Depletion Of Docosahexaenoic Acid Research Articles

Acyl‐CoA synthetase 6 is required for brain docosahexaenoic acid retention and neuroprotection during aging

The omega-3 fatty acid docosahexaenoic acid (DHA) inversely relates to neurological impairments with aging. However, limited non-dietary in vivo models specifically depleting brain DHA have limited direct linkage of DHA to neurological aging processes. We discovered that loss of long-chain acyl-CoA synthetase 6 (ACSL6) depletes brain membrane phospholipid DHA levels. Here, the effects of membrane phospholipid DHA depletion on behavioral and neurological outcomes across the natural progression of aging in control and Acsl6 knockout mice (Acsl6-/-) were determined. Across the lifespan, Acsl6-/- brains contained lower DHA compared to controls. The loss of DHA-enriched and increased arachidonic acid-enriched phospholipids was visualized by MALDI imaging, predominantly in neuronal rich regions where robust Acsl6 gene expression localized by smFISH to neurons across the brain, including pyramidal, Purkinje, and within the cerebellar granular layer. ACSL6 was also found in astrocytes; however, astrocyte-specific loss of ACSL6 did not regulate membrane DHA, a phenomenon attributed to astrocyte-specific expression of alternative-exon ACSL6 variants that do not prefer DHA as substrate. Total ACSL6 knockout mice exhibited hyperlocomotion across the lifespan, early-onset impairments in working spatial memory, and increased expression of cholesterol biosynthesis genes. In response to aging, cerebellar neuroinflammation and gliosis developed. Neuroinflammation was not accompanied by major alterations of lipid mediators but was preceded by decreased expression of synaptic proteins. Together our findings suggest that ACSL6 is enriched in neurons to promote membrane DHA enrichment, is important for brain DHA levels across the lifespan, protects against disordered motor function, memory, and age-related neuroinflammation reflecting the importance of DHA, and its metabolism by ACSL6, early in life and in age-related neuroprotection.

Docosahexaenoic acid and the brain- what is its role?

Docosahexaenoic acid (DHA) is a 22-carbon omega 3 PUFA highly enriched in the neuronal cell membranes and rod outer segment membranes. When DHA is depleted from these cell membranes it is replaced nearly quantitatively by a 22-carbon omega 6 PUFA, docosapentaenoic acid, which has similar, but less potent, biophysical and physiological properties to DHA. It is speculated that omega 6-docosapentaenoic acid is a buffer to prevent the possible catastrophic effects of DHA depletion on brain and visual function. The primary insult from the loss of DHA from cell membrane glycerophospholipids, and replacement by omega 6-docosapentaenoic acid, is on the flexibility/compression of the membrane lipids which affects the optimal function of integral membrane proteins (receptors, voltage-gated ion channels and enzymes). This leads to effects on second messenger systems, and subsequently affects neurotransmitter concentrations due to 'weakened' signals from the initiating receptors. Remembering there are more than 80 billion neurones and many times more synaptic connections between neurons, a very small loss of "efficiency" in signal due to altered properties of membrane proteins would likely result in meaningful changes in brain and visual function. Additionally, impairment of neurotransmission could be due, in part, to sub-optimal brain energy metabolism (glucose entry into the brain), which is significantly reduced in omega 3 deficiency. Many studies report that dietary omega 3 deficiency results in changes in learning, coping with stress, behavioural changes, and responses in visual function. It is thus concluded that DHA is an essential fatty acid for optimal neuronal function.

The cirrhotic liver is depleted of docosahexaenoic acid (DHA), a key modulator of NF-\u03baB and TGF\u03b2 pathways in hepatic stellate cells

Liver cirrhosis results from chronic hepatic damage and is characterized by derangement of the organ architecture with increased liver fibrogenesis and defective hepatocellular function. It frequently evolves into progressive hepatic insufficiency associated with high mortality unless liver transplantation is performed. We have hypothesized that the deficiency of critical nutrients such as essential omega-3 fatty acids might play a role in the progression of liver cirrhosis. Here we evaluated by LC-MS/MS the liver content of omega-3 docosahexaenoic fatty acid (DHA) in cirrhotic patients and investigated the effect of DHA in a murine model of liver injury and in the response of hepatic stellate cells (HSCs) (the main producers of collagen in the liver) to pro-fibrogenic stimuli. We found that cirrhotic livers exhibit a marked depletion of DHA and that this alteration correlates with the progression of the disease. Administration of DHA exerts potent anti-fibrogenic effects in an acute model of liver damage. Studies with HSCs show that DHA inhibits fibrogenesis more intensely than other omega-3 fatty acids. Data from expression arrays revealed that DHA blocks TGFβ and NF-κB pathways. Mechanistically, DHA decreases late, but not early, SMAD3 nuclear accumulation and inhibits p65/RelA-S536 phosphorylation, which is required for HSC survival. Notably, DHA increases ADRP expression, leading to the formation of typical quiescence-associated perinuclear lipid droplets. In conclusion, a marked depletion of DHA is present in the liver of patients with advanced cirrhosis. DHA displays anti-fibrogenic activities on HSCs targeting NF-κB and TGFβ pathways and inducing ADPR expression and quiescence in these cells.

Ferroptosis, Mechanism Of Cell Death In Vitamin E Deficiency During Embryogenesis?

Vitamin E (α-tocopherol), discovered in 1922, prevents rodent fetal resorption, but the mechanisms are unknown. Adult zebrafish maintained on vitamin E-deficient (E–) or sufficient (E+) diets were spawned to obtained E– and E+ embryos, respectively, which we evaluated up to 12 days post-fertilization (dpf). Initially, we investigated mechanisms causing lethality using metabolomic analyses of E– embryos daily from 1 to 5 dpf. By 5 dpf, 80% of E– embryos experienced increased morbidity or mortality; even normally appearing E– embryos at 4 dpf were 84% less responsive to light-dark stimuli in a locomotor assay. We found that vitamin E deficiency not only caused behavioral abnormalities, it caused: 1) lipid peroxidation of docosahexaenoic acid (DHA), depletion of DHA-containing phospholipids, especially phosphatidylcholine, and choline depletion; 2) glucose depletion, which was potentiated by shunting it to the pentose phosphate pathway for NADPH production; and 3) impairment of oxygen consumption and energy homeostasis. The observed morbidity and behavioral outcomes could be attenuated by glucose injection into E– embryos at 1 dpf. In subsequent experiments, normally appearing E– and E+ embryos at 5 dpf were fed an adequate diet (containing DHA and vitamin E) from 5-12 dpf. Both the E– and E+ groups survived and grew normally; however, by 12 dpf E– larvae continued to have behavioral defects. These defects coincided with sustained vitamin E deficiency despite adequate dietary supplementation. We also found in E– vs. E+ larvae DHA depletion with increased lipid peroxidation, along with defective energy metabolism. Thus, embryonic vitamin E deficiency in zebrafish leads to a metabolic reprogramming that adversely affects the neurologic status of embryos that is not readily repaired by an adequate diet suggesting neuronal cell death in the developing brain, possibly by ferroptotic mechanisms.

Basal ganglia vulnerability to oxidative stress.

Basal ganglia vulnerability to oxidative stress.

Depletion of Brain Docosahexaenoic Acid Impairs Recovery from Traumatic Brain Injury

Omega-3 fatty acids are crucial for proper development and function of the brain where docosahexaenoic acid (DHA), the primary omega-3 fatty acid in the brain, is retained avidly by the neuronal membranes. We investigated the effect of DHA depletion in the brain on the outcome of traumatic brain injury (TBI). Pregnant mice were put on an omega-3 fatty acid adequate or deficient diet from gestation day 14 and the pups were raised on the respective diets. Continuation of this dietary regime for three generations resulted in approximately 70% loss of DHA in the brain. Controlled cortical impact was delivered to both groups of mice to produce severe TBI and the functional recovery was compared. Compared to the omega-3 adequate mice, the DHA depleted mice exhibited significantly slower recovery from motor deficits evaluated by the rotarod and the beam walk tests. Furthermore, the DHA deficient mice showed greater anxiety-like behavior tested in the open field test as well as cognitive deficits evaluated by the novel object recognition test. The level of alpha spectrin II breakdown products, the markers of TBI, was significantly elevated in the deficient mouse cortices, indicating that the injury is greater in the deficient brains. This observation was further supported by the reduction of NeuN positive cells around the site of injury in the deficient mice, indicating exacerbated neuronal death after injury. These results suggest an important influence of the brain DHA status on TBI outcome.

Omega‐3 Fatty Acids and Neural Development to 2 Years of Age: Do We Know Enough for Dietary Recommendations?

The omega (omega)-3 fatty acids are essential nutrients, explained by the absence of a Delta-15 desaturase in mammalian cells. The omega-3 fatty acids are found in the diet as alpha-linolenic acid (18:3omega-3) and eicosapentaenoic acid (20:5omega-3), as well as docosahexaenoic acid (DHA), with different functions of each of the omega-3 fatty acids in different cells. One essential role of the omega-3 fatty acids is fulfilled by the 22 carbon DHA (22:6omega-3). Depletion of DHA from brain and retina interferes with normal neurogenesis and neurological function, and visual signaling pathways. Observation and intervention studies with pregnant and lactating women, and with infants fed some formulas show that dietary DHA is associated with higher scores on tests of visual and neural development in infants and children. The estimated average requirement and variability in requirement among individuals both of which are needed to set dietary recommended intakes (DRIs) for the different omega-3 fatty acids are unknown. However, because omega-3 fatty acids are essential, adequate intakes to minimize risk of poor neural development and function can be justified, but dose-response data to provide a safe upper limit with different omega-6 fatty acid intakes are needed. Dietary recommendations do affect the food supply and supplements and are used in labeling, all impacting population health. When scientific information is incomplete, consideration must be given to the implications of recommendations that focus on individual nutrients, rather than dietary patterns such as breast-feeding and consuming fish that promote health and minimize disease risk.

Omega‐3 LC‐PUFA Supply and Neurological Outcomes in Children With Phenylketonuria (PKU)

Children with phenylketonuria (PKU) follow a diet with very low intakes of natural protein, which is devoid of food sources of the omega-3 docosahexaenoic acid (DHA). A resulting DHA depletion has been demonstrated in PKU children and may account for detectable subtle neurological deficits that are not explained by variation in plasma phenylalanine concentrations. We supplemented 36 children with PKU ages 1 to 11 years for 3 months with encapsulated fish oil providing a daily dose of 15 mg DHA/kg body weight. DHA supplementation resulted in significantly faster visual evoked potential latencies, indicating more rapid central nervous system information processing. In addition, DHA significantly improved outcomes in a test of motor function and coordination. No changes over time were seen in age-matched healthy controls. Because the PKU children had a good supply of the omega-3 precursor alpha-linolenic acid, these observations lead us to conclude that endogenous conversion of alpha-linolenic acid is not sufficient to provide adequate amounts of DHA that support optimal function, and hence DHA appears to be a conditional essential substrate for children with PKU. Because early treated PKU children are healthy, with normal fatty acid turnover, these data may indicate a need to supply some DHA to children in general. Further studies are ongoing aiming at establishing quantitative DHA requirements in children.

Fatty acid facts, Part IV: Docosahexaenoic acid and Alzheimer's disease. A story of mice, men and fish

The primary pathological hallmark of Alzheimer's disease (AD) is neurodegeneration by neuronal cell death caused by the development of aggregates of beta- amyloid peptide. Epidemiologically, low fish intake and low blood levels of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) have been related to an increased risk of AD. Test animals on dietary DHA depletion show learning and memory deficits, whereas their brains show inflammatory and oxidative damage to neurons and synaptic defects. The behavioral defects could be reversed by DHA supplementation exemplified by improved cognitive function. Mechanistically, these phenomena have been explained by the antiinflammatory action of DHA. This immunomodulation has been ascribed to incorporation of increased amounts of DHA in cell membrane phospholipids, leading to decreased production of proinflammatory omega-6 eicosanoids. The latter molecules may cause vascular damage which promotes the clinical signs of AD. This review will provide an overview on the available knowledge with regard to the role of DHA in AD with a focus on mechanistic and epidemiological investigations.

Docosahexaenoic Acid is More Stable to Oxidation when Located at the sn‐2 Position of Triacylglycerol Compared to sn‐1(3)

AbstractRegio‐isomeric effects on the oxidative stability of triacylglycerols (TAG) containing docosahexaenoic acid (DHA) were investigated using two pairs of regio‐isomerically pure TAG, namely 1,3‐dihexadecanoyl‐2‐(4,7,10,13,16,19‐docosahexaenoyl)glycerol (PDP)/1,2‐dihexadecanoyl‐3‐(4,7,10,13,16,19‐docosahexaenoyl)glycerol (PPD) and 1,3‐dioctadecenoyl‐2‐(4,7,10,13,16,19‐docosahexaenoyl)glycerol (ODO)/1,2‐dioctadecenoyl‐3‐(4,7,10,13,16,19‐docosahexaenoyl)glycerol (OOD) where P, O, and D represent palmitic acid, oleic acid, and DHA respectively. Each pair of regio‐isomers was subjected to accelerated auto‐oxidation (at 40 or 50 °C inside a dark oven). In each case, the TAG oxidized more slowly when DHA was located at the sn‐2 position (PDP and ODO) compared to the sn‐1(3) position (PPD and OOD), as evidenced by slower development of peroxide value, slower depletion of DHA, and slower generation of secondary oxidation products propanal and trans, trans‐2,4‐heptadienal. The positional effect on auto‐oxidation was more pronounced when DHA occurred in combination with oleic acid than with palmitic acid.

Neuroprotective action of omega-3 polyunsaturated fatty acids against neurodegenerative diseases: Evidence from animal studies

Studies in animals clearly show that oral intake of docosahexaenoic acid (DHA) can alter brain DHA concentrations and thereby modify brain functions. This provides us with an opportunity to use DHA as a nutraceutical or pharmaceutical tool in brain disorders such as Alzheimer disease (AD) and Parkinson disease (PD). Most of the published epidemiological studies are consistent with a positive association between high reported DHA consumption or high DHA blood levels and a lower risk of developing AD later in life. Such observations have prompted the investigation of DHA in three different transgenic models of AD. These analyses show that animal models of AD are more vulnerable to DHA depletion than controls and that DHA exerts a beneficial effect against pathological signs of AD, including A β accumulation, cognitive impairment, synaptic marker loss, and hyperphosphorylation of tau. Multiple mechanisms of action can be associated with the neuroprotective effects of DHA and include antioxidant properties and activation of distinct cell signaling pathways. Although the first randomized clinical assays have yet failed to demonstrate convincing beneficial effects of DHA for AD patients, the knowledge gathered in recent years holds out a hope for prevention and suggests that the elderly and people bearing a genetic risk for AD should at least avoid DHA deficiency.

Survival signalling in Alzheimer's disease

Significant advancements in our understanding of cell-survival signalling in AD (Alzheimer's disease) stem from recent investigations into the metabolism, trafficking and fate of the essential omega-3 fatty acid DHA (docosahexaenoic acid) (C(22:6), n=3). Brain synaptic terminals and neuronal plasma membranes are highly enriched in DHA, and deficiencies in this polyunsaturated fatty acid are characteristic of AD-affected brain. Oxidative stress, targeting phospholipids containing DHA, and age-related DHA depletion are associated with the progressive erosion of normal cognitive function in AD. Current studies support the idea that DHA itself and novel DHA-derived neural synapse- and membrane-derived lipid messengers have considerable potential to modulate cell survival signalling in stressed cultured neural cell models in vitro and in mammalian models of learning, memory and AD in vivo. Key players in this intrinsic rescue system include the alpha-secretase-processed neurotrophin sAPPalpha [soluble APPalpha (amyloid precursor protein alpha)] peptide, the DHA-derived 10,17S-docosatriene NPD1 (neuroprotectin D1), a tandem brain cytosolic phospholipase A(2) and 15-lipoxygenase enzymatic system that biosynthesizes NPD1, and a small family of anti-apoptotic neuroprotective genes that encode Bcl-2, Bcl-X(L) and Bfl-1 (A1). This paper reviews current ideas regarding DHA and the oxygenated DHA derivative NPD1, intrinsically triggered biolipid neuroprotectants that along with their associated rescue pathways, contribute to life-or-death decisions of brain cells during homoeostasis, aging and neurodegenerative disease.

Docosahexaenoic Acid Protects from Amyloid and Dendritic Pathology in an Alzheimer's Disease Mouse Model

Genetic data argues that Alzheimer's disease (AD) can be initiated by aggregates of a 42 amino acid beta amyloid peptide (Abeta42). The Abeta aggregates, notably small oligomer species, cause a cascade of events including oxidative damage, inflammation, synaptic toxicity and accumulation of intraneuronal inclusions; notably neurofibrillary tangles. Cognitive deficits are likely to begin with a failure of synaptogenesis and synaptic plasticity with dendritic spine loss and dying back of dendritic arbor. This is followed by neuron loss in key areas involved in learning and memory. Significant prevention or delay of clinical onset may be achievable by modifying environmental risk factors that impact the underlying pathogenic pathways. Because low fish intake and low blood levels of the marine lipid, docosahexaenoic acid (DHA) have been associated with increased AD risk we have tested the impact of depleting or supplementing with dietary DHA on AD pathogenesis in transgenic mice bearing a mutant human gene known to cause AD in people. We reported that even with intervention late in life dietary DHA depletion dramatically enhanced oxidative damage and the loss of dendritic markers, while DHA supplementation markedly reduced Abeta42 accumulation and oxidative damage, corrected many synaptic deficits and improved cognitive function. Loss of brain DHA was exacerbated in mice expressing the mutant human AD transgene, this is consistent with evidence for increased oxidative attack on DHA oxidation in AD. Treatment with the curry spice extract curcumin, a polyphenolic antioxidant that inhibits AP aggregation, has been strongly protective in the same mouse model. Many Western diets are typically deficient in DHA and low in polyphenolic antioxidant intake. These and other data argue that increasing dietary intake of both DHA and polyphenolic antioxidants may be useful for AD prevention.

Perinatal biochemistry and physiology of long-chain polyunsaturated fatty acids

Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are important structural components of the central nervous system. These fatty acids are transferred across the placenta, are present in human milk, and are accumulated in the brain and retina during fetal and infant development. The high concentrations of DHA in the retina and of DHA and ARA in brain gray matter suggests that these fatty acids have important roles in retinal and neural function. Animal studies have shown that depletion of DHA from the retina and brain results in reduced visual function and learning deficits. The latter effects may be explained by changes in the membrane bilayer that alter membrane-associated receptors and signal transduction systems, ion channel activity, or direct effects on gene expression. DHA can be formed in the liver from alpha linolenic acid, but it is unclear if the rate of DHA synthesis in humans is sufficient to support optimal brain and retinal development. Although there is no evidence that the ability to form ARA from linoleic acid is limiting, supplementation with DHA reduces tissue ARA, possibly creating a conditional need for ARA in infants with a dietary intake of DHA. The amount of DHA in human milk varies widely and is positively correlated with visual and language development in breast-fed infants. Advances in understanding essential fatty acid requirements will benefit from intervention studies that use functionally relevant tests to probe the deficiency or adequacy of physiologically important pools of DHA and ARA in developing infants.

Depletion of docosahexaenoic acid in red blood cell membranes of depressive patients.

Conference Article| May 01 1998 Depletion of docosahexaenoic acid in red blood cell membranes of depressive patients Rhian Edwards; Rhian Edwards 1University Department of Psychiatry, Northern General Hospital, Herries Road, Sheffield, UK. S5 7AU Search for other works by this author on: This Site PubMed Google Scholar Malcolm Peet; Malcolm Peet 1University Department of Psychiatry, Northern General Hospital, Herries Road, Sheffield, UK. S5 7AU Search for other works by this author on: This Site PubMed Google Scholar Janet Shay; Janet Shay *Scotia Research Institute, Castle Business Park, Stirling, UK. FK94 4TZ Search for other works by this author on: This Site PubMed Google Scholar David Horrobin David Horrobin *Scotia Research Institute, Castle Business Park, Stirling, UK. FK94 4TZ Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1998) 26 (2): S142. https://doi.org/10.1042/bst026s142 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Cite Icon Cite Get Permissions Citation Rhian Edwards, Malcolm Peet, Janet Shay, David Horrobin; Depletion of docosahexaenoic acid in red blood cell membranes of depressive patients. Biochem Soc Trans 1 May 1998; 26 (2): S142. doi: https://doi.org/10.1042/bst026s142 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search Keywords: PUFAs - polyunsaturated fatty acids, DHA - docosahexaenoic acid, an omega-3 PUFA, RBC - red blood cell, EPA - eicosapentaenoic acid, an omega-3 PUFA, A-LA - alpha-linolenic acid, an omega-3 PUFA This content is only available as a PDF. © 1998 Biochemical Society1998 Article PDF first page preview Close Modal You do not currently have access to this content.

Depletion of docosahexaenoic acid in retinal lipids of rats fed a linolenic acid-deficient, linoleic acid-containing diet

Rats were raised for 2 generations on a diet in which 1.25% methyl linoleate was the only source of fat. Control rats were given 1.0% methyl linoleate plus 0.25% methyl linolenate. Lipids were extracted from retinas and their fatty acids were analyzed by gas-liquid chromatography. Docosahexaenoic acid accounted for 33.8% of total fatty acids in control retinas, for 13% of fatty acids in first-generation deficient retinas, and for 2.7% of fatty acids in second-generation deficient retinas.