RESUMEN
BACKGROUND AND AIMS: Inflammatory, oxidative stress, and endothelial dysfunction play a key role in the pathogenesis of long-term cardiovascular complications in patients with diabetes. The present observational prospective study is aimed at evaluating the effects of micronutrients and phytochemicals contained in the dietary supplement Flebotrofine® (AMNOL Chimica Biologica) on biochemical markers of inflammation, endothelial dysfunction, and glycemic control in patients with diabetes. METHODS: 105 type 1 or type 2 diabetes patients regularly took a daily dose of the dietary supplement Flebotrofine® for three consecutive months, and haematological and biochemical parameters were checked at baseline, after three months of treatment, and one month after its suspension. Statistical comparison of the laboratory parameters was performed using the two-tailed ANOVA test for repeated samples with a statistical significance level set at p < 0.05. RESULTS: The daily use of Flebotrofine® did not change the glycemic metabolic compensation of enrolled patients. After three months of regular Flebotrofine® intake, the plasma levels of the antioxidant ß-carotene and of arginine were significantly higher compared with the baseline values, with a decrease in the ADMA/arginine ratio. In contrast, apolipoprotein B, ApoB/ApoA1 ratio, and platelet and leukocyte counts significantly dropped. CONCLUSION: The daily use of Flebotrofine® might be a valid supplement of arginine, the precursor of NO, and essential in the prevention of endothelial dysfunction. The regular intake of arginine and phytochemicals also improved the antioxidant and antithrombotic profile of enrolled patients. Therefore, Flebotrofine® could be a useful dietary supplement to prevent long-term complications in patients with diabetes.
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Arginina/administración & dosificación , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diosmina/administración & dosificación , Hesperidina/administración & dosificación , Hidroxietilrutósido/análogos & derivados , Antioxidantes/metabolismo , Apolipoproteína A-I/metabolismo , Apolipoproteína B-100/metabolismo , Biomarcadores/metabolismo , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/metabolismo , Suplementos Dietéticos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Femenino , Humanos , Hidroxietilrutósido/administración & dosificación , Masculino , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Proyectos Piloto , Estudios ProspectivosRESUMEN
CONTEXT: Evidence for an association between sphingolipids and metabolic disorders is increasingly reported. Omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) improve apolipoprotein B100 (apoB100)-containing lipoprotein metabolism, but their effects on the sphingolipid content in lipoproteins remain unknown. OBJECTIVES: In subjects with hypertriglyceridemia, we analyzed the effect of n-3 LC-PUFAs on the turnover apoB100-containing lipoproteins and on their sphingolipid content and looked for the possible association between these lipid levels and apoB100-containing lipoprotein turnover parameters. METHODS: Six subjects underwent a kinetic study before and after n-3 supplementation for 2 months with 1 g of fish oil 3 times day containing 360 mg of eicosapentaenoic acid (EPA) and 240 mg of docosahexaenoic acid (DHA) in the form of triglycerides. We examined apoB100-containing lipoprotein turnover by primed perfusion labeled [5,5,5-2H3]-leucine and determined kinetic parameters using a multicompartmental model. We quantified sphingolipid species content in lipoproteins using mass spectrometry. RESULTS: Supplementation decreased very low-density lipoprotein (VLDL), triglyceride, and apoB100 concentrations. The VLDL neutral and polar lipids showed increased n-3 LC-PUFA and decreased n-6 LC-PUFA content. The conversion rate of VLDL1 to VLDL2 and of VLDL2 to LDL was increased. We measured a decrease in total apoB100 production and VLDL1 production. Supplementation reduced the total ceramide concentration in VLDL while the sphingomyelin content in LDL was increased. We found positive correlations between plasma palmitic acid and VLDL ceramide and between VLDL triglyceride and VLDL ceramide, and inverse correlations between VLDL n-3 LC-PUFA and VLDL production. CONCLUSION: Based on these results, we hypothesize that the improvement in apoB100 metabolism during n-3 LC-PUFA supplementation is contributed to by changes in sphingolipids.
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Apolipoproteína B-100/metabolismo , Suplementos Dietéticos , Ácidos Grasos Omega-3/administración & dosificación , Hipertrigliceridemia/tratamiento farmacológico , Esfingolípidos/metabolismo , Adulto , Humanos , Hipertrigliceridemia/sangre , Hipertrigliceridemia/metabolismo , Lipoproteínas VLDL/sangre , Lipoproteínas VLDL/metabolismo , Masculino , Persona de Mediana Edad , Proyectos Piloto , Esfingolípidos/sangre , Resultado del TratamientoRESUMEN
This study was carried out to investigate the effects of policosanol on high-fat and high-cholesterol diet-induced hypercholesterolemic rats to provide strong evidence in support of its hypocholesterolemic effect. The hypercholesterolemic rats showed elevations in liver weight, total triglycerides, total cholesterol, and low-density lipoprotein (LDL) cholesterol in serum; however, policosanol supplementation reduced these markers significantly. In addition, we found that policosanol supplementation stimulated an increase in fecal cholesterol and bile acid contents and deactivated 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase by AMP-activated protein kinase (AMPK) phosphorylation during high-fat and high-cholesterol-containing diet-induced development of hypercholesterolemia. Policosanol supplementation decreased ApoB levels and increased LDL-receptor expression, but it did not affect the hepatic ACAT2 level in livers from hypercholesterolemic rats. Moreover, supplementation with policosanol significantly decreased aortic wall thickness and levels of P-selectin and soluble vascular cell adhesion molecule (sVCAM-1) in serum. In conclusion, we suggest that policosanol supplementation induces antihypercholesterolemia by inhibiting cholesterol biosynthesis, LDL cholesterol uptake, and cholesterol excretion.
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Proteínas Quinasas Activadas por AMP/metabolismo , Anticolesterolemiantes/farmacología , Colesterol/biosíntesis , Alcoholes Grasos/farmacología , Hipercolesterolemia/tratamiento farmacológico , Animales , Aorta , Apolipoproteína B-100/metabolismo , HDL-Colesterol/sangre , Dieta Alta en Grasa , Hidroximetilglutaril-CoA Reductasas/metabolismo , Hipercolesterolemia/enzimología , Hígado/metabolismo , Masculino , Selectina-P/sangre , Ratas , Ratas Sprague-Dawley , Receptores de LDL/metabolismo , Esterol O-Aciltransferasa/metabolismo , Triglicéridos/sangre , Molécula 1 de Adhesión Celular Vascular/sangre , Esterol O-Aciltransferasa 2RESUMEN
The aim of this study was to explore the effect of emodin on lipid accumulation and inflammation in hepatocytes. The cell morphology was observed by microscopy. LDH release was detected by the kit. Levels of intracellular lipid droplets were observed by oil red O staining. The contents of TC and TG in cells were detected by the kit. Western blot was used to determine protein expressions of FASN,SREBF2,APOB,IL-6 and p-NF-κB in hepatocytes. The results showed that the levels of L02 cell LDH were significantly increased after being treated with emodin,and the cells showed shrinkage,volume reduction,decrease in quantity with the increase of dose. Red lipid droplets were observed in L02 hepatocytes. Intracellular TC and TG contents of L02 cell increased in a concentrationdependent manner,with significant differences between medium and high-dose groups( P < 0. 05). Protein expressions of FASN,SREBF2,IL-6 and p-NF-κB were significantly higher than those of the control group,and the expression level of APOB was significantly lower than that of the control group( P<0. 05). In conclusion,emodin could induce lipid accumulation and inflammatory damage in hepatocytes in a dose-dependent manner,which in turn could damage liver cells. This process was related to the up-regulation of FASN,SREBF2,IL-6,p-NF-κB,as well as the down-regulation of the protein expression of APOB.
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Emodina/farmacología , Hepatocitos/efectos de los fármacos , Metabolismo de los Lípidos , Apolipoproteína B-100/metabolismo , Células Cultivadas , Acido Graso Sintasa Tipo I/metabolismo , Hepatocitos/metabolismo , Humanos , Inflamación , Interleucina-6/metabolismo , Lípidos , FN-kappa B/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismoRESUMEN
The present study aimed to investigate the effects of n-3 fatty acid supplements on urine metabolite profiling and their correlation with metabolic risk factors in Chinese T2D patients. A double-blind randomized controlled trial was conducted in 59 Chinese patients with T2D, who were randomized to receive fish oil (FO), flaxseed oil (FSO) or corn oil (CO, serving as a control group) capsules for 180 days. Morning urine samples were collected before and after the intervention and were analyzed for metabolomics by UHPLC-Q-Exactive Orbitrap/MS in positive and negative ionization modes. In the FO group, levels of 2-hexenoylcarnitine (C6:1) (p < 0.001) and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) (p = 0.004) were significantly increased while hydroxyisovaleroyl carnitine (C5:OH) (p < 0.001) was significantly decreased compared with the CO group. In addition, geranylacetone (p = 0.023) and citronellyl propionate (p = 0.038) levels were significantly elevated, while dihydrojasmonic acid (p = 0.003) was significantly reduced in the FSO group compared with that in the CO group. Moreover, increased C6:1 was correlated with decreased serum triglycerides (r = -0.340, p = 0.020). The change of urine CMPF showed inverse correlation with blood urea nitrogen (BUN) (r = -0.338, p = 0.020), while C5:OH was positively correlated with apolipoprotein B (APOB) and BUN (r = 0.386, p = 0.015; r = 0.327, p = 0.025). Besides, the change of urine CMPF was positively correlated with serum CMPF (r = 0.646, p < 0.001). In conclusion, the present study confirmed that CMPF is a strong biomarker of fish oil, and indicated that marine n-3 PUFA intake might have a beneficial effect on lipid metabolism and renal function in patients with T2D.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ácidos Grasos Omega-3/administración & dosificación , Apolipoproteína B-100/genética , Apolipoproteína B-100/metabolismo , Aceite de Maíz/administración & dosificación , Aceite de Maíz/química , Aceite de Maíz/orina , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/orina , Suplementos Dietéticos/análisis , Ácidos Grasos Omega-3/química , Ácidos Grasos Omega-3/orina , Aceites de Pescado/administración & dosificación , Aceites de Pescado/química , Aceites de Pescado/orina , Humanos , Aceite de Linaza/administración & dosificación , Aceite de Linaza/química , Orina/químicaRESUMEN
Curcumin, a naturally occurring plant polyphenolic compound, may have beneficial effects in nonalcoholic steatohepatitis (NASH) development. We examined whether curcumin supplementation could be used in both prevention and treatment of NASH with fibrosis. Female Wistar rats were provided ad libitum access to a "western diet" (WD) high in fat (43% kcal), sucrose (29% kcal), and cholesterol (2% w/v), as well as 15% fructose drinking water. Intraperitoneal CC14 injections (0.5 mL/kg) were also administered at weeks 1, 2, 4, and 6 to accelerate development of a NASH with fibrosis phenotype. Rats were randomized to four groups (n = 9-12/group) and fed ad libitum: (1) WD for 8-weeks (8WD), (2) WD enriched with curcumin for 8-weeks (8WD+C; 0.2% curcumin, BCM-95, DolCas Biotech) to assess prevention, (3) WD for 12-weeks (12WD), (4) WD for 8-weeks followed by 4-weeks WD+C (12WD+C) to assess treatment. Curcumin prevention (8WD vs. 8WD+C) attenuated (P < 0.05) histological liver inflammation, molecular markers of fibrosis (Col1a1 mRNA) and a serum marker of liver injury (AST). Curcumin treatment (12WD vs. 12WD+C) reduced (P < 0.05) hepatocellular inflammation, steatosis, NAFLD Activity Scores, and serum markers of liver injury (AST, ALP). Moreover, curcumin treatment also increased hepatic pACC/ACC, ApoB100, and SOD1 protein, and decreased hepatic FGF-21 levels; whereas, curcumin prevention increased hepatic glutathione levels. Both curcumin prevention and treatment reduced molecular markers of hepatic fibrosis (Col1a1 mRNA) and inflammation (TNF-α, SPP1 mRNA). Curcumin supplementation beneficially altered the NASH phenotype in female Wistar rats, particularly the reversal of hepatocellular inflammation.
Asunto(s)
Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Curcumina/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Animales , Antiinflamatorios/administración & dosificación , Apolipoproteína B-100/metabolismo , Colágeno/metabolismo , Curcumina/administración & dosificación , Dieta Alta en Grasa/efectos adversos , Femenino , Glutatión/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Osteopontina/metabolismo , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
ETNOPHARMACOLOGICAL RELEVANCE: Syzygium cumini (L.) Skeels is a plant widely used in folk medicine to treat diabetes mellitus (DM). The tea from its leaves is frequently used by diabetics for lowering hyperglycemia. There is a close relationship between DM and atherosclerosis, a chronic immuno-inflammatory disease, were the early stages encompass oxidative and glycative modifications in the structure of low density lipoprotein (LDL). AIM OF THIS STUDY: To investigate the potential protective effects of aqueous-leaf extract from Syzygium cumini (S.cExt) against CuSO4-induced oxidation and methylglyoxal (MG)-induced glycation of human LDL in vitro. MATERIALS AND METHODS: LDL oxidative changes were evaluated by measuring conjugated dienes (CD) formation, thiobarbituric acid reactive substances (TBARS) levels, quenching of tryptophan (Trp) fluorescence and structural modifications in LDL particle. In LDL glycated by MG (glyLDL), we determined the levels of fluorescent advanced glycation end products (AGEs) and mobility by agarose gel electrophoresis. RESULTS: S.cExt blocked oxidative events induced by CuSO4 in human LDL, plasma and serum. Fourier transform infrared spectroscopy (FT-IR) revealed that specific regions of apoB100 were oxidized by CuSO4 in human LDL and that S.cExt reduced these oxidations. Unlike, the increased AGEs levels and eletrophoretic mobility observed in LDL MG-glycated were not modified by S.cExt. CONCLUSION: The findings herein indicate that S.cExt could be tested in atherogenesis models as potential protective agent against LDL oxidation.
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Lipoproteínas LDL/metabolismo , Extractos Vegetales/farmacología , Syzygium/química , Apolipoproteína B-100/metabolismo , Sulfato de Cobre/administración & dosificación , Electroforesis en Gel de Agar , Productos Finales de Glicación Avanzada/metabolismo , Humanos , Medicina Tradicional , Oxidación-Reducción , Hojas de la Planta , Espectroscopía Infrarroja por Transformada de Fourier , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
To investigate the etiopathogenesis of fatty liver hemorrhagic syndrome (FLHS) and the protective effects of soybean lecithin against FLHS in laying hens, 135 healthy 300-day-old Hyline laying hens were randomly divided into groups: control (group 1), diseased (group 2), and protected (group 3). Each group contained 45 layers with 3 replicates. The birds in these 3 groups were fed a control diet, a high-energy/low-protein (HELP) diet or the HELP diet supplemented with 3% soybean lecithin instead of maize. The fat percent in the liver was calculated. Histopathological changes in the liver were determined by staining, and the mRNA expression levels of apolipoproteinA I (apoA I) and apolipoprotein B100 (apoB100) in the liver were determined by RT-PCR. The results showed that the fat percent in the liver of group 2 was much higher (P < 0.01) than that of group 1 and group 2 on d 30 and 60. The histology of the liver in group 2 on d 30 and 60 displayed various degrees of liver lesions, while the hepatocytes showed a normal structure in group 3 with mild microvesicular steatosis in the liver cell on d 30 and 60. The mRNA expression levels of apoA I and apoB100 in the livers were variable throughout the experiment. The expression level of apoA I in group 2 significantly decreased on d 60 (P < 0.05); the expression level of apoB100 slightly increased on d 30 in group 2, while it sharply decreased on d 60. Compared to group 1, the expression level of apoB100 showed no significant difference in group 3 (P < 0.05). This study indicated that FLHS induced pathological changes and abnormal expression of apoA I and apoB100 in the livers of laying hens and that soybean lecithin alleviated these abnormal changes.
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Apolipoproteína A-I/genética , Apolipoproteína B-100/genética , Proteínas Aviares/genética , Pollos , Hígado Graso/veterinaria , Lecitinas/metabolismo , Enfermedades de las Aves de Corral/fisiopatología , Alimentación Animal/análisis , Animales , Apolipoproteína A-I/metabolismo , Apolipoproteína B-100/metabolismo , Proteínas Aviares/metabolismo , Distribución de la Grasa Corporal , Dieta/veterinaria , Suplementos Dietéticos/análisis , Hígado Graso/tratamiento farmacológico , Hígado Graso/metabolismo , Hígado Graso/fisiopatología , Femenino , Lecitinas/administración & dosificación , Hígado/metabolismo , Hígado/fisiopatología , Enfermedades de las Aves de Corral/tratamiento farmacológico , Enfermedades de las Aves de Corral/metabolismo , Distribución Aleatoria , Glycine max/químicaRESUMEN
α-Linolenic acid (ALA) supplementation or exercise training can independently prevent hepatic lipid accumulation and reduced insulin signaling; however, this may occur through different mechanisms of action. In the current study, obese Zucker rats displayed decreased phospholipid (PL) content in association with hepatic lipid abundance, and therefore, we examined whether ALA and exercise training would prevent these abnormalities differently to reveal additive effects on the liver. To achieve this aim, obese Zucker rats were fed control diet alone or supplemented with ALA and were sedentary or exercise trained for 4 wk (C-Sed, ALA-Sed, C-Ex, and ALA-Ex). ALA-Sed rats had increased microsomal-triglyceride transfer protein (MTTP), a protein required for lipoprotein assembly/secretion, as well as modestly increased PL content in the absence of improvements in mitochondrial content, lipid accumulation, or insulin sensitivity. In contrast, C-Ex rats had increased mitochondrial content and insulin sensitivity; however, this corresponded with minimal improvements in PL content and hepatic lipid accumulation. Importantly, ALA-Ex rats demonstrated additive improvements in PL content and hepatic steatosis, which corresponded with increased mitochondrial content, MTTP and apolipoprotein B100 content, greater serum triacylglyceride, and insulin sensitivity. Overall, these data demonstrate additive effects of ALA and exercise training on hepatic lipid accumulation, as exercise training preferentially increased mitochondrial content, while ALA promoted an environment conducive for lipid secretion. These data highlight the potential for combination therapy to mitigate liver disease progression.
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Proteínas Portadoras/agonistas , Suplementos Dietéticos , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Obesidad/dietoterapia , Condicionamiento Físico Animal , Ácido alfa-Linolénico/uso terapéutico , Animales , Apolipoproteína B-100/metabolismo , Biomarcadores/sangre , Biomarcadores/metabolismo , Western Blotting , Proteínas Portadoras/metabolismo , Terapia Combinada , Resistencia a la Insulina , Metabolismo de los Lípidos , Masculino , Microsomas Hepáticos/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Obesidad/metabolismo , Obesidad/fisiopatología , Obesidad/terapia , Fosfolípidos/metabolismo , Distribución Aleatoria , Ratas Zucker , Triglicéridos/sangreRESUMEN
Low-density lipoprotein (LDL) oxidation is the primary event in atherosclerosis, and LDL lipoperoxidation leads to modifications in apolipoprotein B-100 (apo B-100) and lipids. Intermediate species of lipoperoxidation are known to be able to generate amino acid-centered radicals. Thus, we hypothesized that lipoperoxidation intermediates induce protein-derived free radical formation during LDL oxidation. Using DMPO and immuno-spin trapping, we detected the formation of protein free radicals on LDL incubated with Cu(2+) or the soybean lipoxidase (LPOx)/phospholipase A2 (PLA2). With low concentrations of DMPO (1mM), Cu(2+) dose-dependently induced oxidation of LDL and easily detected apo B-100 radicals. Protein radical formation in LDL incubated with Cu(2+) showed maximum yields after 30 min. In contrast, the yields of apo B-100 radicals formed by LPOx/PLA2 followed a typical enzyme-catalyzed kinetics that was unaffected by DMPO concentrations of up to 50mM. Furthermore, when we analyzed the effect of antioxidants on protein radical formation during LDL oxidation, we found that ascorbate, urate, and Trolox dose-dependently reduced apo B-100 free radical formation in LDL exposed to Cu(2+). In contrast, Trolox was the only antioxidant that even partially protected LDL from LPOx/PLA2. We also examined the kinetics of lipid radical formation and protein radical formation induced by Cu(2+) or LPOx/PLA2 for LDL supplemented with α-tocopherol. In contrast to the potent antioxidant effect of α-tocopherol on the delay of LDL oxidation induced by Cu(2+), when we used the oxidizing system LPOx/PLA2, no significant protection was detected. The lack of protection of α-tocopherol on the apo B-100 and lipid free radical formation by LPOx may explain the failure of vitamin E as a cardiovascular protective agent for humans.
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Antioxidantes/farmacología , Apolipoproteína B-100/química , Cobre/farmacología , Radicales Libres/metabolismo , Lipoproteínas LDL/química , Lipooxigenasa/farmacología , Vitamina E/farmacología , Apolipoproteína B-100/metabolismo , Humanos , Cinética , Peroxidación de Lípido/efectos de los fármacos , Oxidación-Reducción , Detección de SpinRESUMEN
Even total resemblance of content of fatty acids in triglycerides has both no standing for their functional unity nor even identity of their physical chemical characteristics. The etherification of fatty acids in various positions of three-atomic glycerin separates triglycerides on palmitic and oleic substrates for energy acquiring by cells. The kinetic parameters of biochemical reactions under palmitic mode of metabolism of fatty acids are always low. The myocytes in biological reaction of exotrophy experience deficiency of exogenous fatty acids which in vivo is to permanently supply through activation of biological reaction of endotrophy--enhancement of lipolysis in adipocytes. The biological role of insulin is to prevent formation in vivo of palmitic mode of metabolism of saturated and monoenic fatty acids. Under this condition, the necessity to activate lipolysis and to increase in blood plasma concentration of unesteritied fatty acids forms syndrome of resistance to insulin. The surplus of palmitic fatty acid in food and deficiency of insulin show in vivo unidirectional a physiologic action. The formation of palmitic mode of metabolism of energy substrates--portion of pathogenesis of atherosclerosis, metabolic syndrome, obesity, non-alcoholic fatty infiltration of liver and partiallly essential arterial hypertension.
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Apolipoproteína B-100/metabolismo , Ácido Oléico/metabolismo , Ácido Palmítico/metabolismo , Aceites de Plantas/metabolismo , Triglicéridos/metabolismo , Animales , Humanos , Isomerismo , Plantas/metabolismo , Triglicéridos/químicaRESUMEN
High serum concentrations of nonesterified fatty acids (NEFA), which may affect the synthesis and assembly of very low density lipoproteins (VLDL), are associated with fatty liver during the early lactation period. Therefore, the objective of this study was to investigate the effects of NEFA on the synthesis and assembly of VLDL in bovine hepatocytes. Bovine hepatocytes were cultured and treated with different concentrations of NEFA. The mRNA expression of apolipoprotein B100 (ApoB100) and apolipoprotein E (ApoE) was significantly lower in the NEFA treatment groups than in the control group (0mM NEFA). The abundance of mRNA from microsomal triglyceride transfer protein (MTP) and the low density lipoprotein receptor (LDLR) was significantly lower in the medium- and high-dose NEFA treatment groups. The protein expression of ApoB100, ApoE, MTP, and LDLR was found to be significantly and dose-dependently decreased in groups of NEFA-treated hepatocytes. The VLDL content was also significantly decreased in the NEFA-treated hepatocytes. Large amounts of triglycerides accumulated in the hepatocytes. These results indicate that NEFA significantly inhibits the expression of ApoB100, ApoE, MTP, and LDLR, thereby decreasing the synthesis and assembly of VLDL and inducing TG accumulation in bovine hepatocytes.
Asunto(s)
Ácidos Grasos no Esterificados/sangre , Hepatocitos/efectos de los fármacos , Lipoproteínas VLDL/biosíntesis , Animales , Apolipoproteína B-100/genética , Apolipoproteína B-100/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Bovinos , Células Cultivadas , Hepatocitos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Triglicéridos/metabolismoRESUMEN
OBJECTIVE: Overproduction of triglyceride-rich lipoproteins (TRLs) by liver and intestine contributes to hypertriglyceridemia and may increase cardiovascular risk. Dietary carbohydrates, especially fructose, have been shown to amplify postprandial lipemia but little is known about its effect on intestinal TRL particle production. Here, we examined intestinal and hepatic TRL particle production in response to enteral glucose or fructose in the presence of enteral lipid. APPROACH AND RESULTS: In 2 randomized studies, 4 to 6 weeks apart, 7 healthy male subjects received intraduodenal infusion of Intralipid plus saline or glucose. TRL-apolipoprotein (apo) B48 and apoB100 kinetics were assessed under pancreatic clamp conditions. In a separate study of another 7 subjects under similar conditions, glucose was replaced by fructose. When coinfused with Intralipid into the duodenum, glucose markedly stimulated TRL-apoB48 production (P<0.01), with a concomitant moderate increase in fractional clearance (P<0.05), resulting in net elevation of TRL-apoB48 concentration. TRL-apoB100 concentration, fractional clearance, and production were not significantly affected by glucose. When glucose was replaced by fructose, both TRL-apoB100 and apoB48 production (P<0.05), but not fractional clearance, were enhanced compared with Intralipid alone. CONCLUSIONS: These results reveal a novel role of monosaccharides in acutely enhancing intestinal lipoprotein particle production, thereby aggravating hyperlipidemia.
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Fructosa/metabolismo , Glucosa/metabolismo , Mucosa Intestinal/metabolismo , Lipoproteínas/biosíntesis , Triglicéridos/biosíntesis , Adulto , Apolipoproteína B-100/metabolismo , Apolipoproteína B-48/metabolismo , Glucemia/análisis , Emulsiones/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Fosfolípidos/metabolismo , Aceite de Soja/metabolismoRESUMEN
High levels of low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] are associated with early morbidity and mortality caused by cardiovascular disease (CVD). There are hints that a reduction of LDL-C levels beyond currently advocated targets, and the use of drugs that also have Lp(a)-lowering potential, could provide further clinical benefit. Today, LDL apheresis is the only available treatment option to achieve further lowering of apolipoprotein-B (apo-B)-containing lipoproteins, especially Lp(a). Mipomersen is currently being studied in patients with mild to severe hypercholesterolaemia as add-on therapy to other lipid-lowering therapy, as monotherapy in patients who are intolerant of HMG-CoA reductase inhibitors (statins) and who are at high risk for CVD. Patients affected by homozygous or heterozygous familial hypercholesterolaemia (FH), which are inherited autosomal co-dominant disorders characterized by a marked elevation of serum LDL-C concentration, remain a clinical challenge, especially when their CVD risk is aggravated by additionally elevated Lp(a) levels. Mipomersen is a 20-mer oligonucleotide [2'-O-(2-methoxy) ethyl-modified oligonucleotide], a second-generation antisense oligonucleotide (AOS), complementary to the coding region for human-specific apo-B-100 messenger RNA (mRNA). Mipomersen inhibits apo-B-100 synthesis and is consequently a new treatment strategy to lower apo-B-containing lipoproteins like LDL-C and Lp(a) in patients at high risk for CVD not on target or intolerant to statins. This article focuses on mipomersen and gives an overview of the current status of mipomersen as a promising treatment option. Recent studies have shown a decrease in LDL-C levels of 22-42.2% and in Lp(a) of 19.6-31.1% from baseline, depending on study design. Dose-dependent reductions of very low-density lipoprotein cholesterol (VLDL-C) and triglyceride levels have also been observed. Although the short-term efficacy and safety of mipomersen have been proven, side effects like injection-site reactions (up to 90-100%), increased liver enzymes, cephalgias, nasopharyngitis, myalgia, nausea and fatigue must be mentioned and critically discussed. Furthermore, we need more data on the long-term side effects, especially regarding the long-term potential for hepatic steatosis. Data on cardiovascular outcomes with mipomersen are also not yet available.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Oligonucleótidos/uso terapéutico , Animales , Anticolesterolemiantes/efectos adversos , Apolipoproteína B-100/antagonistas & inhibidores , Apolipoproteína B-100/sangre , Apolipoproteína B-100/metabolismo , LDL-Colesterol/sangre , LDL-Colesterol/metabolismo , VLDL-Colesterol/sangre , VLDL-Colesterol/metabolismo , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Método Doble Ciego , Evaluación Preclínica de Medicamentos , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/metabolismo , Lipoproteína(a)/sangre , Lipoproteína(a)/metabolismo , Oligonucleótidos/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
INTRODUCTION: The anti-atherogenic and hypotriglyceridemic properties of fish oil are attributed to its enrichment in eicosapentaenoic acid (EPA; 20:5, n-3) and docosahexaenoic acid (DHA; 22:6, n-3). Echium oil contains stearidonic acid (SDA; 18:4, n-3), which is metabolized to EPA in humans and mice, resulting in decreased plasma triglycerides. OBJECTIVE: We used apoB100 only, LDLrKO mice to investigate whether echium oil reduces atherosclerosis. METHODS: Mice were fed palm, echium, or fish oil-containing diets for 16 weeks and plasma lipids, lipoproteins, and atherosclerosis were measured. RESULTS: Compared to palm oil, echium oil feeding resulted in significantly less plasma triglyceride and cholesterol levels, and atherosclerosis, comparable to that of fish oil. CONCLUSION: This is the first report that echium oil is anti-atherogenic, suggesting that it may be a botanical alternative to fish oil for atheroprotection.
Asunto(s)
Apolipoproteína B-100/metabolismo , Aterosclerosis/prevención & control , Echium , Aceites de Plantas/administración & dosificación , Receptores de LDL/deficiencia , Animales , Apolipoproteína B-100/sangre , Apolipoproteína B-100/genética , Aterosclerosis/sangre , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Colesterol/sangre , Dieta , Modelos Animales de Enfermedad , Aceites de Pescado/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Aceite de Palma , Receptores de LDL/genética , Factores de Tiempo , Triglicéridos/sangreRESUMEN
Phospholipid transfer protein (PLTP) plays an important role in atherogenesis and lipoprotein metabolism. PLTP exerts its functions intracellularly and extracellularly. Both PLTP and microsomal triglyceride transfer protein (MTP) have been shown to regulate the secretion of apolipoprotein B (apoB) in hepatocytes. We have previously reported the characterization of inhibitors that selectively inhibit PLTP activity and reduce apoB secretion in hepatocytes. In the present study, we identified more compounds that inhibit both PLTP and MTP activity to various extents. These dual inhibitors are structurally different from the PLTP-selective inhibitors. In human hepatoma cell lines, dual inhibitors seem to be more effective in reducing apoB secretion than selective PLTP or MTP inhibitors. Furthermore, the dual inhibitors markedly reduced triglyceride secretion from hepatocytes. In the absence of PLTP, the dual inhibitors can further reduce apoB secretion, whereas selective PLTP inhibitors had no effect. We conclude that MTP and PLTP may work coordinately in the process of hepatic apoB assembly and secretion. To avoid liver toxicity mediated by MTP inhibition, selective PLTP inhibitors should be pursued.
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Proteínas Portadoras/antagonistas & inhibidores , Hipolipemiantes/farmacocinética , Proteínas de Transferencia de Fosfolípidos/antagonistas & inhibidores , Animales , Apolipoproteína B-100/metabolismo , Apolipoproteína B-48/metabolismo , Apolipoproteínas B/metabolismo , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Hipolipemiantes/química , Lipoproteínas HDL3/metabolismo , Liposomas/metabolismo , Ratones , Ratones Noqueados , Estructura Molecular , Fosfatidilcolinas/metabolismo , Proteínas de Transferencia de Fosfolípidos/genética , Proteínas de Transferencia de Fosfolípidos/metabolismo , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Triglicéridos/metabolismo , Trioleína/metabolismoRESUMEN
Some dietary fats are a risk factor for Alzheimer's disease (AD) but the mechanisms for this association are presently unknown. In the present study we showed in wild-type mice that chronic ingestion of SFA results in blood-brain barrier (BBB) dysfunction and significant delivery into the brain of plasma proteins, including apo B lipoproteins that are endogenously enriched in amyloid-beta (Abeta). Conversely, the plasma concentration of S100B was used as a marker of brain-to-blood leakage and was found to be increased two-fold because of SFA feeding. Consistent with a deterioration in BBB integrity in SFA-fed mice was a diminished cerebrovascular expression of occludin, an endothelial tight junction protein. In contrast to SFA-fed mice, chronic ingestion of MUFA or PUFA had no detrimental effect on BBB integrity. Utilising highly sensitive three-dimensional immunomicroscopy, we also showed that the cerebral distribution and co-localisation of Abeta with apo B lipoproteins in SFA-fed mice are similar to those found in amyloid precursor protein/presenilin-1 (APP/PS1) amyloid transgenic mice, an established murine model of AD. Moreover, there was a strong positive association of plasma-derived apo B lipoproteins with cerebral Abeta deposits. Collectively, the findings of the present study provide a plausible explanation of how dietary fats may influence AD risk. Ingestion of SFA could enhance peripheral delivery to the brain of circulating lipoprotein-Abeta and exacerbate the amyloidogenic cascade.
Asunto(s)
Enfermedad de Alzheimer/etiología , Péptidos beta-Amiloides/metabolismo , Apolipoproteína B-100/metabolismo , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Grasas de la Dieta/farmacología , Ácidos Grasos/farmacología , Enfermedad de Alzheimer/metabolismo , Animales , Apolipoproteína B-100/sangre , Biomarcadores/metabolismo , Modelos Animales de Enfermedad , Ácidos Grasos/metabolismo , Ácidos Grasos Insaturados/metabolismo , Femenino , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Microscopía/métodos , Ocludina , Presenilina-1 , Factores de Riesgo , Distribución TisularRESUMEN
BACKGROUND: Stearoyl-CoA desaturase 1 (SCD1) is a critical regulator of energy metabolism and inflammation. We have previously reported that inhibition of SCD1 in hyperlipidemic mice fed a saturated fatty acid (SFA)-enriched diet prevented development of the metabolic syndrome, yet surprisingly promoted severe atherosclerosis. In this study we tested whether dietary fish oil supplementation could prevent the accelerated atherosclerosis caused by SCD1 inhibition. METHODS AND RESULTS: LDLr(-/-), ApoB(100/100) mice were fed diets enriched in saturated fat or fish oil in conjunction with antisense oligonucleotide (ASO) treatment to inhibit SCD1. As previously reported, in SFA-fed mice, SCD1 inhibition dramatically protected against development of the metabolic syndrome, yet promoted atherosclerosis. In contrast, in mice fed fish oil, SCD1 inhibition did not result in augmented macrophage inflammatory response or severe atherosclerosis. In fact, the combined therapy of dietary fish oil and SCD1 ASO treatment effectively prevented both the metabolic syndrome and atherosclerosis. CONCLUSIONS: SCD1 ASO treatment in conjunction with dietary fish oil supplementation is an effective combination therapy to comprehensively combat the metabolic syndrome and atherosclerosis in mice.
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Aterosclerosis/prevención & control , Grasas Insaturadas en la Dieta/farmacología , Aceites de Pescado/farmacología , Síndrome Metabólico/prevención & control , Oligorribonucleótidos Antisentido/farmacología , Estearoil-CoA Desaturasa/genética , Animales , Apolipoproteína B-100/genética , Apolipoproteína B-100/metabolismo , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/inmunología , Terapia Combinada , Ácidos Grasos/farmacología , Hígado Graso/tratamiento farmacológico , Hígado Graso/prevención & control , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/prevención & control , Resistencia a la Insulina , Macrófagos/inmunología , Masculino , Síndrome Metabólico/dietoterapia , Síndrome Metabólico/inmunología , Ratones , Ratones Mutantes , Obesidad/tratamiento farmacológico , Obesidad/prevención & control , Receptores de LDL/genética , Receptores de LDL/metabolismo , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Receptor Toll-Like 4/inmunologíaRESUMEN
Elevated apolipoprotein (apo) B-100 is a common abnormality in insulin-resistant subjects with obesity and type 2 diabetes mellitus that increases risk of cardiovascular disease. ApoB-100 metabolism is complex. Kinetic studies using stable isotope tracer have provided useful mechanistic insight into its therapeutic regulation. Dysregulation of apoB-100 metabolism is integral to dyslipidaemia in the metabolic syndrome (MetS). This is dynamically related to a combination of overproduction of very-low density lipoprotein apoB-100 and decreased catabolism of apoB-containing particles, with accelerated catabolism of high-density lipoprotein (HDL) particles. These abnormalities may be consequent on a global effect of insulin resistance and accumulation of visceral and liver fat. Several therapeutic interventions, such as weight loss, physical exercise, statins, fibrates, fish oils and cholesteryl ester transfer protein inhibitors can correct apoB-100 metabolism in MetS. This encapsulates several kinetic mechanisms of action, including decreased secretion of apoB-100, increased catabolism of apoB-100 and delayed catabolism of HDL particles. Other agents, including cholesterol absorption inhibitors, niacins, and endocannabinoid-1 receptor blockers, have also been shown to improve plasma lipid and lipoprotein abnormalities in insulin resistance; their mechanisms of action require further investigation in MetS. The complementary mechanisms of action of different therapies support the use of combination regimens to treat dyslipoproteinaemia in MetS, including type 2 diabetes. Tracer methodology is a powerful tool to evaluate established and new lipid-regulating therapies.
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Apolipoproteína B-100/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Resistencia a la Insulina , Animales , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , HDL-Colesterol/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Humanos , Síndrome Metabólico/fisiopatología , Síndrome Metabólico/terapia , Obesidad/complicaciones , Obesidad/fisiopatología , Factores de RiesgoRESUMEN
BACKGROUND: Patients with type 2 diabetes are under high oxidative stress, and levels of hyperglycemia correlate strongly with levels of LDL oxidation. Carnitine favorably modulates oxidative stress. OBJECTIVE: This objective of this study was to evaluate the efficacy of L-carnitine on the reduction of oxidized LDL cholesterol in patients with type 2 diabetes. DESIGN: Eighty-one patients with diabetes were randomly assigned to 1 of 2 treatment groups for 3 mo. The 2 groups received either 2 g L-carnitine once daily (n = 41) or placebo (n = 40). The following variables were assessed at baseline, after washout, and at 1, 2, and 3 mo of treatment: body mass index, fasting plasma glucose, glycosylated hemoglobin, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apolipoprotein A1, apolipoprotein B-100, oxidized LDL cholesterol, thiobarbituric acid-reactive substances, and conjugated dienes. RESULTS: At the end of the study period, the L-carnitine-treated patients showed significant improvements compared with the placebo group in the following markers: oxidized LDL levels decreased by 15.1 compared with 3.0 U/L (P < 0.001); LDL cholesterol decreased by 0.45 compared with 0.16 mmol/L (P < 0.05); triglycerides decreased by 1.02 compared with 0.09 mmol/L (P < 0.001); apolipoprotein A1 concentrations decreased by 0.12 compared with 0.03 mg/dL (P < 0.05); apolipoprotein B-100 concentrations decreased by 0.13 compared with 0.04 mg/dL (P < 0.05); thiobarbituric acid-reactive substance concentrations decreased by 1.92 compared with 0.05 (P < 0.001), and conjugated diene concentrations decreased by 0.72 compared with 0.11 in the placebo group (P < 0.001). CONCLUSION: Our study indicates that oral administration of L-carnitine reduces oxidized LDL cholesterol levels in patients with type 2 diabetes.