated fatty acids to produce C22 Delta4 fatty acids. In order to identify putative precursors of these C22 fatty acids and to completely describe the pathways for polyunsaturated fatty acid biosynthesis in trypanosomatids, we have performed a search in the three genomes and identified four different elongase genes in T. brucei, five in T. cruzi and 14 in L. major. After a phylogenetic analysis of the encoded proteins together with elongases from a variety of other organisms, we selected four candidate polyunsaturated fatty acid elongases. Leishmania major CAJ02037, T. brucei AAX69821 and T. cruzi XP_808770 share 57-52% identity, and group together with C20 Delta5 polyunsaturated fatty acid elongases from algae. The predicted activity was corroborated by functional characterization after expression in yeast. T. brucei elongase was also able to elongate Delta8 and Delta11 C20 polyunsaturated fatty acids. L. major CAJ08636, which shares 33% identity with Mortierella alpinaDelta6 elongase, showed a high specificity for C18 Delta6 polyunsaturated fatty acids. In all cases, a preference for n6 polyunsaturated fatty acids was observed. This indicates that L. major has, as predicted, Delta6 and Delta5 elongases and a complete pathway for polyunsaturated fatty acid biosynthesis. Trypanosomes contain only Delta5 elongases, which, together with Delta4 desaturases, allow them to use eicosapentaenoic acid and arachidonic acid, a precursor that is relatively abundant in the host, for C22 polyunsaturated fatty acid biosynthesis.     

Oxygen radical chemistry of polyunsaturated fatty acids

Polyunsaturated fatty acids (PUFA) are readily susceptible to autoxidation. A chain oxidation of PUFA is initiated by hydrogen abstraction from allylic or bis-allylic positions leading to oxygenation and subsequent formation of peroxyl radicals. In media of low hydrogen-donating capacity the peroxyl radical is free to react further by competitive pathways resulting in cyclic peroxides, double bond isomerization and formation of dimers and oligomers. In the presence of good hydrogen donators, such as alpha-tocopherol or PUFA themselves, the peroxyl radical abstracts hydrogen to furnish PUFA hydroperoxides. Given the proper conditions or catalysts, the hydroperoxides are prone to further transformations by free radical routes. Homolytic cleavage of the hydroperoxy group can afford either a peroxyl radical or an alkoxyl radical. The products of peroxyl radicals are identical to those obtained during autoxidation of PUFA; that is, it makes no difference whether the peroxyl radical is generated in the process of autoxidation or from a performed hydroperoxide. Of particular interest is the intramolecular rearrangement of peroxyl radicals to furnish cyclic peroxides and prostaglandin-like bicyclo endoperoxides. Other principal peroxyl radical reactions are the beta-scission of O2, intermolecular addition and self-combination. Alkoxyl radicals of PUFA, contrary to popular belief, do not significantly abstract hydrogens, but rather are channeled into epoxide formation through intramolecular rearrangement. Other significant reactions of PUFA alkoxyl radicals are beta-scission of the fatty chain and possibly the formation of ether-linked dimers and oligomers. Although homolytic reactions of PUFA hydroperoxides have received the most attention, hydroperoxides are also susceptible to heterolytic transformations, such as nucleophilic displacement and acid-catalyzed rearrangement.     

Isotope-reinforced polyunsaturated fatty acids protect yeast cells from oxidative stress

The facile abstraction of bis-allylic hydrogens from polyunsaturated fatty acids (PUFAs) is the hallmark chemistry responsible for initiation and propagation of autoxidation reactions. The products of these autoxidation reactions can form cross-links to other membrane components and damage proteins and nucleic acids. We report that PUFAs deuterated at bis-allylic sites are much more resistant to autoxidation reactions, because of the isotope effect. This is shown using coenzyme Q-deficient Saccharomyces cerevisiae coq mutants with defects in the biosynthesis of coenzyme Q (Q). Q functions in respiratory energy metabolism and also functions as a lipid-soluble antioxidant. Yeast coq mutants incubated in the presence of the PUFA α-linolenic or linoleic acid exhibit 99% loss of colony formation after 4 h, demonstrating a profound loss of viability. In contrast, coq mutants treated with monounsaturated oleic acid or with one of the deuterated PUFAs, 11,11-D₂-linoleic or 11,11,14,14-D₄-α-linolenic acid, retain viability similar to wild-type yeast. Deuterated PUFAs also confer protection to wild-type yeast subjected to heat stress. These results indicate that isotope-reinforced PUFAs are stabilized compared to standard PUFAs, and they protect coq mutants and wild-type yeast cells against the toxic effects of lipid autoxidation products. These findings suggest new approaches to controlling ROS-inflicted cellular damage and oxidative stress.     

Anti-HCV activities of selective polyunsaturated fatty acids

HCV infection can lead to chronic infectious hepatitis disease with serious sequelae. Interferon-alpha, or its PEGylated form, plus ribavirin is the only treatment option to combat HCV. Alternative and more effective therapy is needed due to the severe side effects and unsatisfactory curing rate of the current therapy. In this study, we found that several polyunsaturated fatty acids (PUFAs) including arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) are able to exert anti-HCV activities using an HCV subgenomic RNA replicon system. The EC(50) (50% effective concentration to inhibit HCV replication) of AA was 4microM that falls in the range of physiologically relevant concentration. At 100microM, alpha-linolenic acid, gamma-linolenic, and linoleic acid only reduced HCV RNA levels slightly and saturated fatty acids including oleic acid, myristic acid, palmitic acid, and steric acid had no inhibitory activities toward HCV replication. When AA was combined with IFN-alpha, strong synergistic anti-HCV effect was observed as revealed by an isobologram analysis. It will be important to determine whether PUFAs can provide synergistic antiviral effects when given as food supplements during IFN-based anti-HCV therapy. Further elucidation of the exact anti-HCV mechanism caused by AA, DHA, and EPA may lead to the development of agents with potent activity against HCV or related viruses.