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BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] is a causal, genetically determined cardiovascular risk factor. Limited evidence suggests that dietary unsaturated fat may increase serum Lp(a) concentration by 10-15 %. Linoleic acid may increase Lp(a) concentration through its endogenous conversion to arachidonic acid, a process regulated by the fatty acid desaturase (FADS) gene cluster. We aimed to compare the Lp(a) and other lipoprotein trait-modulating effects of dietary alpha-linolenic (ALA) and linoleic acids (LA). Additionally, we examined whether FADS1 rs174550 genotype modifies Lp(a) responses. METHODS: A genotype-based randomized trial was performed in 118 men homozygous for FADS1 rs174550 SNP (TT or CC). After a 4-week run-in period, the participants were randomized to 8-week intervention diets enriched with either Camelina sativa oil (ALA diet) or sunflower oil (LA diet) 30-50 mL/day based on their BMI. Serum lipid profile was measured at baseline and at the end of the intervention. RESULTS: ALA diet lowered serum Lp(a) concentration by 7.3 % (p = 0.003) and LA diet by 9.5 % (p < 0.001) (p = 0.089 for between-diet difference). Both diets led to greater absolute decreases in individuals with higher baseline Lp(a) concentration (p < 0.001). Concentrations of LDL cholesterol (LDL-C), non-HDL-C, remnant-C, and apolipoprotein B were lowered more by the ALA diet (p < 0.01). Lipid or lipoprotein responses were not modified by the FADS1 rs174550 genotype. CONCLUSIONS: A considerable increase in either dietary ALA or LA from vegetable oils has a similar Lp(a)-lowering effect, whereas ALA may lower other major atherogenic lipids and lipoproteins to a greater extent than LA. Genetic differences in endogenous PUFA conversion may not influence serum Lp(a) concentration.
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delta-5 Desaturasa de Ácido Graso , Ácido Graso Desaturasas , Lipoproteína(a) , Ácido alfa-Linolénico , Humanos , Lipoproteína(a)/sangre , Masculino , Persona de Mediana Edad , Ácido alfa-Linolénico/administración & dosificación , Ácido Graso Desaturasas/genética , Adulto , Polimorfismo de Nucleótido Simple , Aterosclerosis/prevención & control , Aterosclerosis/sangre , Aterosclerosis/genética , Ácido Linoleico/sangre , Ácido Linoleico/administración & dosificación , Genotipo , Ácidos Linoleicos/sangre , Aceites de Plantas/administración & dosificación , Lipoproteínas/sangre , Aceite de GirasolRESUMEN
INTRODUCTION: Oxylipins are mediators of oxidative stress. To characterize the underlying inflammatory processes and phenotype effect of iron metabolism disorders, we investigated the oxylipin profile in hereditary hemochromatosis (HH) and dysmetabolic iron overload syndrome (DIOS) patients. METHODS: An LC-MS/MS-based method was performed to quantify plasma oxylipins in 20 HH and 20 DIOS patients in fasting conditions and 3 h after an iron-rich meal in HH patients. RESULTS: Principal component analysis showed no separation between HH and DIOS, suggesting that the clinical phenotype has no direct impact on oxylipin metabolism. 20-HETE was higher in DIOS and correlated with hypertension (p = 0.03). Different oxylipin signatures were observed in HH before and after the iron-rich meal. Discriminant oxylipins include epoxy fatty acids derived from docosahexaenoic acid and arachidonic acid as well as 13-HODE and 9-HODE. Mediation analysis found no major contribution of dietary iron absorption for 16/22 oxylipins significantly affected by the meal. DISCUSSION: The oxylipin profiles of HH and DIOS seemed similar except for 20-HETE, possibly reflecting different hypertension prevalence between the two groups. Oxylipins were significantly affected by the iron-rich meal, but the specific contribution of iron was not clear. Although iron may contribute to oxidative stress and inflammation in HH and DIOS, this does not seem to directly affect oxylipin metabolism.
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Eicosanoides , Hemocromatosis , Sobrecarga de Hierro , Hierro de la Dieta , Oxilipinas , Humanos , Oxilipinas/sangre , Masculino , Femenino , Hemocromatosis/sangre , Hemocromatosis/genética , Persona de Mediana Edad , Hierro de la Dieta/administración & dosificación , Adulto , Eicosanoides/sangre , Sobrecarga de Hierro/sangre , Ácidos Hidroxieicosatetraenoicos/sangre , Espectrometría de Masas en Tándem , Estrés Oxidativo , Análisis de Componente Principal , Anciano , Ácidos Linoleicos/sangre , Cromatografía LiquidaRESUMEN
OBJECTIVE: To assess the maternal blood levels of fatty acids (FAs) in pregnancies with fetal growth restriction (FGR). METHODS: This prospective cross-sectional study included pregnant women with gestational age between 26 and 37 + 6 weeks with FGR and appropriate for gestational age (AGA) fetuses. The levels of saturated, trans, monounsaturated, and polyunsaturated FAs were measured using centrifugation and liquid chromatography. The Student's t-test, Mann-Whitney test, and general linear model, with gestational age and maternal weight as covariants, were used to compare FA levels and the FGR and AGA groups. The Chi-square was used to evaluate the association between groups and studied variables. RESULTS: Maternal blood sample was collected from 64 pregnant women, being 24 FGR and 40 AGA. A weak positive correlation was found between the palmitoleic acid level and maternal weight (r = 0.285, p = 0.036). A weak negative correlation was found between the gamma-linoleic acid level and gestational age (r = - 0.277, p = 0.026). The median of the elaidic acid level (2.3 vs. 4.7 ng/ml, p = 0.045) and gamma-linoleic acid (6.3 vs. 6.6 ng/ml, p = 0.024) was significantly lower in the FGR than the AGA group. The palmitoleic acid level was significantly higher in the FGR than AGA group (50.5 vs. 47.6 ng/ml, p = 0.033). CONCLUSION: Pregnant women with FGR had lower elaidic acid and gamma-linoleic acid levels and higher palmitoleic acid levels than AGA fetuses.
OBJETIVO: Avaliar os níveis sanguíneos maternos de ácidos graxos (AGs) em gestações com restrição de crescimento fetal (RCF). MéTODOS:: Este estudo prospectivo transversal incluiu gestantes com idade gestacional entre 26 e 37 semanas e 6 dias com RCF e fetos adequados para a idade gestacional (AIG). Os níveis de ácidos graxos saturados, trans, monoinsaturados e poliinsaturados foram medidos usando centrifugação e cromatografia líquida. O teste t-Student, o teste de Mann-Whitney e o modelo linear geral, com idade gestacional e peso materno como covariantes, foram utilizados para comparar os níveis de AGs e os grupos RCF e AIG. O teste Qui-quadrado foi utilizado para avaliar a associação entre os grupos e as variáveis estudadas. RESULTADOS: Amostra de sangue materno foi coletada de 64 gestantes, sendo 24 RCF e 40 AIG. Uma correlação positiva fraca foi encontrada entre o nível de ácido palmitoleico e o peso materno (r = 0,285, p = 0,036). Uma correlação negativa fraca foi encontrada entre o nível de ácido gama-linoleico e a idade gestacional (r = − 0,277, p = 0,026). A mediana do nível de ácido elaídico (2,3 vs. 4,7 ng/ml, p = 0,045) e ácido gama-linoleico (6,3 vs. 6,6 ng/ml, p = 0,024) foram significativamente menores no grupo RCF do que no grupo AIG. O nível de ácido palmitoleico foi significativamente maior no grupo RCF do que no grupo AIG (50,5 vs. 47,6 ng/ml, p = 0,033). CONCLUSãO:: Gestantes com RCF apresentaram níveis mais baixos de ácido elaídico e ácido gama-linoleico e níveis mais elevados de ácido palmitoleico do que os fetos AIG.
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Ácidos Grasos , Retardo del Crecimiento Fetal , Femenino , Humanos , Lactante , Embarazo , Estudios Transversales , Ácidos Grasos/sangre , Retardo del Crecimiento Fetal/sangre , Edad Gestacional , Ácidos Linoleicos/sangre , Estudios Prospectivos , Ultrasonografía PrenatalRESUMEN
[Figure: see text].
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Ácido Araquidónico/sangre , Fumar Cigarrillos/sangre , Glutatión/sangre , Hemo Oxigenasa (Desciclizante)/sangre , Ácidos Linoleicos/sangre , Vapeo/sangre , Adulto , Bilirrubina/sangre , Biomarcadores/sangre , Fumar Cigarrillos/efectos adversos , Femenino , Humanos , Masculino , Estrés Oxidativo , Vapeo/efectos adversosRESUMEN
COVID-19 pneumonia has specific features and outcomes that suggests a unique immunopathogenesis. Severe forms of COVID-19 appear to be more frequent in obese patients, but an association with metabolic disorders is not established. Here, we focused on lipoprotein metabolism in patients hospitalized for severe pneumonia, depending on COVID-19 status. Thirty-four non-COVID-19 and 27 COVID-19 patients with severe pneumonia were enrolled. Most of them required intensive care. Plasma lipid levels, lipoprotein metabolism, and clinical and biological (including plasma cytokines) features were assessed. Despite similar initial metabolic comorbidities and respiratory severity, COVID-19 patients displayed a lower acute phase response but higher plasmatic concentrations of non-esterified fatty acids (NEFAs). NEFA profiling was characterised by higher level of polyunsaturated NEFAs (mainly linoleic and arachidonic acids) in COVID-19 patients. Multivariable analysis showed that among severe pneumonia, COVID-19-associated pneumonia was associated with higher NEFAs, lower apolipoprotein E and lower high-density lipoprotein cholesterol concentrations, independently of body mass index, sequential organ failure (SOFA) score, and C-reactive protein levels. NEFAs and PUFAs concentrations were negatively correlated with the number of ventilator-free days. Among hospitalized patients with severe pneumonia, COVID-19 is independently associated with higher NEFAs (mainly linoleic and arachidonic acids) and lower apolipoprotein E and HDL concentrations. These features might act as mediators in COVID-19 pathogenesis and emerge as new therapeutic targets. Further investigations are required to define the role of NEFAs in the pathogenesis and the dysregulated immune response associated with COVID-19.Trial registration: NCT04435223.
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COVID-19/patología , Ácidos Grasos no Esterificados/sangre , Anciano , Apolipoproteínas E/sangre , Ácidos Araquidónicos/sangre , COVID-19/sangre , COVID-19/virología , HDL-Colesterol/sangre , Citocinas/sangre , Femenino , Humanos , Ácidos Linoleicos/sangre , Masculino , Persona de Mediana Edad , Análisis de Componente Principal , SARS-CoV-2/aislamiento & purificación , Índice de Severidad de la EnfermedadRESUMEN
Linoleic acid (LNA)-derived 13-hydroxyoctadecadienoic acid (13-HODE) is a bioactive lipid mediator that regulates multiple signaling processes in vivo. 13-HODE is also produced when LNA is oxidized during food processing. However, the absorption and incorporation kinetics of dietary 13-HODE into tissues is not known. The present study measured unesterified d4-13-HODE plasma bioavailability and incorporation into rat liver, adipose, heart and brain following gavage or intravenous (IV) injection (n = 3 per group). Mass spectrometry analysis revealed that d4-13-HODE was absorbed within 20 min of gavage, and continued to incorporate into plasma esterified lipid fractions throughout the 90 min monitoring period (incorporation half-life of 71 min). Following IV injection, unesterified d4-13-HODE was rapidly eliminated from plasma with a half-life of 1 min. Analysis of tracer incorporation kinetics into rat tissues following IV injection or gavage revealed that the esterified tracer preferentially incorporated into liver, adipose and heart compared to unesterified d4-13-HODE. No tracer was detected in the brain. This study demonstrates that dietary 13-HODE is absorbed, and incorporated into peripheral tissues from esterified plasma lipid pools. Understanding the chronic effects of dietary 13-HODE exposure on peripheral tissue physiology and metabolism merits future investigation.
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Ácidos Linoleicos/metabolismo , Tejido Adiposo/metabolismo , Animales , Encéfalo/metabolismo , Esterificación , Ácido Linoleico/metabolismo , Ácidos Linoleicos/administración & dosificación , Ácidos Linoleicos/sangre , Hígado/metabolismo , Masculino , Miocardio/metabolismo , Ratas , Ratas Endogámicas F344RESUMEN
Nonalcoholic fatty liver disease (NAFLD) is becoming a major public health problem worldwide. The study aimed to evaluate the concentration of eicosanoids in serum and liver tissue during steatosis progression and to assess whether eicosanoid change scores may predict liver tissue remodeling. Thirty six eight-week-old male Sprague Dawley rats were enrolled and sacrificed at different stages of NAFLD. Eicosanoid concentrations, namely lipoxin A4, hydroxyeicosatetraenoic acids (HETE), hydroxyloctadecadienoic acids (HODE), protectin DX, Maresine1, leucotriene B4, prostaglandin E2, and resolvin D1 measurement in serum and liver tissue with Agilent Technologies 1260 liquid chromatography were evaluated. For the liver and serum concentrations of 9-HODE and 13-HODE, the correlations were found to be strong and positive (r > 0.7, p < 0.05). Along with NAFLD progression, HODE concentration significantly increased, and change scores were more abundant in the liver. The moderate positive correlation between liver and serum (r = 0.52, p < 0.05) was also observed for resolvin E1. The eicosanoid concentration decreased during NAFLD progression, but mostly in serum. There were significant correlations between HETE concentrations in liver and serum, but their associations were relatively low and changes the most in liver tissue. Eicosanoids profile, predominantly 9-HODE and 13-HODE, may serve as a potential biomarker for NAFLD development.
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Eicosanoides/sangre , Eicosanoides/metabolismo , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Biomarcadores/análisis , Biomarcadores/sangre , Biomarcadores/metabolismo , Cromatografía Liquida , Dinoprostona/análisis , Dinoprostona/sangre , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ácidos Docosahexaenoicos/análisis , Ácidos Docosahexaenoicos/sangre , Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/análisis , Ácido Eicosapentaenoico/sangre , Ácido Eicosapentaenoico/metabolismo , Ácidos Hidroxieicosatetraenoicos/análisis , Ácidos Hidroxieicosatetraenoicos/sangre , Ácidos Hidroxieicosatetraenoicos/metabolismo , Ácidos Linoleicos/análisis , Ácidos Linoleicos/sangre , Ácidos Linoleicos/metabolismo , Lipoxinas/análisis , Lipoxinas/sangre , Lipoxinas/metabolismo , Hígado/patología , Masculino , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Ratas , Ratas Sprague-DawleyRESUMEN
Nonalcoholic steatohepatitis (NASH) is a common liver disease that occurs in both alcoholics and nonalcoholics. Oxidative stress is a possible causative factor for liver diseases including NASH. Gut microorganisms, especially lactic acid bacteria, can produce unique fatty acids, including hydroxy, oxo, conjugated, and partially saturated fatty acids. The oxo fatty acid 10-oxo-11(E)-octadecenoic acid (KetoC) provides potent cytoprotective effects against oxidative stress through activation of Nrf2-ARE pathway. The aim of this study was to explore the preventive and therapeutic effects of gut microbial fatty acid metabolites in a NASH mouse model. The mice were divided into 3 experimental groups and fed as follows: (1) high-fat diet (HFD) (2) HFD mixed with 0.1% KetoA (10-oxo-12(Z)-octadecenoic acid), and (3) HFD mixed with 0.1% KetoC. After 3 weeks of feeding, plasma parameters, liver histology, and mRNA expression of multiple genes were assessed. There was hardly any difference in fat accumulation in the histological study; however, no ballooning occurred in 2/5 mice of KetoC group. Bridging fibrosis was not observed in the KetoA group, although KetoA administration did not significantly suppress fibrosis score (p = 0.10). In addition, KetoC increased the expression level of HDL related genes and HDL cholesterol levels in the plasma. These results indicated that KetoA and KetoC may partly affect the progression of NASH in mice models.
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Bacterias/metabolismo , Redes Reguladoras de Genes/efectos de los fármacos , Ácidos Linoleicos/administración & dosificación , Enfermedad del Hígado Graso no Alcohólico/dietoterapia , Animales , HDL-Colesterol/sangre , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Microbioma Gastrointestinal , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Ácidos Linoleicos/sangre , Ácidos Linoleicos/química , Ácidos Linoleicos/farmacología , Masculino , Ratones , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/genética , Estrés Oxidativo/efectos de los fármacos , Estreptozocina/efectos adversosRESUMEN
OBJECTIVES: To determine the production of 9-hydroxyoctadecadienoic acid and 13-hydroxyoctadecadienoic acid during cardiopulmonary bypass in infants and children undergoing cardiac surgery, evaluate their relationship with increase in cell-free plasma hemoglobin, provide evidence of bioactivity through markers of inflammation and vasoactivity (WBC count, milrinone use, vasoactive-inotropic score), and examine their association with overall clinical burden (ICU/hospital length of stay and mechanical ventilation duration). DESIGN: Prospective observational study. SETTING: Twelve-bed cardiac ICU in a university-affiliated children's hospital. PATIENTS: Children were prospectively enrolled during their preoperative clinic appointments with the following criteria: greater than 1 month to less than 18 years old, procedures requiring cardiopulmonary bypass INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS: Plasma was collected at the start and end of cardiopulmonary bypass in 34 patients. 9-hydroxyoctadecadienoic acid, 13-hydroxyoctadecadienoic acid, plasma hemoglobin, and WBC increased. 9:13-hydroxyoctadecadienoic acid at the start of cardiopulmonary bypass was associated with vasoactive-inotropic score at 2-24 hours postcardiopulmonary bypass (R = 0.25; p < 0.01), milrinone use (R = 0.17; p < 0.05), and WBC (R = 0.12; p < 0.05). 9:13-hydroxyoctadecadienoic acid at the end of cardiopulmonary bypass was associated with vasoactive-inotropic score at 2-24 hours (R = 0.17; p < 0.05), 24-48 hours postcardiopulmonary bypass (R = 0.12; p < 0.05), and milrinone use (R = 0.19; p < 0.05). 9:13-hydroxyoctadecadienoic acid at the start and end of cardiopulmonary bypass were associated with the changes in plasma hemoglobin (R = 0.21 and R = 0.23; p < 0.01). The changes in plasma hemoglobin was associated with milrinone use (R = 0.36; p < 0.001) and vasoactive-inotropic score less than 2 hours (R = 0.22; p < 0.01), 2-24 hours (R = 0.24; p < 0.01), and 24-48 hours (R = 0.48; p < 0.001) postcardiopulmonary bypass. Cardiopulmonary bypass duration, 9:13-hydroxyoctadecadienoic acid at start of cardiopulmonary bypass, and plasma hemoglobin may be risk factors for high vasoactive-inotropic score. Cardiopulmonary bypass duration, changes in plasma hemoglobin, 9:13-hydroxyoctadecadienoic acid, and vasoactive-inotropic score correlate with ICU and hospital length of stay and/mechanical ventilation days. CONCLUSIONS: In low-risk pediatric patients undergoing cardiopulmonary bypass, 9:13-hydroxyoctadecadienoic acid was associated with changes in plasma hemoglobin, vasoactive-inotropic score, and WBC count, and may be a risk factor for high vasoactive-inotropic score, indicating possible inflammatory and vasoactive effects. Further studies are warranted to delineate the role of hydroxyoctadecadienoic acids and plasma hemoglobin in cardiopulmonary bypass-related dysfunction and to explore hydroxyoctadecadienoic acid production as a potential therapeutic target.
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Puente Cardiopulmonar/métodos , Ácidos Grasos Insaturados/sangre , Cardiopatías Congénitas/cirugía , Ácidos Linoleicos/sangre , Oxilipinas/sangre , Biomarcadores/sangre , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Procedimientos Quirúrgicos Cardíacos/métodos , Puente Cardiopulmonar/efectos adversos , Niño , Preescolar , Ácidos Grasos Insaturados/metabolismo , Femenino , Cardiopatías Congénitas/tratamiento farmacológico , Hemoglobinas/análisis , Humanos , Lactante , Unidades de Cuidados Intensivos , Tiempo de Internación , Recuento de Leucocitos , Ácidos Linoleicos/metabolismo , Masculino , Milrinona/uso terapéutico , Oxilipinas/metabolismo , Estudios Prospectivos , Respiración Artificial , Factores de Riesgo , Vasodilatadores/uso terapéuticoRESUMEN
BACKGROUND: Pituitary adenoma accounts as a complex and multifactorial intracranial neoplasm with wide range of clinical symptoms which its underlying molecular mechanism has yet to be determined. The bioactive lipid mediators received attentions toward their contribution in cancer cell proliferation, progression and death. Amongst, 15-Lipoxygense (15-Lox) enzymes and products display appealing role in cancer pathogenesis which their possible effect in pituitary adenoma tumor genesis is perused in the current study. METHODS: The 15-Lipoxygenses isoforms expression level was evaluated in tumor tissues of prevalent functional and non-functional pituitary adenomas and normal pituitary tissues via Real-Time PCR. The circulating levels of 15(S) HETE and 13(S) HODE as 15-Lox main products were assessed in serum of patients and healthy subjects using enzyme immunoassay kits. RESULTS: Our results revealed that 15-Lox-1 and 15-Lox-2 expression levels were elevated in tumor tissues of pituitary adenomas comparing to normal pituitary tissues. The elevated levels of both isoforms were accompanied with 15(S) HETE and 13(S) HODE elevation in the serum of patients. The 15-Lox-1 expression and activity was higher in invasive tumors as well as tumors with bigger size indicating the possible pro-tumorigenic role of 15-Lox-1, more than 15-Lox-2 in pituitary adenomas. The diagnostic value of 15-Lipoxygense isoforms and products were considerable between patients and healthy groups. CONCLUSION: The possible involvement of 15-Lipoxygense pathway especially 15-Lox-1 in the regulation of pituitary tumor growth and progression may open up new molecular mechanism regarding pituitary adenoma pathogenesis and might shed light on its new therapeutic strategies.
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Adenoma/enzimología , Araquidonato 15-Lipooxigenasa/genética , Neoplasias Hipofisarias/enzimología , Adenoma/patología , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Ácidos Hidroxieicosatetraenoicos/sangre , Ácidos Linoleicos/sangre , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/patología , Regulación hacia Arriba , Adulto JovenRESUMEN
Perilla oil is abundant in α-linolenic acid, which is metabolized to long-chain n-3 fatty acids. This study aimed to determine thermal stability and bioavailability of perilla oil that was powdered by inclusion complexation with γ-cyclodextrin. Fatty acid analysis revealed that the relative abundance of α-linolenic and linoleic acids in the complexes was not affected by heating at 40⯰C for six days but decreased after heating at 60⯰C for three days. No adverse events occurred in rats fed with an experimental diet containing the complexes for two weeks. Plasma α-linolenic and eicosapentaenoic acids in rats fed with diets containing complexes and liquid perilla oil were equally high, indicating the preserved bioavailability of perilla oil in the complexes. Plasma arachidonic acid decreased only in rats fed with a diet containing the complexes. Results suggest that the complexes have potential as a useful source of α-linolenic acid to increase plasma n-3 fatty acids.
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Ácido alfa-Linolénico/química , gamma-Ciclodextrinas/química , Animales , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Dieta , Ácidos Grasos/sangre , Cromatografía de Gases y Espectrometría de Masas , Ácidos Linoleicos/sangre , Masculino , Aceites de Plantas/química , Aceites de Plantas/metabolismo , Ratas , Ratas Wistar , Espectrometría de Masa por Ionización de Electrospray , Temperatura , Ácido alfa-Linolénico/metabolismo , gamma-Ciclodextrinas/metabolismoRESUMEN
The prospero homeobox 1 (PROX1) gene may show pleiotropic effects on metabolism. We evaluated postprandial metabolic alterations dependently on the rs340874 genotypes, and 28 non-diabetic men were divided into two groups: high-risk (HR)-genotype (CC-genotype carriers, n = 12, 35.3 ± 9.5 years old) and low-risk (LR)-genotype (allele T carriers, n = 16, 36.3 ± 7.0 years old). Subjects participated in two meal-challenge-tests with high-carbohydrate (HC, carbohydrates 89%) and normo-carbohydrate (NC, carbohydrates 45%) meal intake. Fasting and 30, 60, 120, and 180 min after meal intake plasma samples were fingerprinted by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). In HR-genotype men, the area under the curve (AUC) of acetylcarnitine levels was higher after the HC-meal [+92%, variable importance in the projection (VIP) = 2.88] and the NC-meal (+55%, VIP = 2.00) intake. After the NC-meal, the HR-risk genotype carriers presented lower AUCs of oxidized fatty acids (-81-66%, VIP = 1.43-3.16) and higher linoleic acid (+80%, VIP = 2.29), while after the HC-meal, they presented lower AUCs of ornithine (-45%, VIP = 1.83), sphingosine (-48%, VIP = 2.78), linoleamide (-45%, VIP = 1.51), and several lysophospholipids (-40-56%, VIP = 1.72-2.16). Moreover, lower AUC (-59%, VIP = 2.43) of taurocholate after the HC-meal and higher (+70%, VIP = 1.42) glycodeoxycholate levels after the NC-meal were observed. Our results revealed differences in postprandial metabolites from inflammatory and oxidative stress pathways, bile acids signaling, and lipid metabolism in PROX1 HR-genotype men. Further investigations of diet-genes interactions by which PROX1 may promote T2DM development are needed.
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Ácidos y Sales Biliares/sangre , Diabetes Mellitus Tipo 2/genética , Carbohidratos de la Dieta/metabolismo , Proteínas de Homeodominio/genética , Inflamación/sangre , Metabolismo de los Lípidos/genética , Polimorfismo de Nucleótido Simple , Proteínas Supresoras de Tumor/genética , Acetilcarnitina/sangre , Adulto , Alelos , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/etiología , Dieta , Interacción Gen-Ambiente , Genotipo , Humanos , Ácidos Linoleicos/sangre , Masculino , Comidas , Metaboloma , Ornitina/sangre , Estrés Oxidativo , Periodo Posprandial , Transducción de Señal , Esfingosina/sangreRESUMEN
We previously reported that lower systemic antioxidant capacity is involved in primary open-angle glaucoma (POAG) and exfoliation syndrome pathogeneses as measured by ferric-reducing activity. In the present study, we measured hydroxylinoleate (HODE) and hydroxyarachidonate (HETE) isomer serum levels after sample reduction and saponification to investigate POAG pathogenesis. POAG patients (n = 198) were recruited and divided into normal- and high-tension glaucoma groups (n = 84 and 114, respectively) depending on intraocular pressure. Total HODE (/linoleic acid) and HETE (/arachidonic acid) serum levels were significantly higher in the POAG group (211.9 ± 143.0 and 181.0 ± 164.1 µmol/mol, respectively) than in controls (167.1 ± 105.2 and 132.5 ± 139.7 µmol/mol, p = 0.0025 and 0.0101, respectively). The associations between HODEs/HETEs and glaucoma were further confirmed by multivariate analyses after adjusting for differences in demographic parameters. Among the HODE isomers, the levels of 9- and 13-(Z,E)-HODEs (p = 0.0014) and singlet oxygen-specific products (i.e., 10- and 12-(Z,E)-HODEs, p = 0.0345) were higher in the POAG group than in controls, while free radical-mediated oxidation-specific products (i.e., 9- and 13-(E,E)-HODEs, p = 0.0557) demonstrated a marginal difference. Enzymatic and singlet oxygen-mediated fatty acid oxidation may be major pathways of oxidation process in glaucoma subjects.
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Glaucoma de Ángulo Abierto/sangre , Ácidos Hidroxieicosatetraenoicos/sangre , Ácidos Linoleicos/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Biomarcadores/química , Estudios de Casos y Controles , Femenino , Humanos , Ácidos Hidroxieicosatetraenoicos/química , Hidroxilación , Isomerismo , Ácidos Linoleicos/química , Masculino , Persona de Mediana Edad , Oxidación-Reducción , Adulto JovenRESUMEN
BACKGROUND: Evidence suggests that inflammation increases risk for ovarian cancer. Aspirin has been shown to decrease ovarian cancer risk, though the mechanism is unknown. Studies of inflammatory markers, lipid molecules such as arachidonic acid, linoleic acid, and alpha-linoleic acid metabolites, and development of ovarian cancer are essential to understand the potential mechanisms. METHODS: We conducted a nested case-control study (157 cases/156 matched controls) within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Unconditional logistic regression was used to estimate the association between prediagnostic serum levels of 31 arachidonic acid/linoleic acid/alpha-linoleic acid metabolites and risk of ovarian cancer. RESULTS: Five of the 31 arachidonic acid/linoleic acid/alpha-linoleic acid (free fatty acids) metabolites were positively associated with ovarian cancer risk: 8-HETE [tertile 3 vs. 1: OR 2.53 (95% confidence interval [CI] 1.18-5.39), P trend 0.02], 12,13-DHOME [2.49 (1.29-4.81), 0.01], 13-HODE [2.47 (1.32-4.60), 0.005], 9-HODE [1.97 (1.06-3.68), 0.03], 9,12,13-THOME [2.25 (1.20-4.21), 0.01]. In analyses by subtype, heterogeneity was suggested for 8-HETE [serous OR (95% CI): 2.53 (1.18-5.39) vs. nonserous OR (95% CI): 1.15 (0.56-2.36), P het 0.1] and 12,13-EpOME [1.95 (0.90-4.22) vs. 0.82 (0.39-1.73), 0.05]. CONCLUSIONS: Women with increased levels of five fatty acid metabolites (8-HETE, 12,13-DHOME, 13-HODE, 9-HODE, and 9,12,13-THOME) were at increased risk of developing ovarian cancer in the ensuing decade. All five metabolites are derived from either arachidonic acid (8-HETE) or linoleic acid (12,13-DHOME, 13-HODE, 9-HODE, 9,12,13-THOME) via metabolism through the LOX/cytochrome P450 pathway. IMPACT: The identification of these risk-related fatty acid metabolites provides mechanistic insights into the etiology of ovarian cancer and indicates the direction for future research.
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Ácidos Araquidónicos/sangre , Biomarcadores de Tumor/sangre , Ácidos Linoleicos/sangre , Neoplasias Ováricas/sangre , Anciano , Ácidos Araquidónicos/metabolismo , Estudios de Casos y Controles , Detección Precoz del Cáncer , Femenino , Humanos , Ácidos Hidroxieicosatetraenoicos/sangre , Inflamación , Ácidos Linoleicos/metabolismo , Modelos Logísticos , Persona de Mediana Edad , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/metabolismoRESUMEN
Long-chain fatty acids (LCFA) play key roles in mammalian cells as sources of energy, structural components and signaling molecules. Given their importance in numerous physiological processes, the roles of LCFAs in health and disease have been extensively investigated. In the majority of studies, correlations are established using a single measurement in plasma or red blood cells (RBCs). Although a few studies have reported on reproducibility of individual fatty acid measurements, the comprehensive analysis of intra-individual LCFA variability has not been performed. Therefore, our goal was to determine intra-individual variability for the 22 most abundant LCFAs in both plasma and RBC samples collected from healthy individuals on a regular diet after overnight fasting. The measurements of LCFAs in RBCs were consistent throughout the course of study reflecting long-term nutritional status. In contrast, the results in plasma showed considerable LCFA intra-individual variability, even between fatty acids of the same type. Plasma intra-individual variability for omega-3 alpha-linolenic and eicosapentaenoic acids in some participants were >40% whereas the variability of docosahexaenoic acid was consistently <12.8%. Omega-6 linoleic and arachidonic acids also showed low variability in plasma. The results suggest that some LCFAs have less variability and would be more reliable as biomarkers. Reliability of biomarkers can have a profound impact on the research outcomes. Intra-individual variability of LCFAs should be taken into consideration in designing, conducting and interpreting results of clinical studies.
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Ácidos Araquidónicos/sangre , Ácido Eicosapentaenoico/sangre , Eritrocitos/química , Ácidos Linoleicos/sangre , Plasma/química , Ácido alfa-Linolénico/sangre , Adulto , Variación Biológica Individual , Biomarcadores/sangre , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Estado Nutricional , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
BACKGROUND AND AIMS: High-cholesterol and high-fat diets alter biochemical composition and anti-oxidant properties of high-density lipoproteins (HDL) in animals. Whether this occurs in humans is unknown. Therefore, we examined the effect of a short-term elevation in dietary cholesterol and fat intake on HDL composition in healthy subjects. METHODS AND RESULTS: In a randomized, crossover clinical trial, 14 healthy young volunteers followed a 14-day low-cholesterol/low-fat diet (LChF) and a 14-day isocaloric high-cholesterol/high-fat diet (HChF) in a random order. After each diet, we measured HDL concentrations of hydroxyeicosatetraenoic acids (HETE), hydroxyoctadecadienoic acids (HODE), and haptoglobin, as well as serum amyloid A (SAA) and paroxonase-1 activity (PON-1). HDL concentrations of 15-HETE (+254%, p = 0.002), 5-HETE (+116%, p = 0.004), 13-HODE (+102%, p = 0.049), and SAA levels (+75%, p = 0.007) were significantly higher after the HChF than after the LChF. Furthermore, haptoglobin was marginally increased (+32%, p = 0.091) while PON-1 activity was unaffected (-16%, p = 0.366) by the HChF. CONCLUSION: In healthy subjects, a short-term elevation in dietary cholesterol and fat intake increases HDL lipid hydroperoxide content (15-HETE, 5-HETE, 13-HODE) and SAA levels, which are key features of dysfunctional HDL. This is the first study showing that a physiologic manipulation of dietary cholesterol and fat intake affects HDL lipidome and proteome in healthy subjects independently of weight changes. CLINICAL TRIAL REGISTRATION: NCT02549144.
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Colesterol en la Dieta/administración & dosificación , Dieta Alta en Grasa , Peróxidos Lipídicos/sangre , Lipoproteínas HDL/sangre , Adulto , Biomarcadores/sangre , Colesterol en la Dieta/efectos adversos , Colesterol en la Dieta/sangre , Estudios Cruzados , Dieta Alta en Grasa/efectos adversos , Femenino , Voluntarios Sanos , Humanos , Ácidos Hidroxieicosatetraenoicos/sangre , Italia , Ácidos Linoleicos/sangre , Masculino , Periodo Posprandial , Estudios Prospectivos , Proteína Amiloide A Sérica/metabolismo , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: RT001 is a deuterated ethyl linoleate that inhibits lipid peroxidation and is hypothesized to reduce cellular damage and recover mitochondrial function in degenerative diseases such as Friedreich's ataxia. OBJECTIVE: To evaluate the safety, pharmacokinetics, and preliminary efficacy of RT001 in Friedreich's ataxia patients. DESIGN/METHODS: We conducted a phase I/II double-blind, comparator-controlled trial with 2 doses of RT001 in Friedreich's ataxia patients (9 subjects each cohort). Subjects were randomized 2:1 to receive either RT001 (1.8 or 9.0 g/day), or a matching dose of nondeuterated ethyl linoleate as comparator for 28 days. The primary endpoints were safety, tolerability, and pharmacokinetic analysis. Secondary endpoints included cardiopulmonary exercise testing and timed 25-foot walk. RESULTS: Nineteen patients enrolled in the trial, and 18 completed all safety and efficacy measurements. RT001 was found to be safe and tolerable, with plasma levels approaching saturation by 28 days. One subject with a low body mass index experienced steatorrhea taking a high dose and discontinued the study. Deuterated arachidonic acid (a brain-penetrant metabolite of RT001) was found to be present in plasma on day 28. There was an improvement in peak workload in the drug group compared to placebo (0.16 watts/kg; P = 0.008), as well as an improvement trend in peak oxygen consumption (change of 0.16 L/min; P = 0.116), and in stride speed (P = 0.15). CONCLUSIONS: RT001 was found to be safe and tolerable over 28 days, and improved peak workload. Further research into the effect of RT001 in Friedreich's ataxia is warranted. © 2018 International Parkinson and Movement Disorder Society.
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Ataxia de Friedreich/tratamiento farmacológico , Ácido Linoleico/uso terapéutico , Ácidos Linoleicos/uso terapéutico , Adolescente , Adulto , Ácido Araquidónico/metabolismo , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Ataxia de Friedreich/sangre , Humanos , Ácido Linoleico/sangre , Ácidos Linoleicos/sangre , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Increased plasma free fatty acids (FFAs) are associated with cardiometabolic risk factors in adults with abdominal obesity (AO). However, this association remains controversial in children. This study analyzed plasma FFA concentration in children with and without AO. Twenty-nine children classified with AO were matched by age and sex with 29 non-obese individuals. Blood samples were collected after fasting for 10-12 h. Plasma concentration of glucose, insulin, triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were determined by automatized methods. FFAs were analyzed by gas chromatography. Children with and without AO had similar age (7.1 ± 2.6 vs. 7.2 ± 2.7 years; p > 0.05) but obese children showed higher (p < 0.05) body mass index (BMI) (+4.3 kg/m²), systolic blood pressure (+5.1 mmHg), and insulin (+27.8 pmol/L). There were no significant differences in plasma total FFA concentration between groups (1.02 ± 0.61 vs. 0.89 ± 0.37 mmol/L; p > 0.05). However, children with AO had higher palmitoleic acid (0.94 vs. 0.70 wt %; p < 0.05) and dihomo-gamma linoleic acid (DHGL) (2.76 vs. 2.07 wt %; p < 0.05). Palmitoleic and DHGL acids correlated (p < 0.05) with BMI (r = 0.397; r = 0.296, respectively) and with waist circumference (r = 0.380; r = 0.276, respectively). Palmitoleic acid correlated positively with systolic blood pressure (r = 0.386; p < 0.05) and negatively with HDL-C (-0.572; p < 0.01). In summary, children with AO have higher plasmatic concentrations of free palmitoleic and DHGL fatty acids, which correlate with cardiometabolic risk factors.
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Ácidos Grasos Monoinsaturados/sangre , Ácidos Linoleicos/sangre , Obesidad Abdominal/sangre , Obesidad Infantil/sangre , Factores de Edad , Biomarcadores/sangre , Presión Sanguínea , Índice de Masa Corporal , Enfermedades Cardiovasculares/etiología , Estudios de Casos y Controles , Niño , Preescolar , Estudios Transversales , Ácido Graso Desaturasas/sangre , Femenino , Humanos , Masculino , Síndrome Metabólico/etiología , Obesidad Abdominal/complicaciones , Obesidad Abdominal/diagnóstico , Obesidad Abdominal/fisiopatología , Obesidad Infantil/complicaciones , Obesidad Infantil/diagnóstico , Obesidad Infantil/fisiopatología , Factores de Riesgo , América del Sur , Regulación hacia Arriba , Circunferencia de la CinturaRESUMEN
INTRODUCTION: Chronic hepatitis B virus (HBV) infection is the main etiologic risk factor for hepatocellular carcinoma (HCC). Early studies indicated that the increase of omega-6-derived oxylipins may be involved in the pathogenesis of HBV-related HCC, yet their changes during the distinct clinical phases of chronic HBV infection remain unclear. To fill this gap, in this study we investigated the omega-6-derived oxylipin profiles in patients with three major clinical stages of chronic HBV infection (chronic hepatitis B, liver cirrhosis, and HCC). METHODS: Eighteen omega-6-derived oxylipins were quantified in serum samples of 34 patients with chronic hepatitis B, 46 patients with HBV-related liver cirrhosis, 38 patients with HBV-related HCC, and 50 healthy controls using liquid chromatography tandem mass spectrometry. RESULTS: Seven oxylipins were found to be altered in patients with HBV-related liver diseases, including 9,10-dihydroxyoctadecenoic acid (9,10-DiHOME), 12,13-DiHOME, 14,15-dihydroxyeicosatrienoic acid (14,15-DiHETrE), 13-hydroxyoctadecadienoic acid (13-HODE), 12-hydroxyeicosatetraenoic acid (12-HETE), 11-HETE, and thromboxane B2 (TXB2). Of these, three oxylipins derived from the cytochrome P450 (CYP450) pathways including 9,10-DiHOME, 12,13-DiHOME, and 14,15-DiHETrE were found to be associated with the levels of α-fetoprotein (AFP), a tumor marker. In combination with AFP, age, and gender, a combination of these seven differential oxylipins could significantly enhance the prediction of HBV-related liver diseases, particularly for liver cirrhosis (p < 0.05). CONCLUSION: This study for the first time shows the correlations between CYP450-derived oxylipins and the progression of chronic HBV infection, and sheds a new light on the surveillance of HBV-related live diseases using oxylipins.
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Biomarcadores de Tumor/sangre , Carcinoma Hepatocelular/sangre , Hepatitis B Crónica/complicaciones , Cirrosis Hepática/sangre , Neoplasias Hepáticas/sangre , Oxilipinas/sangre , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/sangre , Adulto , Anciano , Carcinoma Hepatocelular/virología , Femenino , Humanos , Ácidos Linoleicos/sangre , Cirrosis Hepática/virología , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Ácidos Oléicos/sangre , Tromboxano B2/sangreRESUMEN
This double-blind, randomized, placebo-controlled crossover trial determined if ingestion of a supplement containing a tomato complex with lycopene, phytoene, and phytofluene (T-LPP) and other compounds for 4 weeks would attenuate inflammation, muscle damage, and oxidative stress postexercise and during recovery from a 2-hr running bout that included 30 min of -10% downhill running. Study participants ingested the T-LPP supplement or placebo with the evening meal for 4 weeks prior to running 2 hr at high intensity. Blood samples and delayed onset muscle soreness ratings were taken pre- and post-4-week supplementation, and immediately following the 2-hr run, and then 1-hr, 24-hr, and 48-hr postrun. After a 2-week washout period, participants crossed over to the opposite treatment and repeated all procedures. Plasma lycopene, phytoene, and phytofluene increased significantly in T-LPP compared with placebo (p < .001 for each). Significant time effects were shown for serum creatine kinase, delayed onset muscle soreness, C-reactive protein, myoglobin, 9- and 13-hydroxyoctadecadienoic acids, ferric reducing ability of plasma, and six plasma cytokines (p < .001 for each). The pattern of increase for serum myoglobin differed between T-LPP and placebo (interaction effect, p = .016, with lower levels in T-LPP), but not for creatine kinase, delayed onset muscle soreness, C-reactive protein, the six cytokines, 9- and 13-hydroxyoctadecadienoic acids, and ferric reducing ability of plasma. No significant time or interaction effects were measured for plasma-oxidized low-density lipoprotein or serum 8-hydroxy-2'-deoxyguanosine. In summary, supplementation with T-LPP over a 4-week period increased plasma carotenoid levels 73% and attenuated postexercise increases in the muscle damage biomarker myoglobin, but not inflammation and oxidative stress.