J Inherit Metab Dis. 2013 May;36(3):411-25.
Disorders of phospholipids, sphingolipids and fatty acids biosynthesis: toward a new category of inherited metabolic diseases.
Neurometabolic Unit, Pitié-Salpêtrière Hospital, AP-HP & U of Pierre and Marie Curie, Paris, France.
ABSTRACT: We wish to delineate a novel, and rapidly expanding, group of inborn errors of metabolism with neurological/muscular presentations: the defects in phospholipids, sphingolipids and long chain fatty acids biosynthesis. At least 14 disorders have been described so far. Clinical presentations are diverse but can be divided into (1) diseases of the central nervous system; (2) peripheral neuropathies; and (3) muscular/cardiac presentations. (1) Leukodystrophy and/or iron deposits in basal ganglia is a common feature of phospholipase A2 deficiency, fatty acid hydroxylase deficiency, and pantothenate kinase-associated neurodegeneration. Infantile epilepsy has been reported in GM3 synthetase deficiency. Spastic quadriplegia with ichthyosis and intellectual disability are the presenting signs of the elongase 4 deficiency and the Sjogren-Larsson syndrome caused by fatty aldehyde dehydrogenase deficiency. Spastic paraplegia and muscle wasting are also seen in patients with mutations in the neuropathy target esterase gene. (2) Peripheral neuropathy is a prominent feature in PHARC syndrome due to α/β-hydrolase 12 deficiency, and in hereditary sensory autonomic neuropathy type I due to serine palmitoyl-CoA transferase deficiency. (3) Muscular/cardiac presentations include recurrent myoglobinuria in phosphatidate phosphatase 1 (Lipin1) deficiency; cardiomyopathy and multivisceral involvement in Barth syndrome secondary to tafazzin mutations; congenital muscular dystrophy due to choline kinase deficiency, Sengers syndrome due to acylglycerol kinase deficiency and Chanarin Dorfman syndrome due to α/β- hydrolase 5 deficiency. These synthesis defects of complex lipid molecules stand at the frontier between classical inborn errors of metabolism and other genetic diseases involving the metabolism of structural proteins.
Biochim Biophys Acta. 2013 Aug 15.
Sphingolipids and lifespan regulation.
Department of Molecular and Cellular Biochemistry and the Lucille Markey Cancer Center, University of Kentucky College of Medicine, 741 S. Limestone, Lexington, KY 40536, USA.
ABSTRACT: Diseases including cancer, type 2 diabetes, cardiovascular and immune dysfunction and neurodegeneration become more prevalent as we age, and combined with the increase in average human lifespan, place an ever increasing burden on the health care system. In this chapter we focus on finding ways of modulating sphingolipids to prevent the development of age-associated diseases or delay their onset, both of which could improve health in elderly, fragile people. Reducing the incidence of or delaying the onset of diseases of aging has blossomed in the past decade because of advances in understanding signal transduction pathways and cellular processes, especially in model organisms, that are largely conserved in most eukaryotes and that can be modulated to reduce signs of aging and increase health span. In model organisms such interventions must also increase lifespan to be considered significant, but this is not a requirement for use in humans. The most encouraging interventions in model organisms involve lowering the concentration of one or more sphingolipids so as to reduce the activity of key signaling pathways, one of the most promising being the Target of Rapamycin Complex 1 (TORC1) protein kinase pathway. Other potential ways in which modulating sphingolipids may contribute to improving the health profile of the elderly is by reducing oxidative stresses, inflammatory responses and growth factor signaling. Lastly, perhaps the most interesting way to modulate sphingolipids and promote longevity is by lowering the activity of serine palmitoyltransferase, the first enzyme in the de novo sphingolipid biosynthesis pathway. Available data in yeasts and rodents are encouraging and as we gain insights into molecular mechanisms the strategies for improving human health by modulating sphingolipids will become more apparent. This article is part of a Special Issue entitled New frontiers in sphingolipid biology.
Sci Transl Med. 2012 Jun 6;4(137):137ra73.
Identification of naturally occurring fatty acids of the myelin sheath that resolve neuroinflammation.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
ABSTRACT: Lipids constitute 70% of the myelin sheath, and autoantibodies against lipids may contribute to the demyelination that characterizes multiple sclerosis (MS). We used lipid antigen microarrays and lipid mass spectrometry to identify bona fide lipid targets of the autoimmune response in MS brain, and an animal model of MS to explore the role of the identified lipids in autoimmune demyelination. We found that autoantibodies in MS target a phosphate group in phosphatidylserine and oxidized phosphatidylcholine derivatives. Administration of these lipids ameliorated experimental autoimmune encephalomyelitis by suppressing activation and inducing apoptosis of autoreactive T cells, effects mediated by the lipids’ saturated fatty acid side chains. Thus, phospholipids represent a natural anti-inflammatory class of compounds that have potential as therapeutics for MS.
Psychiatry Res. 2012 Aug 15;198(3):347-52.
Impaired plasmalogens in patients with schizophrenia.
Duke University Medical Center, Department of Psychiatry and Behavioral Sciences, DUMC Box 3950 Durham, NC 27710, USA. firstname.lastname@example.org
ABSTRACT: Plasmalogens are a subclass of glycerophospholipids and ubiquitous constituents of cellular membranes and serum lipoproteins. Several neurological disorders show decreased level of plasmogens. An earlier study found differences in plasma phospholipids between unmedicated patients with schizophrenia and matched healthy control subjects. We here report a comparison of plasma plasmalogen levels across 20 drug-naïve patients experiencing first psychotic episodes, 20 recently unmedicated patients experiencing psychotic relapses after failing to comply with prescribed medications, and 17 matched healthy control subjects. Multiple plasma phosphatidylcholine and phosphatidylethanolamine plasmalogen levels were significantly lower in first episode patients and patients with recurrent disease compared to healthy controls. Reduced plasmalogen levels appear to be a trait evident at the onset of psychotic illness and after multiple psychotic relapses. It is implied that reductions in plasmalogen levels are not related to antipsychotic treatment but due to the illness itself. Reduced plasmalogen levels suggest impairments in membrane structure and function in patients with schizophrenia that might happen early in development. This may serve as a clue to the neurobiology of schizophrenia and should be studied as a potential biomarker for individuals at risk for schizophrenia.
PLoS Genet. 2012;8(2):e1002490.
Genome-wide association study identifies novel loci associated with circulating phosphor, and sphingolipid concentrations.
EUROSPAN consortium. Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands. and on behalf of the EUROSPAN consortium, Greg Gibson, Editor.
ABSTRACT: Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10×10(-57)). After a correction for multiple comparisons (P-value<2.2×10(-9)), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nine novel phospho- and sphingolipid loci, substantially increasing our knowledge of the genetic basis for these traits.
Front Biosci (Schol Ed). 2011 Jan 1;3:298-330.
Cognition, dopamine and bioactive lipids in schizophrenia.
Department of Psychiatry and Western Psychiatric Institute and Clinic University of Pittsburgh School of Medicine, 3811 O’Hara Street, Pittsburgh, PA 15213, USA.
ABSTRACT: Schizophrenia is a remarkably complex disorder with a multitude of behavioral and biological perturbations. Cognitive deficits are a core feature of this disorder, and involve abnormalities across multiple domains, including memory, attention, and perception. The complexity of this debilitating illness has led to a view that the key to unraveling its pathophysiology lies in deconstructing the clinically-defined syndrome into pathophysiologically distinct intermediate phenotypes. Accumulating evidence suggests that one of these intermediate phenotypes may involve phospholipid signaling abnormalities, particularly in relation to arachidonic acid (AA). Our data show relationships between levels of AA and performance on tests of cognition for schizophrenia patients, with defects in AA signaling associated with deficits in cognition. Moreover, dopamine may moderate these relationships between AA and cognition. Taken together, cognitive deficits, dopaminergic neurotransmission, and bioactive lipids have emerged as related features of schizophrenia. Existing treatment options for cognitive deficits in schizophrenia do not specifically target lipid-derived signaling pathways; understanding these processes could inform efforts to identify novel targets for treatment innovation.
J Proteomics. 2011 Nov 18;74(12):2826-36.
Lipidomic investigations for the characterization of circulating serum lipids in multiple sclerosis.
Department of Biomedical Sciences, G. d’Annunzio University, Chieti-Pescara, Italy. email@example.com
ABSTRACT: Multiple Sclerosis (MS) is a neurodegenerative autoimmune demyelinating disease affecting young adults. The aetiology still remains a mystery and diagnosis is impaired by the lack of defined molecular markers. Autoimmune response remains the main topic under investigation and recent studies suggest additional non-proteic mediators of brain inflammation such as lipids. We carried out an LC-MS based lipidomics approach to highlight serum lipids profiling in MS. Method was optimised and applied in a preliminary clinical cross-sectional investigation of MS patients vs Healthy Controls (HC) and patients with Other Neurological Diseases (OND). Ten significant metabolites were highlighted and tentatively identified by accurate mass and MS/MS experiments. Our most relevant data show altered level of lyso-glycerophosphatidylcholine (lysoPC) and glycerophosphatidylcholine (PC) species. Total lysoPC/PC ratio showed significant decrease in pathological groups (MS, OND) and, in addition, MS subjects had a relevant decrease of this ratio also in respect to OND. These findings suggest that there may be an altered phospholipid metabolism in MS that can be evaluated in serum. Some of these features are distinctive and may be considered specific for MS. Our lipidomics data show, for the first time, evidence in serum of a relationship between LysoPC/PC ratio and MS.
Prostaglandins Leukot Essent Fatty Acids. 2011 Jan-Feb;84(1-2):7-11.
Differential distribution of DHA-phospholipids in rat brain after feeding: A lipidomic approach.
Laboratory of Mass Spectrometry-APLIPID, ER7-UPMC, Paris, France.
ABSTRACT: On a per-weight basis, the brain is the organ richest in lipids, including a remarkable proportion of polyunsaturated fatty acids (PUFAs) of the omega 3 series, namely eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. The cerebral effects of exogenous DHA likely depend on its degree of incorporation into neuronal phospholipids and on its distribution among the various brain structures, after intake. Hence, because PUFAs are not evenly distributed among the brain phospholipid classes and because the existence of class-specific phospholipases that regulate their turnover, we sought to investigate the incorporation of omega 3 PUFAs in selected brain areas regions and specific phospholipid classes. Rats (n=7) were administered, by oral gavage, 100mg/kg/d of a commercially available fish oil (containing ∼84% of long-chain omega 3 fatty acids, of which ∼38% of DHA and ∼46% of EPA). Control rats (n=7) received liquid paraffin. This treatment was continued for 30 days. Thereafter, we dissected three areas, namely the hippocampus, the striatum, and the cortex. Quantization of individual phospholipid classes and their molecular species was performed by ESI-MS/MS. Principal component analysis was used to examine the variation of the molecular lipid profiles (as percentage) induced by omega 3 supplementation. Our results show that provision of omega 3 fatty acids to rats results in their incorporation into brain phospholipids, the extent of which is lower in the striatum as compared with cortex and hippocampus. These data might in part explain the mixed therapeutic results obtained in neurological disorders, many of which are likely region-specific.
Neuropathology. 2010 Dec;30(6):597-605.
Maternal docosahexaenoic acid-enriched diet prevents neonatal brain injury.
Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan.
ABSTRACT: Hypoxic-ischemic encephalopathy due to neonatal asphyxia is one of the most important causes of delayed neurological development. Prolonged neuronal apoptosis plays an important role in the processes contributing to neuronal degeneration. Docosahexaenoic acid (DHA), a major component of brain membrane phospholipids, prevents neuronal cell apoptosis and plays an important role as an anti-oxidant agent. We investigated the neuroprotective and anti-oxidant effects of maternal DHA supplementation during pregnancy in a model of neonatal hypoxic-ischemic encephalopathy. Pregnant rats were randomly assigned to two experimental groups: a control group or a DHA-enriched diet group. Hypoxic-ischemic encephalopathy was produced by left common carotid artery occlusion and exposure to 8% oxygen for 1.5 h. TUNEL assay, immunohistochemistry for caspase-3 and 8-hydroxy-deoxyguanosine (8-OHdG), and Western blot for caspase-3 were performed at postnatal days 8, 10 and 14. Fatty acid composition of brain was estimated on postnatal day 7. Maternal diet clearly influenced brain fatty acid composition in pups. Numbers of apoptotic neuronal cells and 8-OHdG immunoreactivity were significantly decreased in the DHA-enriched group. Our findings indicate that maternal DHA-enriched diet during pregnancy provides neuroprotection by inhibiting oxidative stress and apoptotic neuronal death. Dietary supplementation of DHA during pregnancy may thus be beneficial in preventing neonatal brain injury.
Front Aging Neurosci. 2010 Sep 1;2. pii: 34.
Brain mitochondrial dysfunction in aging, neurodegeneration, and Parkinson’s disease.
Department of Biochemistry and Molecular Biology, Faculty of Medicine, U of Cádiz , Cádiz, Spain.
ABSTRACT: Brain senescence and neurodegeneration occur with a mitochondrial dysfunction characterized by impaired electron transfer and by oxidative damage. Brain mitochondria of old animals show decreased rates of electron transfer in complexes I and IV, decreased membrane potential, increased content of the oxidation products of phospholipids and proteins and increased size and fragility. This impairment, with complex I inactivation and oxidative damage, is named “complex I syndrome” and is recognized as characteristic of mammalian brain aging and of neurodegenerative diseases. Mitochondrial dysfunction is more marked in brain areas as rat hippocampus and frontal cortex, in human cortex in Parkinson’s disease and dementia with Lewy bodies, and in substantia nigra in Parkinson’s disease. The molecular mechanisms involved in complex I inactivation include the synergistic inactivations produced by ONOO- mediated reactions, by reactions with free radical intermediates of lipid peroxidation and by amine-aldehyde adduction reactions. The accumulation of oxidation products prompts the idea of antioxidant therapies. High doses of vitamin E produce a significant protection of complex I activity and mitochondrial function in rats and mice, and with improvement of neurological functions and increased median life span in mice. Mitochondria-targeted antioxidants, as the Skulachev cations covalently attached to vitamin E, ubiquinone and PBN and the SS tetrapeptides, are negatively charged and accumulate in mitochondria where they exert their antioxidant effects. Activation of the cellular mechanisms that regulate mitochondrial biogenesis is another potential therapeutic strategy, since the process generates organelles devoid of oxidation products and with full enzymatic activity and capacity for ATP production.
J Nutr. 2010 Apr;140(4):858-63.
Lipid-mediated cell signaling protects against injury and neurodegeneration.
Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
ABSTRACT: Deficiency in docosahexaenoic acid (DHA) is associated with impaired visual and neurological development, cognitive decline, macular degeneration, and other neurodegenerative diseases. DHA is concentrated in phospholipids of the brain and retina, with photoreceptor cells having the highest DHA content of all cell membranes. The discovery that neuroprotectin D1 (NPD1; 10R, 17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid) is a bioactive mediator of DHA sheds light on the biological importance of this fatty acid. In oxidative stress-challenged human retinal pigment epithelial (RPE) cells, human brain cells, or brain ischemia-reperfusion, NPD1 synthesis is enhanced as a response for sustaining homeostasis. Thus, neurotrophins, Abeta peptide (Abeta)42, calcium ionophore A23187, interleukin-1beta (IL-1beta), or DHA supply enhances NPD1 synthesis. NPD1, in turn, upregulates the antiapoptotic proteins of the Bcl-2 family and decreases the expression of proapoptotic Bcl-2 family members. In human neural cells, DHA attenuates Abeta42 secretion, resulting in concomitant formation of NPD1. NPD1 repressed Abeta42-triggered activation of pro-inflammatory genes and upregulated the antiapoptotic genes encoding Bcl-2, Bcl-xl, and Bfl-1(A1) in human brain cells
in culture. Overall, NPD1 signaling regulates brain and retinal cell survival via the induction of antiapoptotic and neuroprotective gene-expression programs that suppress Abeta42-induced neurotoxicity and other forms of cell injury. These in turn support homeostasis during brain and retinal aging, counteract inflammatory signaling, and downregulate events that support the initiation and progression of neurodegenerative disease.
Drugs Today (Barc). 2009 Dec;45(12):877-90.
Association of phosphatidylcholine and NSAIDs as a novel strategy to reduce gastrointestinal toxicity.
Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center, Houston, Texas 77030, USA.
ABSTRACT: Nonsteroidal anti-inflammatory drugs (NSAIDs) are highly effective drugs that inhibit pain and inflammation, and perhaps due to the role of inflammation in the underlying etiology, NSAIDs have also demonstrated efficacy in reducing a patient’s risk of developing a number of cancers and neurological diseases (e.g. Alzheimer’s disease). The utility of these powerful drugs is limited due to their gastrointestinal (GI) side-effects, notably peptic ulceration and GI bleeding which is briefly reviewed here. We also describe the barrier property of the GI mucosa and how it is affected by NSAIDs, as it is our position that disruption of the surface barrier is an important component in the drugs’ pathogenesis, in addition to selective inhibition of COX-2, which has proven to be problematic. We also discuss current alternative approaches being taken to mitigate the GI side-effects of NSAIDs, including developing combination drugs where NSAIDs are packaged with inhibitors of HCl secretion such as proton pump inhibitors or H2-receptor antagonists. We then present the rationale for the development of the PC associated NSAID technology which came out of our observation that the mammalian gastric mucosa has hydrophobic, non-wettable properties that provides a barrier to luminal acid, and the role of phospholipids and specifically phosphatidylcholine (PC) in this barrier property. In the last section we review the development of our current lipid-based PC-NSAID formulations and our encouraging preclinical and clinical observations validating their GI safety and therapeutic efficacy.
Drugs Today (Barc). 2009 Dec;45(12):877-90.
Association of phosphatidylcholine and NSAIDs as a novel strategy to reduce gastrointestinal toxicity.
Department of Integrative Biology & Pharmacology, The University of Texas Health Science Center, Houston, Texas 77030, USA.
ABSTRACT: Nonsteroidal anti-inflammatory drugs (NSAIDs) are highly effective drugs that inhibit pain and inflammation, and perhaps due to the role of inflammation in the underlying etiology, NSAIDs have also demonstrated efficacy in reducing a patient’s risk of developing a number of cancers and neurological diseases (e.g. Alzheimer’s disease). The utility of these powerful drugs is limited due to their gastrointestinal (GI) side-effects, notably peptic ulceration and GI bleeding which is briefly reviewed here. We also describe the barrier property of the GI mucosa and how it is affected by NSAIDs, as it is our position that disruption of the surface barrier is an important component in the drugs’ pathogenesis, in addition to selective inhibition of COX-2, which has proven to be problematic. We also discuss current alternative approaches being taken to mitigate the GI side-effects of NSAIDs, including developing combination drugs where NSAIDs are packaged with inhibitors of HCl secretion such as proton pump inhibitors or H2-receptor antagonists. We then present the rationale for the development of the PC associated NSAID technology which came out of our observation that the mammalian gastric mucosa has hydrophobic, nonwettable properties that provides a barrier to luminal acid, and the role of phospholipids and specifically phosphatidylcholine (PC) in this barrier property. In the last section we review the development of our current lipid-based PC-NSAID formulations and our encouraging preclinical and clinical observations validating their GI safety and therapeutic efficacy.
Lipids Health Dis. 2008 Mar 18;7:9. Free PMC Article
Can essential fatty acids reduce the burden of disease(s)?
UND Life Sciences, 13800 Fairhill Road, #321, Shaker Heights, OH 44120, USA. firstname.lastname@example.org
ABSTRACT: Coronary heart disease, stroke, diabetes mellitus, hypertension, cancer, depression schizophrenia, Alzheimer’s disease, and collagen vascular diseases are low-grade systemic inflammatory conditions that are a severe burden on health care resources. Essential fatty acids (EFAs) and their metabolites: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), gamma-linolenic acid (GLA), dihomo-gamma-linolenic acid (DGLA), and arachidonic acid (AA) and their products: prostaglandin E1, prostacyclin, lipoxins, resolvins, and protectins suppress inflammation, augment healing, and are of benefit in the prevention and management of these conditions. Hence, supplementation of EFAs could reduce burden of these disease(s).
J Membr Biol. 2009 Dec;232(1-3):25-34.
Red blood cell membrane fluidity in the etiology of multiple sclerosis.
Department of Bio-Medical Sciences, Biomedical Technology, Cape Peninsula University of Technology, Bellville, P.O. Box 1906, 7530 Cape Town, South Africa.
ABSTRACT: Organisms adjust the order, or fluidity, of their cellular membranes in response to changes in their physiochemical environment by adjusting the lipid composition of their membranes. We investigated membrane fluidity using the phospholipid, fatty acid and cholesterol content of red blood cells (RBCs) from multiple sclerosis (MS) patients and correlated this with C-reactive protein (CRP) as well as with the severity of neurological outcome as measured by the Kurtzke Expanded Disability Status Scale (EDSS) and its Functional System Scores. The study group consisted of 31 patients with MS and 30 healthy control subjects. Phospholipids were determined using a colorimetric assay, fatty acids by gas chromatography, cholesterol by an enzymatic assay and CRP by a Beckman nephelometer. Cell membrane fluidity was calculated according to previously established formulae. RBC membrane fluidity as measured by the saturated to polyunsaturated fatty acid ratio was higher in patients than in controls (P = 0.04). The phosphatidylethanolamine saturated to polyunsaturated fatty acid ratio showed highly significant positive correlations with the EDSS and CRP < 5 microg/ml. CRP showed significant inverse correlations with the saturated nature but positive correlations with the ordered-crystalline-phase to liquid-crystalline-phase lipid ratio. In this study we show that membrane fluidity as measured by the relationship between membrane fatty acids, phospholipids and cholesterol is closely interrelated with inflammation and disease outcome in patients with MS. In conclusion, our findings suggest that the membrane lipid composition of patients with MS and, consequently, membrane fluidity are altered, which seems to be influenced by the inflammatory status.
Metab Brain Dis. 2009 Dec;24(4):561-8.
Membrane saturated fatty acids and disease progression in multiple sclerosis patients.
Department of Bio-Medical Sciences, Faculty of Health and Wellness Science, Cape Peninsula University of Technology, P O Box 1906, Bellville, 7530, Cape Town, South Africa.
ABSTRACT: The risk of developing multiple sclerosis is associated with increased dietary intake of saturated fatty acids. We determined the fatty acid composition within the different phospholipid fractions of red blood and peripheral blood mononuclear cell membranes of 31 patients diagnosed with multiple sclerosis and 30 healthy control subjects using gas chromatography. Individual saturated fatty acids were correlated with the severity of neurological outcome as measured by the Kurtzke Expanded Disability Status Scale. Significant increases were found in multiple sclerosis peripheral blood mononuclear cell membrane sphingomyelin C14:0 and phosphatidylinositol C22:0. In the peripheral blood mononuclear cell membranes, C22:0 and C24:0 showed positive correlations, while C14:0, C16:0 and C20:0 showed inverse correlations with the Functional System Scores. In conclusion, this study is in accordance with previous studies that have shown an increase in shorter long-chain SATS in MS patients. In addition, this study also showed that higher C14:0 and C16:0 reflected better disease outcome as demonstrated by the inverse correlation with the EDSS and FSS. We have also characterized the specific SATS, that is, long-chain SATS that may increase the risk of developing MS.
Prostaglandins Leukot Essent Fatty Acids. 2009 Aug-Sep;81(2-3):159-64.
Does dietary DHA improve neural function in children? Observations in phenylketonuria.
Division of Metabolic Diseases and Nutritional Medicine, Dr. von Hauner Children’s Hospital, University of Munich Medical Centre, Lindwurmstr. 4, 80337 Munich, Germany. email@example.com
ABSTRACT: Children with phenylketonuria (PKU) have a restricted protein intake and thus low dietary intakes of long-chain polyunsaturated fatty acids (LC-PUFA), which may cause subtle neurological deficits. We measured plasma phospholipid fatty acids and visual evoked potential (VEP) in 36 children with well-controlled PKU (6.3+/-0.6 years, 19 girls), before and after 3 months of supplementing fish oil capsules providing 15 mg docosahexaenoic acid (DHA)/kg daily. The motometric Rostock-Oseretzky Scale (ROS) was performed before and after supplementation in the 24 PKU children aged >4 years. VEP latencies and ROS were also assessed in omnivorous, age-matched controls without fish oil supply at baseline and after 3 months. Fish oil supply increased plasma phospholipid eicosapentaenoic acid (EPA) (0.40+/-0.03 vs 3.31+/-0.19%, p<0.001) and DHA (2.37+/-0.10 vs 7.05+/-0.24%, p<0.001), but decreased arachidonic acid (AA) (9.26+/-0.23 vs 6.76+/-0.16%, p<0.001). Plasma phenylalanine was unchanged. VEP latencies and ROS results significantly improved after fish oil in PKU children, but remained unchanged in controls. The improvements of VEP latencies, fine motor and coordination skills indicate that preformed n-3 LC-PUFA are needed for neural normalcy in PKU children. The optimal type and dose of supply still needs to be determined. Since PKU children are generally healthy and have normal energy and fatty acid metabolism, these data lead us to conclude that childhood populations in general require preformed n-3 LC-PUFA to achieve optimal neurological function.
Prostaglandins Leukot Essent Fatty Acids. 2009 Oct;81(4):253-64.
Novel plasma phospholipid biomarkers of autism: mitochondrial dysfunction as a putative causative mechanism.
Phenomenome Discoveries Inc., 204-407 Downey Road, Saskatoon, Saskatchewan, Canada S7N 4L8.
ABSTRACT: Autism is a neurological disorder that manifests as noticeable behavioral and developmental abnormalities predominantly in males between the ages of 2 and 10. Although the genetics, biochemistry and neuropathology of this disease have been extensively studied, underlying causal factors to this disease have remained elusive. Using a longitudinal trial design in which three plasma samples were collected from 15 autistic and 12 non-autistic age-matched controls over the course of 1 year, universal and unambiguous alterations in lipid metabolism were observed. Biomarkers of fatty acid elongation and desaturation (poly-unsaturated long chain fatty acids (PUFA) and/or saturated very long chain fatty acids (VLCFA)-containing ethanolamine phospholipids) were statistically elevated in all autistic subjects. In all 8 of the affected/non-affected sibling pairs, the affected sibling had higher levels of these biomarkers than the unaffected sibling. Exposure of neurons, astrocytes and hepatocytes in vitro to elevated extracellular glutamate levels resulted in lipid biomarker changes indistinguishable from those observed in autistic subjects. Glutamate stress also resulted in vitro decreased levels of reduced glutathione (GSH), methionine and cysteine, in a similar way to the decreases we observed in autism plasma. Impaired mitochondrial fatty acid oxidation, elevated plasma VLCFAs, and glutamate toxicity as putative causal factors in the biochemistry, neuropathology, and gender bias in autism are discussed.
Asia Pac J Clin Nutr. 2009;18(1):22-8.
Mental retardation is associated with plasma omega-3 fatty acid levels and the omega-3/omega-6 ratio in children.
Department of Human Nutrition, University of Alabama, Tuscaloosa, Alabama 35487, USA.
ABSTRACT: There is evidence that alteration in plasma fatty acid composition may play a role in certain neurological disorders. This case control study was conducted to evaluate the association between plasma fatty acid levels and mental retardation in Korean children. Plasma phospholipid fatty acids, plasma lipids, dietary fatty acids and selected nutrients were measured in 31 mentally retarded boys (mean age 9.93 +/-1.5 yrs) and matched controls. Total plasma omega-3 fatty acids (Sigmaw3), docosahexaenoic acid (DHA) and high density lipoprotein (HDL) concentrations were significantly lower and the Sigmaomega-6/Sigmaomega-3 ratio was significantly higher in cases than in controls. The odds in favor of mental retardation increased by 69 % for each unit increase in the Sigmaomega-6/ Sigmaomega-3 ratio (adjusted odds ratio = 1.69, 95% CI = 1.25-2.29). Significant variation in plasma Sigmaomega-3 and the Sigmaomega-6/ Sigmaomega-3 ratio was explained by mental retardation and plasma HDL concentrations (45% and 37 % respectively). There was a significant inverse association between plasma DHA and mental retardation. For each unit increase in plasma DHA, odds of mental retardation decreased by 74 %. There was no significant difference in either total dietary fat or fatty acids intakes between cases and controls. The energy intake of cases was significantly higher than the controls. These results suggest that proportion of plasma Sigmaomega-3 fatty acids, particularly, DHA, and the Sigmaomega-6/ Sigmaomega-3 ratio are associated with mental retardation in children in this study.
J Neurol Sci. 2009 Mar 15;278(1-2):5-15.
Ceramide and neurodegeneration: susceptibility of neurons and oligodendrocytes to cell damage and death.
Department of Neurological sciences, Rush University Medical Center, Chicago, IL 60612, USA.
ABSTRACT: Neurodegenerative disorders are marked by extensive neuronal apoptosis and gliosis. Although several apoptosis-inducing agents have been described, understanding of the regulatory mechanisms underlying modes of cell death is incomplete. A major breakthrough in delineation of the mechanism of cell death came from elucidation of the sphingomyelin (SM)-ceramide pathway that has received worldwide attention in recent years. The SM pathway induces apoptosis, differentiation, proliferation, and growth arrest depending upon cell and receptor types, and on downstream targets. Sphingomyelin, a plasma membrane constituent, is abundant in mammalian nervous system, and ceramide, its primary catabolic product released by activation of either neutral or acidic sphingomyelinase, serves as a potential lipid second messenger or mediator molecule modulating diverse cellular signaling pathways. Neutral sphingomyelinase (NSMase) is a key enzyme in the regulated activation of the SM cycle and is particularly sensitive to oxidative stress. In a context of increasing clarification of the mechanisms of neurodegeneration, we thought that it would be useful to review details of recent findings that we and others have made concerning different pro-apoptotic neurotoxins including proinflammatory cytokines, hypoxia-induced SM hydrolysis and ceramide production that induce cell death in human primary neurons and primary oligodendrocytes: redox sensitive events. What has and is emerging is a vista of therapeutically important ceramide regulation affecting a variety of different neurodegenerative and neuroinflammatory disorders.
J Nutr. 2008 Dec;138(12):2515-20.
Arachidonic acid and the brain.
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. firstname.lastname@example.org
ABSTRACT: Kinetic methods in unanesthetized rodents have shown that turnover rates of arachidonic acid (AA) and docosahexaenoic acid (DHA) in brain membrane phospholipids are rapid and energy consuming and that phospholipase A(2) (PLA(2)) and acyl-CoA synthetase enzymes that regulate turnover are specific for one or the other PUFA. Thus, AA turnover in brain phospholipids was reduced, and AA-selective cytosolic cPLA(2) or acyl-CoA synthetase, as well as cyclooxygenase (COX)-2, were downregulated in brains of rats given drugs effective against bipolar disorder, whereas DHA turnover and expression of DHA-selective calcium-independent iPLA(2) were unchanged. Additionally, the brain AA and DHA cascades can be altered reciprocally by dietary or genetic conditions. Thus, following 15 wk of dietary (n-3) PUFA deprivation, DHA loss from rat brain was slowed because of reduced iPLA(2) and COX-1 expression, whereas AA-selective cPLA(2), sPLA(2), and COX-2 were upregulated, as were AA and docosapentaenoic acid concentrations. Measured rates of AA and DHA incorporation into brain represent their respective rates of metabolic consumption, because these PUFA are not synthesized de novo or converted significantly from their precursors in brain. In healthy human volunteers, positron emission tomography (PET) was used to show that the brain consumes AA and DHA at respective rates of 17.8 and 4.6 mg/d, whereas in patients with Alzheimer disease, AA consumption is elevated. In the future, PET could be used to relate human brain rates of AA and DHA consumption to liver PUFA metabolism and dietary PUFA intake.
The information contained in this web site is for educational purposes only and is not intended or implied to be a substitute for professional medical advice. Inclusion here does not imply any endorsement or recommendation. Always seek the advice of your physician or other qualified medical provider for all medical problems prior to starting any new regiment.These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.