RESUMEN
Circulating levels of the soluble ligand-binding ectodomain of the LDL receptor (sLDLR) that is proteolytically cleaved from the cell surface have been shown to correlate with plasma triglycerides, but the lipid and lipoprotein effects of longitudinal changes in sLDLR have not been examined. We sought to assess associations between changes in sLDLR and detailed lipoprotein measurements between baseline and 6 months in participants in the DIETFITS (Diet Intervention Examining The Factors Interacting with Treatment Success) weight loss trial who were randomly assigned to the low-fat (n = 225) or low-carbohydrate (n = 236) diet arms. sLDLR was assayed using a proteomic procedure, lipids and apoprotein (apo) B and apoAI were measured by standard assays, and lipoprotein particle subfractions were quantified by ion mobility methodology. Changes in sLDLR were significantly positively associated with changes in plasma cholesterol, triglycerides, apoB, large-sized and medium-sized VLDL, and small and very small LDL, and inversely with changes in large LDL and HDL. The lipoprotein subfraction associations with sLDLR were independent of age, sex, diet, and BMI, but all except for large LDL were reduced to insignificance when adjusted for triglyceride change. Principal component analysis identified three independent clusters of changes in lipoprotein subfractions that accounted for 78% of their total variance. Change in sLDLR was most strongly correlated with change in the principal component that was loaded positively with large VLDL and small and very small LDL and negatively with large LDL and HDL. In conclusion, sLDLR is a component of a cluster of lipids and lipoproteins that are characteristic of atherogenic dyslipidemia.
Asunto(s)
Lipoproteínas , Proteómica , Humanos , Triglicéridos , Receptores de LDL , Dieta , Pérdida de Peso , Lipoproteínas LDL , Lipoproteínas VLDLRESUMEN
Common noncoding variants at the human 1p13.3 locus associated with SORT1 expression are among those most strongly associated with low-density lipoprotein cholesterol (LDL-C) in human genome-wide association studies. However, validation studies in mice and cell lines have produced variable results regarding the directionality of the effect of SORT1 on LDL-C. This, together with the fact that the 1p13.3 variants are associated with expression of several genes, has raised the question of whether SORT1 is the causal gene at this locus. Using whole exome sequencing in members of an Amish population, we identified coding variants in SORT1 that are associated with increased (rs141749679, K302E) and decreased (rs149456022, Q225H) LDL-C. Further, analysis of plasma lipoprotein particle subclasses by ion mobility in a subset of rs141749679 (K302E) carriers revealed higher levels of large LDL particles compared to noncarriers. In contrast to the effect of these variants in the Amish, the sortilin K302E mutation introduced into a C57BL/6J mouse via CRISPR/Cas9 resulted in decreased non-high-density lipoprotein cholesterol, and the sortilin Q225H mutation did not alter cholesterol levels in mice. This is indicative of different effects of these mutations on cholesterol metabolism in the two species. To our knowledge, this is the first evidence that naturally occurring coding variants in SORT1 are associated with LDL-C, thus supporting SORT1 as the gene responsible for the association of the 1p13.3 locus with LDL-C.
Asunto(s)
Amish , Estudio de Asociación del Genoma Completo , Humanos , Ratones , Animales , LDL-Colesterol/genética , Ratones Endogámicos C57BL , Colesterol , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismoRESUMEN
We propose the hypothesis that small high-density lipoprotein (HDL) particles reduce the risk of Alzheimer's disease (AD) by virtue of their capacity to exchange lipids, affecting neuronal membrane composition and vascular and synaptic functions. Concentrations of small HDLs in cerebrospinal fluid (CSF) and plasma were measured in 180 individuals ≥60 years of age using ion mobility methodology. Small HDL concentrations in CSF were positively associated with performance in three domains of cognitive function independent of apolipoprotein E (APOE) ε4 status, age, sex, and years of education. Moreover, there was a significant correlation between levels of small HDLs in CSF and plasma. Further studies will be aimed at determining whether specific components of small HDL exchange across the blood, brain, and CSF barriers, and developing approaches to exploit small HDLs for therapeutic purposes.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/líquido cefalorraquídeo , Apolipoproteínas E , Apolipoproteína E4 , Encéfalo , Cognición , Péptidos beta-Amiloides/líquido cefalorraquídeoRESUMEN
The fish embryo acute toxicity (FET) test is known to be less sensitive than the fish acute test for some chemicals, including neurotoxicants. Thus, there is an interest in identifying additional endpoints that can improve FET test performance. The goal of this project was to advance alternative toxicity testing methods by determining whether select developmental abnormalities-snout-vent length, eye size, and pericardial area-are linked to adverse alterations in ecologically-relevant behaviors and delayed mortality. Fathead minnow (Pimephales promelas) FET tests were conducted with 3,4-dicholoroaniline, cadmium, and perfluorooctanesulfonic acid (PFOS) and developmental abnormalities were quantified. Surviving eleutheroembryos were reared in clean water to 14 days post fertilization (dpf), during which time behaviors and mortality were evaluated. None of the abnormalities evaluated were predictive of behavioral alterations; however, embryos with ≥14% reductions in length or ≥3.54-fold increases in pericardial area had an 80% chance of mortality by 14 dpf. When these abnormalities were used as markers of mortality, the LC50s for cadmium and PFOS were less than those calculated using only standardized FET test endpoints and similar to those obtained via larval fish tests, indicating that the snout-vent length and pericardial area warrant consideration as standard FET test endpoints.
Asunto(s)
Cyprinidae , Contaminantes Químicos del Agua , Animales , Edema , Embrión no Mamífero , Larva , Pruebas de Toxicidad Aguda , Contaminantes Químicos del Agua/toxicidadRESUMEN
BACKGROUND: Statins lower circulating low-density lipoprotein cholesterol (LDLC) levels and reduce cardiovascular disease risk. Though highly efficacious in general, there is considerable inter-individual variation in statin efficacy that remains largely unexplained. METHODS: To identify novel genes that may modulate statin-induced LDLC lowering, we used RNA-sequencing data from 426 control- and 2 µM simvastatin-treated lymphoblastoid cell lines (LCLs) derived from European and African American ancestry participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial (ClinicalTrials.gov Identifier: NCT00451828). We correlated statin-induced changes in LCL gene expression with plasma LDLC statin response in the corresponding CAP participants. For the most correlated gene identified (ZNF335), we followed up in vivo by comparing plasma cholesterol levels, lipoprotein profiles, and lipid statin response between wild-type mice and carriers of a hypomorphic (partial loss of function) missense mutation in Zfp335 (the mouse homolog of ZNF335). RESULTS: The statin-induced expression changes of 147 human LCL genes were significantly correlated to the plasma LDLC statin responses of the corresponding CAP participants in vivo (FDR = 5%). The two genes with the strongest correlations were zinc finger protein 335 (ZNF335 aka NIF-1, rho = 0.237, FDR-adj p = 0.0085) and CCR4-NOT transcription complex subunit 3 (CNOT3, rho = 0.233, FDR-adj p = 0.0085). Chow-fed mice carrying a hypomorphic missense (R1092W; aka bloto) mutation in Zfp335 had significantly lower non-HDL cholesterol levels than wild-type C57BL/6J mice in a sex combined model (p = 0.04). Furthermore, male (but not female) mice carrying the Zfp335R1092W allele had significantly lower total and HDL cholesterol levels than wild-type mice. In a separate experiment, wild-type mice fed a control diet for 4 weeks and a matched simvastatin diet for an additional 4 weeks had significant statin-induced reductions in non-HDLC (-43 ± 18% and -23 ± 19% for males and females, respectively). Wild-type male (but not female) mice experienced significant reductions in plasma LDL particle concentrations, while male mice carrying Zfp335R1092W allele(s) exhibited a significantly blunted LDL statin response. CONCLUSIONS: Our in vitro and in vivo studies identified ZNF335 as a novel modulator of plasma cholesterol levels and statin response, suggesting that variation in ZNF335 activity could contribute to inter-individual differences in statin clinical efficacy.
Asunto(s)
LDL-Colesterol , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Simvastatina , Animales , Humanos , Ratones , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Simvastatina/farmacología , LDL-Colesterol/sangre , Línea Celular , Masculino , Femenino , Perfilación de la Expresión Génica , Transcriptoma , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Unión al ADN/genética , Colesterol/sangre , Mutación MissenseRESUMEN
Intravascular catabolism of chylomicrons and very low-density lipoproteins (VLDLs) gives rise to a spectrum of partially lipolyzed remnant particles. Their plasma levels and properties are influenced by lipases, lipid transfer proteins, and content of exchangeable lipoproteins. Particularly important among the latter are apoE, which mediates hepatic binding and uptake of remnants, and apoCIII, which can retard this process. In the course of their plasma transit, remnants can acquire pathologic properties that promote the development of atherosclerotic cardiovascular disease (ASCVD) including increased cholesterol content and transport of thrombogenic and inflammatory mediators. Levels of cholesterol-enriched remnant particles determined by various analytic techniques have been significantly linked to the incidence of ASCVD, most dramatically in dyslipidemic patients homozygous for the apoE2 genetic isoform. Further research is warranted for development of clinical assays that can better capture the pathologic impact of remnant lipoprotein subspecies, and for testing the impact on ASCVD of therapies that reduce their levels.
Asunto(s)
Aterosclerosis , Enfermedades Cardiovasculares , Humanos , Triglicéridos/metabolismo , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Colesterol/metabolismo , Quilomicrones/metabolismo , Aterosclerosis/genética , Aterosclerosis/metabolismoRESUMEN
Background: Statins lower circulating low-density lipoprotein cholesterol (LDLC) levels and reduce cardiovascular disease risk. Though highly efficacious in general, there is considerable inter-individual variation in statin efficacy that remains largely unexplained. Methods: To identify novel genes that may modulate statin-induced LDLC lowering, we used RNA-sequencing data from 426 control- and 2 µM simvastatin-treated lymphoblastoid cell lines (LCLs) derived from European and African American ancestry participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial (ClinicalTrials.gov Identifier: NCT00451828). We correlated statin-induced changes in LCL gene expression with plasma LDLC statin response in the corresponding CAP participants. For the most correlated gene identified (ZNF335), we followed up in vivo by comparing plasma cholesterol levels, lipoprotein profiles, and lipid statin response between wild-type mice and carriers of a hypomorphic (partial loss of function) missense mutation in Zfp335 (the mouse homolog of ZNF335). Results: The statin-induced expression changes of 147 human LCL genes were significantly correlated to the plasma LDLC statin responses of the corresponding CAP participants in vivo (FDR=5%). The two genes with the strongest correlations were zinc finger protein 335 (ZNF335 aka NIF-1, rho=0.237, FDR-adj p=0.0085) and CCR4-NOT transcription complex subunit 3 (CNOT3, rho=0.233, FDR-adj p=0.0085). Chow-fed mice carrying a hypomorphic missense (R1092W; aka bloto) mutation in Zfp335 had significantly lower non-HDL cholesterol levels than wild type C57BL/6J mice in a sex combined model (p=0.04). Furthermore, male (but not female) mice carrying the Zfp335R1092W allele had significantly lower total and HDL cholesterol levels than wild-type mice. In a separate experiment, wild-type mice fed a control diet for 4 weeks and a matched simvastatin diet for an additional 4 weeks had significant statin-induced reductions in non-HDLC (-43±18% and -23±19% for males and females, respectively). Wild-type male (but not female) mice experienced significant reductions in plasma LDL particle concentrations, while male mice carrying Zfp335R1092W allele(s) exhibited a significantly blunted LDL statin response. Conclusions: Our in vitro and in vivo studies identified ZNF335 as a novel modulator of plasma cholesterol levels and statin response, suggesting that variation in ZNF335 activity could contribute to inter-individual differences in statin clinical efficacy.
RESUMEN
BACKGROUND: Foods rich in saturated fatty acids (SFAs) have been discouraged by virtue of their cholesterol-raising potential, but this effect is modulated by the food source and background level of carbohydrate. OBJECTIVE: We aimed to compare the consumption of palm stearin (PS) versus butter on circulating cholesterol responses in the setting of both a low-carbohydrate/high-fat (LC/HF) and high-carbohydrate/low-fat (HC/LF) diet in healthy subjects. We also explored effects on plasma lipoprotein particle distribution and fatty acid composition. METHODS: We performed a randomized, controlled-feeding, cross-over study that compared a PS- versus a Butter-based diet in a group of normocholesterolemic, non-obese adults. A controlled canola oil-based 'Run-In' diet preceded the experimental PS and Butter diets. All diets were eucaloric, provided for 3-weeks, and had the same macronutrient distribution but varied in primary fat source (40% of the total fat). The same Run-In and cross-over experiments were done in two separate groups who self-selected to either a LC/HF (n = 12) or a HC/LF (n = 12) diet track. The primary outcomes were low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein (HDL)-C, triglycerides, and LDL particle distribution. RESULTS: Compared to PS, Butter resulted in higher LDL-C in both the LC/HF (13.4%, p = 0.003) and HC/LF (10.8%, p = 0.002) groups, which was primarily attributed to large LDL I and LDL IIa particles. There were no differences between PS and Butter in HDL-C, triglycerides, or small LDL particles. Oxidized LDL was lower after PS than Butter in LC/HF (p = 0.011), but not the HC/LF group. CONCLUSIONS: These results demonstrate that Butter raises LDL-C relative to PS in healthy normocholesterolemic adults regardless of background variations in carbohydrate and fat, an effect primarily attributed to larger cholesterol-rich LDL particles.
Asunto(s)
Mantequilla , Colesterol/sangre , Dieta/métodos , Carbohidratos de la Dieta/administración & dosificación , Grasas de la Dieta/administración & dosificación , Aceite de Palma/administración & dosificación , Adulto , Anciano , Estudios Cruzados , Dieta/efectos adversos , Dieta de Carga de Carbohidratos/efectos adversos , Dieta de Carga de Carbohidratos/métodos , Dieta Baja en Carbohidratos/efectos adversos , Dieta Baja en Carbohidratos/métodos , Dieta con Restricción de Grasas/efectos adversos , Dieta con Restricción de Grasas/métodos , Dieta Alta en Grasa/efectos adversos , Dieta Alta en Grasa/métodos , Femenino , Voluntarios Sanos , Humanos , Lípidos/sangre , Masculino , Persona de Mediana Edad , Aceite de Palma/química , Adulto JovenRESUMEN
BACKGROUND: Platelet aggregation plays a critical role in myocardial infarction and stroke; however, the role of platelet secretion in atherosclerotic vascular disease is poorly understood. Therefore, we examined the hypothesis that platelet dense-granule secretion modulates thrombosis, inflammation, and atherosclerotic vascular remodeling after injury. METHODS AND RESULTS: Functional deletion of the Hermansky-Pudlak syndrome 3 gene (HPS3(-/-)) markedly reduces platelet dense-granule secretion. HPS3(-/-) mice have normal platelet counts, platelet morphology, and alpha-granule number, as well as maximal secretion of the alpha-granule marker P-selectin; however, their capacity to form platelet-leukocyte aggregates is significantly reduced (P<0.05). To examine the role of platelet dense-granule secretion in these processes, atherosclerosis-prone mice with combined genetic deficiency of apolipoprotein E and HPS3 (ApoE(-/-), HPS3(-/-)) were compared with congenic, atherosclerosis-prone mice with normal platelet secretion (ApoE(-/-), HPS3(+/+)). After 16 to 18 weeks on a high-fat diet, both groups of mice had similar fasting cholesterol levels and body weight. Carotid arteries of ApoE(-/-), HPS3(+/+) mice thrombosed rapidly after FeCl(3) injury, but ApoE(-/-), HPS3(-/-) mice were completely resistant to thrombotic arterial occlusion (P<0.01). Three weeks after injury, neointimal hyperplasia (from alpha-smooth muscle actin-positive cells) was significantly less (P<0.001) in arteries from ApoE(-/-), HPS3(-/-) mice. In ApoE(-/-), HPS3(-/-) mice, there were also pronounced reductions in arterial inflammation, as indicated by a 74% decrease in CD45-positive leukocytes (P<0.01) and a 73% decrease in Mac-3-positive macrophages (P<0.05). CONCLUSIONS: In atherosclerotic mice, reduced platelet dense-granule secretion is associated with marked protection against the development of arterial thrombosis, inflammation, and neointimal hyperplasia after vascular injury.
Asunto(s)
Plaquetas/metabolismo , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/patología , Agregación Plaquetaria/fisiología , Trombosis/sangre , Adenosina Trifosfato/metabolismo , Animales , Apolipoproteínas E/genética , Grasas de la Dieta/farmacología , Modelos Animales de Enfermedad , Hiperplasia , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Serotonina/metabolismo , Túnica Íntima/inmunología , Túnica Íntima/patología , Vasculitis/sangre , Vasculitis/patologíaRESUMEN
Cerebral beta-amyloidosis (CA) is a condition in which amyloid-ß (Aß) proteins are deposited in the cerebral cortex and is a predictor of Alzheimer's disease (AD). The Aging Brain Study (ABS) investigated risk factors for CA in persons with diabetes and dyslipidemia. In the ABS, we identified that greater levels of LDL cholesterol and lower levels of HDL cholesterol were associated with increased CA. LDL particles comprise multiple species of varying size, density, and protein composition. For example, within a lipoprotein profile characteristic for persons with obesity and diabetic dyslipidemia, larger LDL particles have a greater ApoE to ApoB ratio, enhancing their binding affinity to LDL receptors. The goal of this study was to identify LDL particles that associate with CA in ABS. LDL particle size fractions were measured by ion mobility in plasma samples of 58 participants (40 women and 18 men). CA was assessed using Pittsburgh Compound B index-Positron Emission Tomography (PiB-PET) imaging. Among the LDL subfractions, greater plasma levels of large LDL particles were significantly associated with greater cerebral amyloidosis and lower hippocampal volumes independent of LDL cholesterol or triglyceride levels. Since Aß is cleared by the LDL receptor family, such as lipoprotein-like receptor 1 (LRP1), one potential mechanism for our findings is competition between ApoE enriched larger LDL particles and brain-derived Aß on hepatic Aß clearance and degradation. We conclude that assessing larger LDL particles in persons with atherogenic dyslipidemia may provide a mechanistic biomarker for the extent of CA.
Asunto(s)
Amiloidosis/etiología , Encefalopatías/etiología , Lipoproteínas LDL/sangre , Anciano , Anciano de 80 o más Años , Amiloidosis/sangre , Amiloidosis/diagnóstico por imagen , Amiloidosis/patología , Apolipoproteínas E/metabolismo , Biomarcadores/sangre , Encefalopatías/sangre , Encefalopatías/diagnóstico por imagen , Encefalopatías/patología , LDL-Colesterol/sangre , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Neuroimagen , Pruebas Neuropsicológicas , Tamaño de la Partícula , Tomografía de Emisión de Positrones , Triglicéridos/sangreRESUMEN
The multi-domain transmembrane serine protease corin cleaves pro-atrial natriuretic peptide (pro-ANP) in vitro to generate an active hormone, ANP. Corin may also contribute to the regulation of the natriuretic peptide system in vivo, and might be an attractive target for treatment of cardiovascular diseases. In order for corin to cleave its substrate pro-ANP, it should be catalytically active and located proximally. However, because knowledge of native corin is limited, we examined the expression, cardiac localization and molecular forms of the native corin protein. Immunofluorescence studies using a series of anti-corin antibodies directed against the stem and protease domains reveal that corin is present on the cell-surface of rat neonatal cardiomyocytes and murine HL-1 cardiomyocyte-like cells. Furthermore, we immunolocalized native corin in pro-ANP expressing cardiomyocytes. Immunoprecipitation of the membrane fraction of mouse heart extract showed that native corin had a relative mass of 205-210 kDa. Under reducing conditions native corin migrates as several different molecular weight forms corresponding to zymogen (uncleaved) and active (cleaved) forms. Studies using a FITC-tagged chloromethyl ketone that mimics the corin cleavage sequence in pro-ANP, suggest that an enzymatically active form of corin is localized to the cell surface of myocardial cells in vivo. Additionally, we showed that the 205-210 kDa form of corin is a glycosylated protein. Treatment of HL-1 cells with tunicamycin reduced the relative mass of expressed corin. We conclude that native corin is a glycosylated protease that is localized on the cell surface of pro-ANP-expressing cardiomyocytes in both zymogen and catalytically active forms.
Asunto(s)
Factor Natriurético Atrial/metabolismo , Precursores Enzimáticos/metabolismo , Miocitos Cardíacos/citología , Miocitos Cardíacos/enzimología , Precursores de Proteínas/metabolismo , Serina Endopeptidasas/metabolismo , Animales , Anticuerpos Monoclonales/biosíntesis , Western Blotting , Catálisis , Línea Celular , Activación Enzimática , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Peso Molecular , Miocitos Cardíacos/metabolismo , Transporte de Proteínas , Ratas , Ratas Sprague-Dawley , Serina Endopeptidasas/químicaRESUMEN
N-glycosylation may influence the subcellular localization and biological activity of the pro-ANP convertase, corin. In HEK293-corin cells, the inhibition of N-glycosylation, with tunicamycin, reduced the cell-surface expression of murine corin, but did not alter the total expression. Therefore, tunicamycin treatment likely caused the intracellular accumulation of non-glycosylated corin. Tunicamycin treatment also significantly reduced corin activity (pro-ANP cleavage) in these cells. We developed an assay to measure the effect of N-glycosylation on corin activity, independent of its effect on corin localization. We determined that the reduction in corin activity was due to a direct effect of N-glycosylation, and was not secondary to the effect of N-glycosylation on corin cell-surface expression. Our data provide evidence that N-glycosylation is essential for the cell-surface expression of murine corin and modulates its functional activity. N-Glycosylation represents a possible mechanism for the regulation of native corin on the surface of cardiomyocytes.
Asunto(s)
Factor Natriurético Atrial/metabolismo , Membrana Celular/enzimología , Serina Endopeptidasas/metabolismo , Animales , Catálisis , Línea Celular , Glicosilación/efectos de los fármacos , Humanos , Ratones , Miocitos Cardíacos/enzimología , Proteínas Recombinantes/metabolismo , Tunicamicina/farmacologíaRESUMEN
Dietary flavonoids have been shown to be protective against various types of cancers. Here we studied the effects of 12 different flavonoids and other substances on cell proliferation and VEGF expression in human ovarian cancer cells, OVCAR-3. Cell growth was determined to pinpoint the best time for drug treatment. By LDH assay, no cytotoxicity was observed for OVCAR-3 cells with all 12 chemicals except mevinolin. Six flavonoids, including apigenin, taxifolin, luteolin, quercetin, genistein, and kaempferol, were shown to inhibit the ovarian cancer cell growth in a dose-dependent manner. From both RT-qPCR and ELISA results, all flavonoids have shown varied degrees of inhibition in VEGF expression. Taxifolin and naringin showed the least inhibition effect. They both lack a double bond in the second ring structure that may be important in inhibiting VEGF expression. The rank order of VEGF protein secretion inhibitory potency was genistein > kaempferol > apigenin > quercetin > tocopherol > luteolin > cisplatin > rutin > naringin > taxifolin. Genistein, quercetin, and luteolin have shown strong inhibition to cell proliferation and VEGF expression of human ovarian cancer cells, and they show promising in the prevention of ovarian cancers.
Asunto(s)
Flavonoides/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , L-Lactato Deshidrogenasa/metabolismo , Neoplasias Ováricas/irrigación sanguínea , Neoplasias Ováricas/patología , ARN Mensajero/análisis , Factor A de Crecimiento Endotelial Vascular/análisisRESUMEN
The aim of this study was to determine whether women with low iron stores (plasma ferritin Asunto(s)
Suplementos Dietéticos
, Hierro/sangre
, Hierro/metabolismo
, Peroxidación de Lípido
, Adolescente
, Adulto
, Índice de Masa Corporal
, Pruebas Respiratorias
, Interpretación Estadística de Datos
, Etano/química
, Femenino
, Humanos
, Hierro/análisis
, Malondialdehído/sangre
, Estrés Oxidativo
, Proyectos de Investigación
, Factores de Tiempo
RESUMEN
BACKGROUND: The presence of small dense low-density lipoprotein (LDL) is associated with obesity, type II diabetes, and an increased risk for cardiovascular disease. Apolipoprotein C-III (apoC-III) is involved in the formation of small dense LDL, but the exact mechanisms are still not well defined. ApoC-III is a glycosylated apolipoprotein, with 3 major glycoforms: apoC-III0, apoC-III1, and apoC-III2 that contain 0, 1, or 2 molecules of sialic acid, respectively. In our previous work, we reported an association among apoC-III0 and apoC-III1, but not apoC-III2 with fasting plasma triglyceride levels in obesity and type II diabetes. OBJECTIVE: The goal of this study was to determine the relationship between changes in the major apoC-III glycoforms and small dense LDL levels after dietary interventions. METHODS: Mass spectrometric immunoassay was performed on fasting plasma samples from 61 subjects who underwent either a high-carbohydrate diet (n = 34) or a weight loss intervention (n = 27). RESULTS: After both dietary interventions, changes in total apoC-III concentrations were associated with changes in LDL peak particle diameter (r = -0.58, P < .0001). Increases in total apoC-III concentrations after the high-carbohydrate diet were associated with decreases in LDL size (r = -0.53, P = .001), and decreases in apoC-III concentrations after weight loss were associated with increases in LDL peak particle diameter (r = -0.54, P = .004). Changes in concentrations of apoC-III1 and apoC-III0, but not apoC-III2, were associated with changes in LDL peak particle diameter in both the weight loss and high-carbohydrate interventions. CONCLUSIONS: We conclude that apoC-III0 and apoC-III1, but not apoC-III2 are associated with the formation of small dense LDL.
Asunto(s)
Apolipoproteína C-III/sangre , Dieta , Carbohidratos de la Dieta/farmacología , Lipoproteínas LDL/sangre , Lipoproteínas LDL/química , Tamaño de la Partícula , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Pérdida de Peso/efectos de los fármacosRESUMEN
Extrinsic and intrinsic iron and zinc labels were used to test iron and zinc absorption from two bean (Phaseolus vulgaris) genotypes, containing normal (common beans, CB) or higher (HFeZnB) iron and zinc concentrations, fed in single meals to young women with low iron reserves. The women were divided into two groups, with one receiving a CB test meal (n = 12) and the other, an HFeZnB test meal (n = 11). The beans were intrinsically labeled hydroponically with (55)Fe (CB and HFeZnB) and with (70)Zn (HFeZnB). Concentrations of zinc and iron were 98 and 65% higher, respectively, in HFeZnB as compared to CB, but phytic acid contents were similar. Extrinsic labels were (59)Fe (CB and HFeZnB), (67)Zn (CB), and (68)Zn (HFeZnB). Iron and zinc percent absorption levels were calculated from radio-iron activity in red blood cells and from urinary excretion of zinc isotopes. Intrinsic and extrinsic iron absorption measures were highly correlated (R (2) = 0.986) (average extrinsic/intrinsic ratio was 1.00). Iron absorption was low (geometric mean < 2%) in both bean types, and total iron absorbed was not different between types. Intrinsic zinc absorption from the HFeZn beans was higher than extrinsic absorption (15.2% vs 13.4%, p < 0.05) (average extrinsic/intrinsic was 0.90). The correlation between intrinsic and extrinsic zinc measures was not as high as that for iron (R (2) = 0.719). Percent zinc absorption levels were similar in both bean types, but total extrinsic zinc absorbed was 90% higher (p < 0.05) from the HFeZnB meal. Thus, the less expensive and time-consuming extrinsic labeling may be used to screen various varieties of beans for iron bioavailability in humans, but it underestimates zinc absorption by approximately 10%. Selective breeding for high-zinc bean genotypes may improve zinc status. However, high-iron genotypes appear to have little effect on iron status when fed alone in single meals to women with low iron reserves.
Asunto(s)
Genotipo , Hierro/farmacocinética , Phaseolus/genética , Zinc/farmacocinética , Adulto , Disponibilidad Biológica , Femenino , Humanos , Isótopos de Hierro/farmacocinética , Radioisótopos de Hierro/farmacocinética , Isótopos de Zinc/farmacocinéticaRESUMEN
The photochemical behavior of Deepwater Horizon oil collected from the surface of the Gulf of Mexico was studied. Thin oil films on water were subjected to simulated sunlight, and the resulting chemical and optical changes were observed. Polycyclic aromatic hydrocarbons (PAHs) showed substantial photodegradation, with larger PAHs being more rapidly decomposed. About 60% of the fluorescence at the excitation and emission maxima was observed with 12h of simulated solar irradiation equivalent to approximately 3d of sunlight. Synchronous scan fluorescence measurements showed 80-90% loss of larger PAHs with 12h of simulated solar irradiation. Absorbance of the oil decreased by only 20% over the same time period. Alkanes showed no significant photochemical losses. After irradiation, the toxicity of water in contact with the oil significantly increased, presumably due to the release of water soluble photoproducts that were toxic. Photocatalyst addition resulted in enhanced degradation rate for PAHs, and toxicity of the aqueous layer was altered in the presence of photocatalysts added to the oil film. Photochemistry is an important pathway for degradation of large PAHs, which are typically resistant to biodegradation.
Asunto(s)
Contaminación por Petróleo , Petróleo/análisis , Procesos Fotoquímicos , Contaminantes Químicos del Agua/química , Alcanos/química , Biodegradación Ambiental , Golfo de México , Modelos Químicos , Fotoquímica , Fotólisis , Hidrocarburos Policíclicos Aromáticos/análisis , Hidrocarburos Policíclicos Aromáticos/química , Contaminantes Químicos del Agua/análisisRESUMEN
Humans are prevalently exposed to organophosphorus flame retardants (OPFRs) contained in consumer products and electronics, though their toxicological effects and mechanisms remain poorly understood. We show here that OPFRs inhibit specific liver carboxylesterases (Ces) and cause altered hepatic lipid metabolism. Ablation of the OPFR target Ces1g has been previously linked to dyslipidemia in mice. Consistent with OPFR inhibition of Ces1g, we also observe OPFR-induced serum hypertriglyceridemia in mice. Our findings suggest novel toxicities that may arise from OPFR exposure and highlight the utility of chemoproteomic and metabolomic platforms in the toxicological characterization of environmental chemicals.
Asunto(s)
Hidrolasas de Éster Carboxílico/antagonistas & inhibidores , Retardadores de Llama/toxicidad , Hipertrigliceridemia/sangre , Hipertrigliceridemia/inducido químicamente , Hígado/enzimología , Compuestos Organofosforados/toxicidad , Animales , Hidrolasas de Éster Carboxílico/metabolismo , Células HEK293 , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , RatonesRESUMEN
Platelet granule exocytosis plays a critical role in thrombosis and wound healing. Platelets have three major types of secretory granules that are defined by their unique molecular contents, kinetics of exocytosis and morphologies. Although the ontogeny of platelet granules is poorly understood, a convergence of new insights into megakaryocyte development, the molecular mechanisms of vesicle trafficking and the genetic basis of platelet granule defects, is beginning to define the cellular and molecular pathways responsible for platelet granule ontogeny.
Asunto(s)
Plaquetas/metabolismo , Plaquetas/ultraestructura , Vesículas Secretoras/fisiología , Animales , Humanos , Lisosomas/fisiologíaRESUMEN
Zinc and iron compete during intestinal absorption, but postabsorptive interactions between these nutrients are less clear. Understanding these interactions is important to determine when supplementation with iron or zinc is proposed. The effect of zinc supplementation (22 mg Zn/d as zinc gluconate) or of iron supplementation (100 mg Fe/d as ferrous sulfate) for 6 wk on iron and zinc metabolism and absorption was evaluated in young women with low iron reserves. Young adult women (ages 20-28 y), nonanemic but with low iron stores (plasma ferritin< 20 microg/L), participated in the 70-d study. The women were divided in two groups (zinc-supplemented, n = 11; iron-supplemented, n = 12). The supplements were taken at bedtime. Iron and zinc biochemical indices and intestinal absorption were measured on d 1 and 56. Radioiron and stable isotopes of zinc were used to measure iron and zinc absorption from a test meal. In the iron-supplemented group, blood hemoglobin, plasma ferritin and the percentage of transferrin saturation increased (P < 0.01). Zinc indices did not change. In the zinc-supplemented group, plasma ferritin and the percentage of transferrin saturation decreased (P < 0.05), whereas the plasma transferrin receptor and erythrocyte zinc protoprophyrin levels increased (P < 0.05). Plasma and urinary zinc also increased (P < 0.01). Iron absorption (%) from the test meal increased (P < 0.01), whereas zinc absorption (%) decreased (P < 0.01) compared with baseline in the Zn-supplemented women. Our results indicate that the use of iron supplements in women with marginal iron status improves iron indices with no effect on zinc status. However, use of a modest zinc supplement improves zinc indices, but also appears to induce a cellular iron deficiency and, possibly, further reduce iron status.