RESUMEN
Deficiency of polyunsaturated fatty acids (PUFAs) is known to induce hepatic steatosis. However, it is not clearly understood which type of PUFA is responsible for the worsening of steatosis. This study observed a marked accumulation of hepatic triacylglycerol and cholesterol in fatty acid desaturase 2 knockout (FADS2-/- ) mice lacking both C18 and ≥ C20 PUFAs that were fed a PUFA-depleted diet. Hepatic triacylglycerol accumulation was associated with enhanced sterol regulatory element-binding protein (SREBP)-1-dependent lipogenesis and decreased triacylglycerol secretion into the plasma via very-low-density lipoprotein (VLDL). Furthermore, upregulation of cholesterol synthesis contributed to increased hepatic cholesterol content in FADS2-/- mice. These results suggest that ≥ C20 PUFAs synthesized by FADS2 are important in regulating hepatic triacylglycerol and cholesterol accumulation during PUFA deficiency.
Asunto(s)
Colesterol/biosíntesis , Ácido Graso Desaturasas/genética , Ácidos Grasos Insaturados/deficiencia , Hígado Graso/genética , Triglicéridos/biosíntesis , Animales , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Dieta/efectos adversos , Modelos Animales de Enfermedad , Ácido Graso Desaturasas/deficiencia , Acido Graso Sintasa Tipo I/genética , Acido Graso Sintasa Tipo I/metabolismo , Hígado Graso/enzimología , Hígado Graso/etiología , Hígado Graso/patología , Expresión Génica , Perfilación de la Expresión Génica , Lipogénesis/genética , Lipoproteínas VLDL/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estearoil-CoA Desaturasa/genética , Estearoil-CoA Desaturasa/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismoRESUMEN
During infection, pathogenic microbes adapt to the nutritional milieu of the host through metabolic reprogramming and nutrient scavenging. For the bacterial pathogen Staphylococcus aureus, virulence in diverse infection sites is driven by the ability to scavenge myriad host nutrients, including lipoic acid, a cofactor required for the function of several critical metabolic enzyme complexes. S. aureus shuttles lipoic acid between these enzyme complexes via the amidotransferase, LipL. Here, we find that acquisition of lipoic acid, or its attachment via LipL to enzyme complexes required for the generation of acetyl-CoA and branched-chain fatty acids, is essential for bacteremia, yet dispensable for skin infection in mice. A lipL mutant is auxotrophic for carboxylic acid precursors required for synthesis of branched-chain fatty acids, an essential component of staphylococcal membrane lipids and the agent of membrane fluidity. However, the skin is devoid of branched-chain fatty acids. We showed that S. aureus instead scavenges host-derived unsaturated fatty acids from the skin using the secreted lipase, Geh, and the unsaturated fatty acid-binding protein, FakB2. Moreover, murine infections demonstrated the relevance of host lipid assimilation to staphylococcal survival. Altogether, these studies provide insight into an adaptive trait that bypasses de novo lipid synthesis to facilitate S. aureus persistence during superficial infection. The findings also reinforce the inherent challenges associated with targeting bacterial lipogenesis as an antibacterial strategy and support simultaneous inhibition of host fatty acid salvage during treatment.
Asunto(s)
Proteínas Bacterianas/metabolismo , Ácidos Grasos Insaturados/deficiencia , Interacciones Huésped-Patógeno , Lipoilación , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/metabolismo , Staphylococcus aureus/patogenicidad , Ácido Tióctico/deficiencia , Animales , Membrana Celular/metabolismo , Modelos Animales de Enfermedad , Lipasa/metabolismo , Lipogénesis/genética , Ratones , Especificidad de Órganos , Piel/metabolismo , Piel/microbiología , Staphylococcus aureus/genéticaAsunto(s)
Trastorno Bipolar/etiología , Trastorno Depresivo Mayor/etiología , Motivación , Esquizofrenia/etiología , Animales , Trastorno Bipolar/metabolismo , Trastorno Bipolar/psicología , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/psicología , Neuronas Dopaminérgicas/fisiología , Ácidos Grasos Omega-3/administración & dosificación , Ácidos Grasos Omega-3/química , Ácidos Grasos Omega-3/deficiencia , Ácidos Grasos Insaturados/química , Ácidos Grasos Insaturados/deficiencia , Humanos , Sistema Límbico/fisiopatología , Ratones , Esquizofrenia/metabolismo , Psicología del Esquizofrénico , Transmisión Sináptica/fisiologíaRESUMEN
Atopic dermatitis (AD) is a common skin disease characterized by chronic inflammation and itchiness. Although skin barrier dysfunction and immune abnormalities are thought to contribute to the development of AD, the precise pathogenic mechanism remains to be elucidated. We have developed a unique, diet-induced AD mouse model based on the findings that deficiencies of certain polyunsaturated fatty acids and starches cause AD-like symptoms in hairless mice. Here, we present a protocol and tips for establishing an AD mouse model using a custom diet modified from a widely used standard diet (AIN-76A Rodent Diet). We also describe methods for evaluating skin barrier dysfunction and analyzing itch-related scratching behavior. This model can be used not only to investigate the complex pathogenic mechanism of human AD but also to study the puzzling relationship between nutrition and AD development.
Asunto(s)
Dermatitis Atópica/inmunología , Modelos Animales de Enfermedad , Ácidos Grasos Insaturados/química , Alimentos Formulados , Prurito/inmunología , Almidón/química , Animales , Conducta Animal , Aceite de Maíz/química , Dermatitis Atópica/etiología , Dermatitis Atópica/fisiopatología , Etanol/química , Ácidos Grasos Insaturados/deficiencia , Ácidos Grasos Insaturados/inmunología , Femenino , Humanos , Ratones , Ratones Pelados , Permeabilidad , Prurito/etiología , Prurito/fisiopatología , Piel/efectos de los fármacos , Piel/inmunología , Piel/patología , Almidón/deficiencia , Almidón/inmunologíaRESUMEN
BACKGROUND: Schizophrenia is a serious long-term psychotic disorder marked by positive and negative symptoms, severe behavioral problems and cognitive function deficits. The cause of this disorder is not completely clear, but is suggested to be multifactorial, involving both inherited and environmental factors. Since human brain regulates all behaviour, studies have focused on identifying changes in neurobiology and biochemistry of brain in schizophrenia. Brain is the most lipid rich organ (approximately 50% of brain dry weight). Total brain lipids is constituted of more than 60% of phospholipids, in which docosahexaenoic acid (DHA, 22:6n-3) is the most abundant (more than 40%) polyunsaturated fatty acid (PUFA) in brain membrane phospholipids. Results from numerous studies have shown significant decreases of PUFAs, in particular, DHA in peripheral blood (plasma and erythrocyte membranes) as well as brain of schizophrenia patients at different developmental phases of the disorder. PUFA deficiency has been associated to psychotic symptoms and cognitive deficits in schizophrenia. These findings have led to a number of clinical trials examining whether dietary omega-3 fatty acid supplementation could improve the course of illness in patients with schizophrenia. Results are inconsistent. Some report beneficial whereas others show not effective. The discrepancy can be attributed to the heterogeneity of patient population. METHODS: In this review, results from recent experimental and clinical studies, which focus on illustrating the role of PUFAs in the development of schizophrenia were examined. The rationale why omega-3 supplementation was beneficial on symptoms (presented by subscales of the positive and negative symptom scale (PANSS), and cognitive functions in certain patients but not others was reviewed. The potential mechanisms underlying the beneficial effects were discussed. RESULTS: Omega-3 fatty acid supplementation reduced the conversion rate to psychosis and improved both positive and negative symptoms and global functions in adolescents at ultra-high risk for psychosis. Omega-3 fatty acid supplementation could also improve negative symptoms and global functions in the first-episode patients with schizophrenia, but improve mainly total or general PANSS subscales in chronic patients. Patients with low PUFA (particularly DHA) baseline in blood were more responsive to the omega-3 fatty acid intervention. CONCLUSION: Omega-3 supplementation is more effective in reducing psychotic symptom severity in young adults or adolescents in the prodromal phase of schizophrenia who have low omega-3 baseline. Omega-3 supplementation was more effective in patients with low PUFA baseline. It suggests that patients with predefined lipid levels might benefit from lipid treatments, but more controlled clinical trials are warranted.
Asunto(s)
Ácidos Grasos Omega-3/uso terapéutico , Esquizofrenia/dietoterapia , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Cognición/efectos de los fármacos , Suplementos Dietéticos , Proteínas de Unión a Ácidos Grasos/metabolismo , Ácidos Grasos Insaturados/deficiencia , Humanos , Estrés Oxidativo , Fosfolipasas A2/metabolismo , Esquizofrenia/etiología , Psicología del EsquizofrénicoRESUMEN
Metabolic changes in sulfatides and other sulfated glycans have been related to various diseases, including Alzheimer's disease (AD). However, the importance of polyunsaturated fatty acids (PUFA) in sulfated lysosomal substrate metabolism and its related disorders is currently unknown. We investigated the effects of deficiency or supplementation of PUFA on the metabolism of sulfatides and sulfated glycosaminoglycans (sGAGs) in sulfatide-rich organs (brain and kidney) of mice. A PUFA-deficient diet for over 5 weeks significantly reduced the sulfatide expression by increasing the sulfatide degradative enzymes arylsulfatase A and galactosylceramidase in brain and kidney. This sulfatide degradation was clearly associated with the activation of autophagy and lysosomal hyperfunction, the former of which was induced by suppression of the Erk/mTOR pathway. A PUFA-deficient diet also activated the degradation of sGAGs in the brain and kidney and that of amyloid precursor proteins in the brain, indicating an involvement in general lysosomal function and the early developmental process of AD. PUFA supplementation prevented all of the above abnormalities. Taken together, a PUFA deficiency might lead to sulfatide and sGAG degradation associated with autophagy activation and general lysosomal hyperfunction and play a role in many types of disease development, suggesting a possible benefit of prophylactic PUFA supplementation.
Asunto(s)
Autofagia , Encéfalo/patología , Dieta con Restricción de Grasas/efectos adversos , Ácidos Grasos Insaturados/deficiencia , Lisosomas/metabolismo , Polisacáridos/metabolismo , Sulfatos/metabolismo , Sulfoglicoesfingolípidos/metabolismo , Animales , Encéfalo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Wounding is a serious environmental stress in plants. Oxylipins such as jasmonic acid play an important role in defense against wounding. Mechanisms to adapt to wounding have been investigated in vascular plants; however, those mechanisms in nonvascular plants remain elusive. To examine the response to wounding in Physcomitrella patens, a model moss, a proteomic analysis of wounded P. patens was conducted. Proteomic analysis showed that wounding increased the abundance of proteins related to protein synthesis, amino acid metabolism, protein folding, photosystem, glycolysis, and energy synthesis. 12-Oxo-phytodienoic acid (OPDA) was induced by wounding and inhibited growth. Therefore, OPDA is considered a signaling molecule in this plant. Proteomic analysis of a P. patens mutant in which the PpAOS1 and PpAOS2 genes, which are involved in OPDA biosynthesis, are disrupted showed accumulation of proteins involved in protein synthesis in response to wounding in a similar way to the wild-type plant. In contrast, the fold-changes of the proteins in the wild-type plant were significantly different from those in the aos mutant. This study suggests that PpAOS gene expression enhances photosynthesis and effective energy utilization in response to wounding in P. patens.
Asunto(s)
Bryopsida/metabolismo , Ácidos Grasos Insaturados/metabolismo , Regulación de la Expresión Génica de las Plantas/genética , Oxidorreductasas Intramoleculares/metabolismo , Proteínas de Plantas/metabolismo , Proteoma/metabolismo , Aminoácidos/genética , Aminoácidos/metabolismo , Bryopsida/genética , Cromatografía Liquida , Ciclo del Ácido Cítrico/genética , Ciclopentanos/metabolismo , Metabolismo Energético/genética , Ácidos Grasos Insaturados/deficiencia , Ácidos Grasos Insaturados/genética , Glucólisis/genética , Oxidorreductasas Intramoleculares/genética , Oxilipinas/metabolismo , Proteínas del Complejo del Centro de Reacción Fotosintética/genética , Proteínas del Complejo del Centro de Reacción Fotosintética/metabolismo , Proteínas de Plantas/genética , Plantas Modificadas Genéticamente , Biosíntesis de Proteínas/genética , Pliegue de Proteína , Proteómica , Especies Reactivas de Oxígeno/metabolismo , Estrés Fisiológico/genética , Espectrometría de Masas en TándemRESUMEN
Sex role reversal is not uncommon in the animal kingdom but is taken to the extreme by the Syngnathidae, in which male pregnancy is one of the most astonishing idiosyncrasies. However, critical and time-dependent environmental effects on developing embryos, such as those extensively studied in mammalian pregnancy, have not been investigated in the male pregnancy context. Here, we tested the hypothesis that seahorse pregnancy is subject to 'critical windows' of environmental sensitivity by feeding male long-snouted seahorses (Hippocampus reidi) a diet deficient in polyunsaturated fatty acids during specific periods before and during pregnancy. Despite embryos being nourished principally by maternally supplied yolk, we found that offspring morphology, fatty acid composition and gene expression profiles were influenced by paternal diet in a manner that depended critically on the timing of manipulation. Specifically, reception of a diet deficient in polyunsaturated fatty acids in the days preceding pregnancy resulted in smaller newborn offspring, while the same diet administered towards the end of pregnancy resulted in substantial alterations to newborn gene expression and elongation of the snout at 10 days old. Although paternal diet did not affect 10 day survival, the observed morphological alterations in some cases could have important fitness consequences in the face of natural selective pressures such as predation and food availability. Our results demonstrate that, under male pregnancy, fine-scale temporal variation in parental diet quality and subsequent critical window effects should not be overlooked as determinants of developing offspring fitness.
Asunto(s)
Dieta/veterinaria , Ácidos Grasos Insaturados/deficiencia , Reproducción , Smegmamorpha/fisiología , Animales , Masculino , Distribución Aleatoria , Factores de TiempoRESUMEN
We sought to investigate how far the growth of Saccharomyces cerevisiae under full anaerobiosis is dependent on the widely used anaerobic growth factors (AGF) ergosterol and oleic acid. A continuous cultivation setup was employed and, even forcing ultrapure N2 gas through an O2 trap upstream of the bioreactor, neither cells from S. cerevisiae CEN.PK113-7D (a lab strain) nor from PE-2 (an industrial strain) washed out after an aerobic-to-anaerobic switch in the absence of AGF. S. cerevisiae PE-2 seemed to cope better than the laboratory strain with this extremely low O2 availability, since it presented higher biomass yield, lower specific rates of glucose consumption and CO2 formation, and higher survival at low pH. Lipid (fatty acid and sterol) composition dramatically altered when cells were grown anaerobically without AGF: saturated fatty acid, squalene and lanosterol contents increased, when compared to either cells grown aerobically or anaerobically with AGF. We concluded that these lipid alterations negatively affect cell viability during exposure to low pH or high ethanol titers.
Asunto(s)
Ergosterol/metabolismo , Ácidos Grasos Insaturados/deficiencia , Ácidos Grasos/análisis , Lípidos/análisis , Oxígeno/metabolismo , Saccharomyces cerevisiae/fisiología , Anaerobiosis , Biomasa , Supervivencia Celular , Etanol/metabolismo , Ácidos Grasos/aislamiento & purificación , Glucosa/metabolismo , Concentración de Iones de Hidrógeno , Metabolismo de los Lípidos , Lípidos/aislamiento & purificación , Saccharomyces cerevisiae/crecimiento & desarrolloRESUMEN
The etiology of altered blood fatty acid (FA) profile in phenylketonuria (PKU) is understood only partially. We aimed to determine whether FAs deficiency is dependent on the diet or metabolic disturbances. The study comprised 40 PKU patients (20 female, 20 male; aged 11 to 35 years; 12 children and 28 adults) and 40 healthy subjects (HS; 20 female, 20 male, aged 18 to 33 years). We assessed the profile of FAs (gas chromatography/mass spectrometry) and analyzed the 72-hour dietary recalls. The amount of C14:0, C16:0 and C16:1n-7, C18:1n-9 did not differ between the analyzed groups. The percentage of C18:0 was higher, while C20:3n-9, C18:2n-6, C20:2n-6, C20:4n-6, C22:4n-6, C22:5n-6 and C22:6n-3 was lower in PKU than in HS. However, C18:3n-6, C18:3n-3 and n-6/n-3 ratio were higher in PKU patients. The C20:4n-6/C20:3n-6 ratio (reaction catalyzed by Δ5-desaturase), the C22:5n-6/C22:4n-6 and the C22:6n-3/C22:5n-3 ratio (both reactions catalyzed by Δ6 desaturase) were significantly lower in PKU patients. Therefore, the deficiency of long-chain polyunsaturated fatty acids in PKU patients may result not only from inadequate supply but also from metabolic disturbances.
Asunto(s)
Ácidos Grasos Insaturados/deficiencia , Fenilcetonurias/etiología , Adolescente , Adulto , Niño , Estudios Transversales , Dieta , Ácido Graso Desaturasas , Ácidos Grasos Insaturados/análisis , Ácidos Grasos Insaturados/metabolismo , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humanos , Masculino , Adulto JovenRESUMEN
PURPOSE OF REVIEW: Advances in our understanding of the treatment of severe acute malnutrition (SAM) in a resource-limited environment are needed to improve outcome. RECENT FINDINGS: Ready-to-use therapeutic foods (RUTFs) made from local products and with reduced milk content lower costs and may be effective in older children. None of the therapeutic foods used to treat severely malnourished children correct long chain polyunsaturated fatty acid deficiencies.Routine short-term antibiotic (amoxicillin) treatment, in the context of adequate healthcare supervision, does not improve the recovery rate. Long-term antibiotic (cotrimoxazole) treatment also does not provide significant benefit to non-HIV-infected children.Increased pathogenic bacteria have been found in the intestinal microbiome of malnourished children and candidate organisms for use as probiotics have been identified. There is, however, no evidence to support the routine use of probiotics in these children. Although exocrine pancreatic function is reduced in malnourished children, routine pancreatic enzyme supplementation does not lead to accelerated recovery. SUMMARY: Alternative RUTF may provide a cheaper and more acceptable alternative to standard RUTF in the near future. Further research is needed to understand the implications of fatty acid deficiencies and dysbiosis that occur in malnourished children. Routine antibiotic administration in the appropriate setting is unnecessary.
Asunto(s)
Trastornos de la Nutrición del Niño/dietoterapia , Disbiosis/complicaciones , Ácidos Grasos Insaturados/deficiencia , Alimentos Especializados , Desnutrición Aguda Severa/dietoterapia , Animales , Antibacterianos/uso terapéutico , Niño , Trastornos de la Nutrición del Niño/complicaciones , Trastornos de la Nutrición del Niño/microbiología , Suplementos Dietéticos , Comida Rápida , Humanos , Leche , Páncreas/enzimología , Desnutrición Aguda Severa/complicaciones , Desnutrición Aguda Severa/microbiologíaRESUMEN
Insufficient intake of polyunsaturated fatty acids (PUFA) causes fatty liver. The mechanism responsible is primarily related to increased lipogenesis and decreased FA degradation based on rodent studies. However, these studies were limited by the fact that the typical PUFA-deficient diets contained insufficient amounts of long-chain FA, the PUFA-containing diets were primarily composed of n-3 PUFA-enriched oil, and the intake of PUFA was excessive compared with the physiological requirement. To address these issues, mice were fed a PUFA-deficient diet containing long-chain FA at a standard fed level and then were orally fed a n-3/n-6-balanced PUFA-containing oil [PUFA (+)] or a PUFA-deficient oil [PUFA (-)] at physiological relevant levels (0.1 mL/mouse/2d). We compared these groups and examined whether fatty liver in PUFA deficiency was attributable to both the effects of increased lipogenesis and decreased FA catabolism. Compared with the PUFA (+) group, the PUFA (-) group showed increases in liver triglyceride and serum FA content. Hepatic gene expression of several mitochondrial ß-oxidation enzymes, the serum 3-hydroxybutyrate level, and DNA-binding ability of peroxisome proliferator-activated receptor α (PPARα) were increased in the PUFA (+) group, whereas these adaptive responses were significantly attenuated in the PUFA (-) group. The hepatic expression of typical lipogenesis genes did not differ between the groups. Therefore, fatty liver in PUFA deficiency is attributable to suppression of the FA-degrading system probably from decreased PPARα adaptive responsiveness, and PUFA may be an essential factor for PPARα functioning. This finding is helpful for managing clinical situations having a risk of PUFA deficiency.
Asunto(s)
Ácidos Grasos Insaturados/metabolismo , Ácidos Grasos/metabolismo , Hígado Graso/metabolismo , Animales , Peso Corporal , Ácidos Grasos Insaturados/deficiencia , Masculino , Ratones , Ratones Endogámicos C57BL , Oxidación-ReducciónRESUMEN
BACKGROUND: Severe acute malnutrition (SAM) has been associated with low polyunsaturated fatty acid (PUFA) status. However, investigations regarding PUFA status and correlates in children with moderate acute malnutrition (MAM) from low-income countries are scarce. The aim of this study was to describe whole-blood PUFA levels in children with moderate acute malnutrition (MAM) and to identify correlates of PUFAs. METHODS: We conducted a cross-sectional study using baseline data from a prospective nutritional intervention trial among 1609 children with MAM aged 6-23 months in Burkina Faso,West Africa. Whole-blood PUFAs were measured by gas chromatography and expressed as percent of total whole-blood fatty acids (FA%). Potential correlates of PUFAs including infection, inflammation, hemoglobin, anthropometry (difference between children diagnosed as having MAM based on low mid-upper-arm-circumference (MUAC) only, low MUAC and weight-for-height z-score (WHZ), or low WHZ only) and diet were assessed by linear regression adjusted for age and sex. RESULTS: Children with MAM had low concentrations of whole-blood PUFAs, particularly n-3 PUFAs. Moreover, children diagnosed with MAM based only on low MUAC had 0.32 (95% confidence interval (CI), 0.14; 0.50) and 0.40 (95% CI, 0.16; 0.63) FA% lower arachidonic acid (AA) than those recruited based on both low WHZ as well as low MUAC and those recruited with low WHZ only, respectively. Infection and inflammation were associated with low levels of all long-chain (LC)-PUFAs, while hemoglobin was positively associated with whole-blood LC-PUFAs. CONCLUSION: While PUFA deficiency was not a general problem, overall whole-blood PUFA concentrations, especially of n-3 PUFAs, were low. Infection, inflammation, hemoglobin, anthropometry and diet were correlates of PUFAs concentrations in children with MAM. TRIAL REGISTRATION: The trial is registered at http://www.isrctn.com ( ISRCTN42569496 ).
Asunto(s)
Ácidos Grasos Insaturados/sangre , Desnutrición/tratamiento farmacológico , Desnutrición/epidemiología , Antropometría , Burkina Faso/epidemiología , Proteína C-Reactiva/metabolismo , Niño , Estudios Transversales , Dieta , Ácidos Grasos Insaturados/administración & dosificación , Ácidos Grasos Insaturados/deficiencia , Femenino , Hemoglobinas/metabolismo , Humanos , Lactante , Masculino , Morbilidad , Evaluación Nutricional , Orosomucoide/metabolismo , Factores SocioeconómicosRESUMEN
The Mga2 and Sre1 transcription factors regulate oxygen-responsive lipid homeostasis in the fission yeast Schizosaccharomyces pombe in a manner analogous to the mammalian sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 transcription factors. Mga2 and SREBP-1 regulate triacylglycerol and glycerophospholipid synthesis, whereas Sre1 and SREBP-2 regulate sterol synthesis. In mammals, a shared activation mechanism allows for coordinate regulation of SREBP-1 and SREBP-2. In contrast, distinct pathways activate fission yeast Mga2 and Sre1. Therefore, it is unclear whether and how these two related pathways are coordinated to maintain lipid balance in fission yeast. Previously, we showed that Sre1 cleavage is defective in the absence of mga2 Here, we report that this defect is due to deficient unsaturated fatty acid synthesis, resulting in aberrant membrane transport. This defect is recapitulated by treatment with the fatty acid synthase inhibitor cerulenin and is rescued by addition of exogenous unsaturated fatty acids. Furthermore, sterol synthesis inhibition blocks Mga2 pathway activation. Together, these data demonstrate that Sre1 and Mga2 are each regulated by the lipid product of the other transcription factor pathway, providing a source of coordination for these two branches of lipid synthesis.
Asunto(s)
Proteínas de Schizosaccharomyces pombe/metabolismo , Schizosaccharomyces/química , Proteínas de Unión a los Elementos Reguladores de Esteroles/metabolismo , Factores de Transcripción/metabolismo , Ácidos Grasos Insaturados/biosíntesis , Ácidos Grasos Insaturados/deficiencia , Regulación Fúngica de la Expresión Génica , Metabolismo de los Lípidos , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Esteroles/biosíntesis , Factores de Transcripción/genéticaRESUMEN
Atopic dermatitis (AD) is a common pruritic chronic skin disease. AD pathogenesis remains elusive, but may involve complex interplays among skin barrier dysfunction, Th2 inflammation, and pruritus. Current treatments for AD are still limited to symptomatic therapies. We previously showed that HR-1 hairless mice fed a special diet (HR-AD) develop AD-like symptoms; however, the ingredient(s) causing dermatitis remain unclear. In this study, we examined whether the deficiency of certain polyunsaturated fatty acids (PUFAs) was involved in the diet-induced AD pathogenesis. In the serum of HR-AD-fed mice, levels of linoleic acid (LA, 18:2n-6) and α-linolenic acid (ALA, 18:3n-3), as well as their metabolites, were markedly decreased. HR-AD-induced AD symptoms were significantly ameliorated by LA supplementation, and to a lesser extent by ALA supplementation. In addition, LA metabolites, such as γ-linolenic acid and arachidonic acid, had effects similar to those of LA. Further, using semi-purified custom diets, we attempted to reproduce HR-AD-induced AD symptoms. Unexpectedly, a deficiency in unsaturated fatty acids (UFAs) alone caused mild symptoms. However, several modifications of fat and carbohydrate components in the diet revealed that dietary deficiencies of UFA and cornstarch were required to fully induce severe AD symptoms. Furthermore, we examined the influence of genetic background on the development of diet-induced AD and found that a hypomorphic mutation in the hairless gene Hr, encoding a nuclear receptor (NR) corepressor, was essential for the complete development of diet-induced pruritic atopic skin. Thus, our findings suggest that certain PUFAs and NRs are new, potential therapeutic targets for treating AD.
Asunto(s)
Dermatitis Atópica/etiología , Dieta/efectos adversos , Ácido Linoleico/deficiencia , Animales , Proteínas Co-Represoras/genética , Dermatitis Atópica/genética , Dermatitis Atópica/terapia , Modelos Animales de Enfermedad , Ácidos Grasos Insaturados/deficiencia , Humanos , Ácido Linoleico/administración & dosificación , Ácido Linoleico/sangre , Ratones Pelados , Terapia Molecular Dirigida , Mutación , Almidón/efectos adversos , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Long-chain polyunsaturated fatty acids (PUFAs) are major components of the phospholipids that forming the cell membrane. Insufficient availability of PUFAs during prenatal period decreases accretion of docosahexaenoic acid (DHA) in the developing brain. DHA deficiency is associated with impaired attention and cognition, and would precipitate psychiatric symptoms. However, clinical studies on the potential benefits of dietary DHA supplementation to neural development have yielded conflicting results. METHODS: To further investigate the neurochemical influence of maternal PUFAs levels, we assessed the functioning of various neurotransmitter systems including glutamatergic, dopaminergic, norepinephrinergic and serotoninergic systems in the brain of neonatal female rats by HPLC-MS/MS. Meanwhile, the cell proliferation of neonatal rats was investigated using immunefluorescence. RESULTS: Different maternal n-3 PUFAs dietary influenced the FA composition, cell proliferation in the dentate gyrus of hippocampus and the contents of γ-aminobutyric acid (GABA), glutamine (GLN), dopamine (DA) and its metabolites [3,4- dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA)], norepinephrine (NE), vanilmandelic acid (VMA) and 5-HT turnover in the brain of neonatal rats. However, the mRNA expression of key synthase of neurotransmitters remains stable. CONCLUSIONS: Our study showed that maternal deficiency of n-3 PUFAs might play an important role in central nervous system of neonatal female rats mainly through impairing the normal neurogenesis and influencing glutamatergic system and 5-HT turnover.
Asunto(s)
Giro Dentado/citología , Giro Dentado/metabolismo , Ácidos Grasos Insaturados/farmacología , Fenómenos Fisiologicos Nutricionales Maternos , Animales , Animales Recién Nacidos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiología , Proliferación Celular/efectos de los fármacos , Giro Dentado/efectos de los fármacos , Dieta , Ácidos Grasos/metabolismo , Ácidos Grasos Insaturados/deficiencia , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Ácido Glutámico/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Neurotransmisores/metabolismo , Embarazo , Ratas Sprague-Dawley , Serotonina/metabolismoRESUMEN
BACKGROUND: In several trials, beneficial prognostic effects of highly unsaturated fatty acids (HUFAs) in heart failure were shown. Because other studies showed no incremental benefit in nearly preserved cardiac function, the question arises, whether the degree of cardiac dysfunction is involved. It is hypothesized that increased left ventricular (LV) wall stress affects the endogenous hepatic HUFA metabolism, which in turn exhibits adverse cardiac consequences. METHODS: Cardiac magnetic resonance imaging was performed in 30 patients with suspected cardiomyopathy. The serum fatty acid profile was assessed using gas chromatography/mass spectrometry. RESULTS: Docosahexaenoic acid (DHA; P = 0.002) and eicosapentaenoic acid (EPA; by trend) levels were decreased in patients with reduced LV ejection fraction (≤ 50%) or LV dilatation (≥ 90 mL/m(2)). Decreased DHA (P = 0.003) and EPA (P = 0.022) levels were associated with a reduced LV ejection fraction. Decreased DHA level was correlated with increased end-diastolic (P = 0.047) and end-systolic LV wall stress (P = 0.001). Pseudocholinesterase activity was inversely correlated with end-diastolic (P = 0.020) and end-systolic LV wall stress (P = 0.025). CONCLUSIONS: DHA level was significantly reduced in heart failure. Similar, but less pronounced effects were found for EPA and arachidonic acid by trend. Increased LV wall stress was correlated with a reduced DHA level. Increased LV wall stress exhibits various adverse consequences (eg, increased oxygen consumption, favouring of arrhythmias, and an unfavourable remodelling). The increase of wall stress was paralleled by reduced HUFA level. Increased LV wall stress was correlated with reduced pseudocholinesterase, which is suggestive of hepatic congestion (ie, a cardiohepatic syndrome, involved in the altered fatty acid profile in heart failure) and has major consequences regarding the dose-efficacy of HUFA treatment.
Asunto(s)
Ácidos Grasos Insaturados/sangre , Insuficiencia Cardíaca/metabolismo , Ventrículos Cardíacos/fisiopatología , Hígado/metabolismo , Función Ventricular Izquierda/fisiología , Ácidos Grasos Insaturados/deficiencia , Femenino , Cromatografía de Gases y Espectrometría de Masas , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/diagnóstico , Ventrículos Cardíacos/patología , Humanos , Imagen por Resonancia Cinemagnética/métodos , Masculino , Pronóstico , Volumen Sistólico/fisiologíaRESUMEN
Preeclampsia is a low-grade systemic inflammatory condition in which oxidative stress and endothelial dysfunction occurs. Plasma levels of soluble receptor for vascular endothelial growth factor (VEGFR)-1, also known as sFlt1 (soluble fms-like tyrosine kinase 1), an antiangiogenic factor have been reported to be elevated in preeclampsia. It was reported that pregnant mice deficient in catechol-O-methyltransferase (COMT) activity show a preeclampsia-like phenotype due to a deficiency or absence of 2-methoxyoestradiol (2-ME), a natural metabolite of estradiol that is elevated during the third trimester of normal human pregnancy. Additionally, autoantibodies (AT1-AAs) that bind and activate the angiotensin II receptor type 1 a (AT1 receptor) also have a role in preeclampsia. None of these abnormalities are consistently seen in all the patients with preeclampsia and some of them are not specific to pregnancy. Preeclampsia could occur due to an imbalance between pro- and antiangiogenic factors. VEGF, an angiogenic factor, is necessary for the transport of polyunsaturated fatty acids (PUFAs) to endothelial cells. Hence reduced VEGF levels decrease the availability of PUFAs to endothelial cells. This leads to a decrease in the formation of anti-inflammatory and angiogenic factors: lipoxins, resolvins, protectins, and maresins from PUFAs. Lipoxins, resolvins, protectins, maresins, and PUFAs suppress insulin resistance; activation of leukocytes, platelets, and macrophages; production of interleukin-6 and tumor necrosis factor-α; and oxidative stress and endothelial dysfunction; and enhance production of prostacyclin and nitric oxide (NO). Estrogen enhances the formation of lipoxin A4 and NO. PUFAs also augment the production of NO and inhibit the activity of angiotensin-converting enzyme and antagonize the actions of angiotensin II. Thus, PUFAs can prevent activation of angiotensin II receptor type 1 a (AT1 receptor). Patients with preeclampsia have decreased plasma phospholipid concentrations of arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), the precursors of lipoxins (from AA), resolvins (from EPA and DHA), and protectins (from DHA) and prostaglandin E1 (PGE1 from DGLA: dihomo-γ-linolenic acid) and prostacyclin (PGI2 derived from AA). Based on these evidences, it is proposed that preeclampsia may occur due to deficiency of PUFAs and their anti-inflammatory products: lipoxins, resolvins, protectins, and maresins.
Asunto(s)
Inhibidores de la Angiogénesis/sangre , Citocinas/sangre , Eicosanoides/sangre , Ácidos Grasos Insaturados/sangre , Inflamación/sangre , Preeclampsia/etiología , Factor A de Crecimiento Endotelial Vascular/sangre , Animales , Endotelio Vascular/metabolismo , Ácidos Grasos Insaturados/deficiencia , Femenino , Humanos , Preeclampsia/sangre , Embarazo , Receptor de Angiotensina Tipo 1/sangre , Factor A de Crecimiento Endotelial Vascular/deficienciaRESUMEN
Long-chain polyunsaturated fatty acid (LCPUFA) status has recently been related to the pathogenesis of obesity. Our aims were to systematically review observational studies investigating LCPUFA status from different blood compartments in overweight or obese subjects and to assess the relationship between LCPUFA profile and obesity. The Ovid MEDLINE, Scopus and Cochrane Library CENTRAL databases were searched from inception to January 2014. The meta-analysis showed significant differences in the LCPUFA composition of total plasma lipids, plasma phospholipids and plasma cholesteryl esters between overweight or obese subjects and controls. Dihomo-γ-linolenic acid (DGLA) values were significantly higher in overweight or obese subjects compared with controls in all the investigated biomarkers. In addition, the DGLA/linoleic acid ratio (surrogate parameter for Δ6 desaturase activity) in plasma phospholipids was significantly elevated (mean difference [MD]: 0.05; 95% confidence interval [CI]: 0.02, 0.08; n = 280), while the arachidonic acid/DGLA ratio (surrogate parameter for Δ5 desaturase activity) was significantly decreased (MD: -0.55; 95% CI: -0.71, -0.39; n = 347) in overweight or obese subjects compared with controls. The results of the present meta-analysis confirm that LCPUFA profile is altered in obesity and suggest that the differences observed in desaturase activities may be responsible for the disturbed LCPUFA metabolism in obesity.
Asunto(s)
Enfermedades Carenciales/etiología , Medicina Basada en la Evidencia , Ácido Graso Desaturasas/metabolismo , Ácidos Grasos Insaturados/deficiencia , Linoleoil-CoA Desaturasa/metabolismo , Obesidad/fisiopatología , Sobrepeso/fisiopatología , Biomarcadores/sangre , delta-5 Desaturasa de Ácido Graso , Ácidos Grasos Insaturados/sangre , Ácidos Grasos Insaturados/metabolismo , Humanos , Estado Nutricional , Obesidad/sangre , Obesidad/enzimología , Estudios Observacionales como Asunto , Sobrepeso/sangre , Sobrepeso/enzimologíaRESUMEN
PURPOSE: Juvenile-onset autosomal dominant Stargardt-like macular dystrophy (STGD3) is caused by mutations in ELOVL4 (elongation of very long fatty acids-4), an elongase necessary for the biosynthesis of very long chain fatty acids (VLC-FAs ≥ C26). Photoreceptors are enriched with VLC polyunsaturated fatty acids (VLC-PUFAs), which are necessary for long-term survival of rod photoreceptors. The purpose of these studies was to determine the effect of deletion of VLC-PUFAs on rod synaptic function in retinas of mice conditionally depleted (KO) of Elovl4. METHODS: Retina function was assessed in wild-type (WT) and KO by electroretinography. Outer plexiform structure was evaluated by immunofluorescence and transmission electron microscopy. Single-cell recordings measured rod ion channel operation and rod bipolar glutamate signaling. Sucrose gradient centrifugation was used to isolate synaptosomes from bovine retina. Proteins and lipids were analyzed by Western blotting and tandem mass spectroscopy, respectively. RESULTS: Inner retinal responses (b-wave, oscillatory potentials, and scotopic threshold responses) of the ERG were decreased in the KO mice compared to controls. However the rod ion channel operation and bipolar glutamate responses were comparable between groups. Biochemical analysis revealed that conventional and ribbon synapses have VLC-PUFAs. Ultrastructural analysis showed that the outer plexiform layer was disorganized and the diameter of vesicles in rod terminals was smaller in the KO mice. CONCLUSIONS: Very long chain PUFAs affect rod function by contributing to synaptic vesicle size, which may alter the dynamics of synaptic transmission, ultimately resulting in a loss of neuronal connectivity and death of rod photoreceptors.