RESUMEN
SCOPE: Interventions that boost NAD+ availability are of potential therapeutic interest for obesity treatment. The potential of nicotinamide (NAM), the amide form of vitamin B3 and a physiological precursor of nicotinamide adenine dinucleotide (NAD)+ , in preventing weight gain has not previously been studied in vivo. Other NAD+ precursors have been shown to decrease weight gain; however, their impact on adipose tissue is not addressed. METHODS AND RESULTS: Two doses of NAM (high dose: 1% and low dose: 0.25%) are given by drinking water to C57BL/6J male mice, starting at the same time as the high-fat diet feeding. NAM supplementation protects against diet-induced obesity by augmenting global body energy expenditure in C57BL/6J male mice. The manipulation markedly alters adipose morphology and metabolism, particularly in inguinal (i) white adipose tissue (iWAT). An increased number of brown and beige adipocyte clusters, protein abundance of uncoupling protein 1 (UCP1), mitochondrial activity, adipose NAD+ , and phosphorylated AMP-activated protein kinase (P-AMPK) levels are observed in the iWAT of treated mice. Notably, a significant improvement in hepatic steatosis, inflammation, and glucose tolerance is also observed in NAM high-dose treated mice. CONCLUSION: NAM influences whole-body energy expenditure by driving changes in the adipose phenotype. Thus, NAM is an attractive potential treatment for preventing obesity and associated complications.
Asunto(s)
Tejido Adiposo Blanco/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Niacinamida/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Adipocitos Beige/efectos de los fármacos , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/fisiología , Tejido Adiposo Blanco/fisiología , Animales , Dieta Alta en Grasa/efectos adversos , Masculino , Ratones Endogámicos C57BL , Niacinamida/administración & dosificación , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , Obesidad/etiología , Obesidad/prevención & control , Aumento de Peso/efectos de los fármacosRESUMEN
The potential of nicotinamide (NAM) to prevent atherosclerosis has not yet been examined. This study investigated the effect of NAM supplementation on the development of atherosclerosis in a mouse model of the disease. The development of aortic atherosclerosis was significantly reduced (NAM low dose: 45%; NAM high dose: 55%) in NAM-treated, apolipoprotein (Apo)E-deficient mice challenged with a Western diet for 4 weeks. NAM administration significantly increased (1.8-fold) the plasma concentration of proatherogenic ApoB-containing lipoproteins in NAM high-dose (HD)-treated mice compared with untreated mice. However, isolated ApoB-containing lipoproteins from NAM HD mice were less prone to oxidation than those of untreated mice. This result was consistent with the decreased (1.5-fold) concentration of oxidized low-density lipoproteins in this group. Immunohistochemical staining of aortas from NAM-treated mice showed significantly increased levels of IL-10 (NAM low-dose (LD): 1.3-fold; NAM HD: 1.2-fold), concomitant with a significant decrease in the relative expression of TNFα (NAM LD: -44%; NAM HD: -57%). An improved anti-inflammatory pattern was reproduced in macrophages cultured in the presence of NAM. Thus, dietary NAM supplementation in ApoE-deficient mice prevented the development of atherosclerosis and improved protection against ApoB-containing lipoprotein oxidation and aortic inflammation.
RESUMEN
INTRODUCTION: High Density Lipoproteins (HDL) are dysfunctional in hypercholesterolemia patients. The hypothesis was tested that nicotinamide (NAM) administration will influence HDL metabolism and reverse cholesterol transport from macrophages to the liver and feces in vivo (m-RCT) in a murine model of hypercholesterolemia. METHODS: Apolipoprotein E-deficient (KOE) mice were challenged with a high-fat diet for 4 weeks. The effect of different doses of NAM on cholesterol metabolism, and the ability of HDL to promote m-RCT was assessed. RESULTS: The administration of NAM to KOE mice produced an increase (â¼1.5-fold; P<0.05) in the plasma levels of cholesterol, which was mainly accounted for by the non-HDL fraction. NAM produced a [3H]-cholesterol plasma accumulation (â¼1.5-fold) in the m-RCT setting. As revealed by kinetic analysis, the latter was mainly explained by an impaired clearance of circulating non-HDL (â¼0.8-fold). The relative content of [3H]-tracer was lowered in the livers (â¼0.6-fold) and feces (>0.5-fold) of NAM-treated mice. This finding was accompanied by a significant (or trend close to significance) up-regulation of the relative gene expression of Abcg5 and Abcg8 in the liver (Abcg5: 2.9-fold; P<0.05; Abcg8: 2.4-fold; P=0.06) and small intestine (Abcg5: 2.1-fold; P=0.15; Abcg8: 1.9-fold; P<0.05) of high-dose, NAM-treated mice. CONCLUSION: The data from this study show that the administration of NAM to KOE mice impaired m-RCT in vivo. This finding was partly due to a defective hepatic clearance of plasma non-HDL.
Asunto(s)
Apolipoproteínas E/deficiencia , Colesterol/metabolismo , Hipercolesterolemia/metabolismo , Hígado/metabolismo , Niacinamida/administración & dosificación , Complejo Vitamínico B/administración & dosificación , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8/genética , Animales , Transporte Biológico/efectos de los fármacos , Colesterol/sangre , Dieta Alta en Grasa , Heces , Expresión Génica , Lipoproteínas/genética , Lipoproteínas HDL , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia ArribaRESUMEN
Cancer is the second leading cause of death worldwide. Compelling evidence supports the hypothesis that the manipulation of dietary components, including plant compounds termed as phytochemicals, demonstrates certain important health benefits in humans, including those in cancer. In fact, beyond their well-known cardiovascular applications, phytosterols may also possess anticancer properties, as has been demonstrated by several studies. Although the mechanism of action by which phytosterols (and derivatives) may prevent cancer development is still under investigation, data from multiple experimental studies support the hypothesis that they may modulate proliferation and apoptosis of tumor cells. Phytosterols are generally considered safe for human consumption and may also be added to a broad spectrum of food matrices; further, they could be used in primary and secondary prevention. However, few interventional studies have evaluated the relationship between the efficacy of different types and forms of phytosterols in cancer prevention. In this context, the purpose of this review was to revisit and update the current knowledge on the molecular mechanisms involved in the anticancer action of phytosterols and their potential in cancer prevention or treatment.
Asunto(s)
Neoplasias/tratamiento farmacológico , Fitosteroles/farmacología , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Neoplasias/patologíaRESUMEN
Dietary phytosterol supplements are readily available to consumers since they effectively reduce plasma low-density lipoprotein cholesterol. Several studies on cell cultures and xenograft mouse models suggest that dietary phytosterols may also exert protective effects against common cancers. We examined the effects of a dietary phytosterol supplement on tumor onset and progression using the well-characterized mouse mammary tumor virus polyoma virus middle T antigen transgenic mouse model of inherited breast cancer. Both the development of mammary hyperplastic lesions (at age 4 weeks) and total tumor burden (at age 13 weeks) were reduced after dietary phytosterol supplementation in female mice fed a high-fat, high-cholesterol diet. A blind, detailed histopathologic examination of the mammary glands (at age 8 weeks) also revealed the presence of less-advanced lesions in phytosterol-fed mice. This protective effect was not observed when the mice were fed a low-fat, low-cholesterol diet. Phytosterol supplementation was effective in preventing lipoprotein oxidation in mice fed the high-fat diet, a property that may explain - at least in part - their anticancer effects since lipoprotein oxidation/inflammation has been shown to be critical for tumor growth. In summary, our study provides preclinical proof of the concept that dietary phytosterols could prevent the tumor growth associated with fat-rich diet consumption.
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Dieta Alta en Grasa/efectos adversos , Lipoproteínas/metabolismo , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Fitosteroles/farmacología , Animales , Antígenos Virales de Tumores/genética , Antineoplásicos Fitogénicos/farmacología , Peso Corporal/efectos de los fármacos , Colesterol/sangre , Suplementos Dietéticos , Femenino , Lipoproteínas HDL/metabolismo , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Transgénicos , FN-kappa B/metabolismo , Oxidación-ReducciónRESUMEN
Epidemiologic studies have demonstrated that increased high-density lipoprotein cholesterol (HDL-C) is a protective factor against cardiovascular disease. However, the beneficial therapeutic effects of raising HDL-C are proving difficult to confirm in humans. Macrophage-specific reverse cholesterol transport (RCT) is thought to be one of the most important HDL-mediated cardioprotective mechanisms. A new approach was developed to measure in vivo RCT from labeled cholesterol macrophages to liver and feces in mice. Since its original publication, this method has been extensively used to assess the effects of genetic manipulation of pivotal genes involved in HDL metabolism on this major HDL antiatherogenic function in mice. These studies indicate that in vivo macrophage-specific RTC is a strong predictor of atherosclerosis susceptibility compared with steady-state plasma HDL-C levels or other global RCT measurements. This review aims to identify the best molecular targets for improving this HDL antiatherogenic function. Strong evidence supports a positive effect of interventions on macrophage adenosine triphosphate-binding cassette transporter (ABC) A1 and neutral cholesteryl ester hydrolase, apolipoprotein (apo) A-I, apoE, liver scavenger receptor class B type I and ABCG5/G8 on in vivo macrophage-specific RCT and atherosclerosis susceptibility. However, other genetic modifications have yielded conflicting results. Several preclinical studies tested the effects on macrophage-specific RCT in vivo of promising new HDL-based therapeutic agents, which include cholesteryl ester transfer protein inhibitors, apoA-I-directed therapies, liver X receptor and peroxisome proliferator-activated receptor agonists, intestinal cholesterol absorption inhibitors, fish oil and phenolic acid intake, inflammatory modulation and non-nucleoside reverse transcriptase inhibitors. This review also discusses recent findings on the potential effects of these therapeutic approaches on macrophage RCT in mice and cardiovascular risk in humans.
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Aterosclerosis/metabolismo , Colesterol/metabolismo , Reguladores del Metabolismo de Lípidos/farmacología , Macrófagos/metabolismo , Animales , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/prevención & control , HDL-Colesterol/metabolismo , Circulación Enterohepática/efectos de los fármacos , Humanos , Reguladores del Metabolismo de Lípidos/uso terapéutico , Macrófagos/efectos de los fármacos , Terapia Molecular DirigidaRESUMEN
INTRODUCTION: High plasma homocysteine (Hcy) concentration or hyperhomocysteinemia is associated with an increased vascular risk of disease in case-control studies and, to a lesser extent, in prospective studies. DEVELOPMENT: Several large randomized, double-blind, placebo-controlled trials have been already conducted using specific vitamin therapies with the aim of reducing secondary cardiovascular (HOPE, NORVIT, WAFACS and WENBIT studies) and cerebrovascular (VISP study) disease risk. The results from these major secondary prevention trials and one meta-analysis, that included other smaller studies up to 12 of them, showed that treatment decreased plasma Hcy concentration but failed to reduce cardiovascular risk. It is nevertheless noteworthy that a recent meta-analysis addressing the effects of these vitamin treatments on cerebrovascular risk found a positive effect on primary stroke prevention. These data would be consistent with the fact that increased Hcy is known to be associated more strongly with stroke risk than with cardiovascular risk. Moreover, folic acid supplementation in grain food has recently been shown to be associated with a decreased stroke incidence in USA and Canada. CONCLUSIONS: Obviously, these data on primary stroke prevention will require extensive confirmation. However, there now appear to be more reasons to expect a positive outcome of Hcy intervention studies.
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Enfermedades Cardiovasculares , Trastornos Cerebrovasculares , Homocisteína/sangre , Hiperhomocisteinemia , Vitaminas/uso terapéutico , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Trastornos Cerebrovasculares/sangre , Trastornos Cerebrovasculares/etiología , Trastornos Cerebrovasculares/prevención & control , Ácido Fólico/uso terapéutico , Alimentos Fortificados , Humanos , Hiperhomocisteinemia/sangre , Hiperhomocisteinemia/complicaciones , Metaanálisis como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/prevención & control , Complejo Vitamínico B/uso terapéuticoRESUMEN
Although most studies have focused on the cholesterol-lowering activity of phytosterols, other biological actions have been ascribed to these plant sterol compounds, one of which is a potential immune modulatory effect. To gain insight into this issue, we used a mouse model of acute, aseptic inflammation induced by a single subcutaneous turpentine injection. Hypercholesterolemic apolipoprotein E-deficient (apoE(-/-)) mice, fed with or without a 2% phytosterol supplement, were treated with turpentine or saline and euthanized 48 h later. No differences were observed in spleen lymphocyte subsets between phytosterol- and control-fed apoE(-/-) mice. However, cultured spleen lymphocytes of apoE(-/-) mice fed with phytosterols and treated with turpentine showed increased IL-2 and IFN-gamma secretion (T-helper type1, Th1 lymphocyte cytokines) compared with turpentine-treated, control-fed animals. In contrast, there was no change in Th2 cytokines IL-4 and IL-10. Phytosterols also inhibit intestinal cholesterol absorption in wild-type C57BL/6J mice but, in this case, without decreasing plasma cholesterol. Spleen lymphocytes of turpentine-treated C57BL/6J mice fed with phytosterols also showed increased IL-2 production, but IFN-gamma, IL-4 and IL-10 production was unchanged. The Th1/Th2 ratio was significantly increased both in phytosterol-fed apoE(-/-) and C57BL/6J mice. We conclude that phytosterols modulate the T-helper immune response in vivo, in part independently of their hypocholesterolemic effect in a setting of acute, aseptic inflammation. Further study of phytosterol effects on immune-based diseases characterized by an exacerbated Th2 response is thus of interest.
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Inmunidad Celular/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Fitosteroles/uso terapéutico , Células TH1/efectos de los fármacos , Análisis de Varianza , Animales , Apolipoproteínas E/genética , Colesterol/sangre , Suplementos Dietéticos , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Inflamación/inducido químicamente , Interferón gamma/metabolismo , Interleucina-2/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fitosteroles/farmacología , Células TH1/metabolismo , Trementina/toxicidadAsunto(s)
Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica , Fitosteroles/química , Proteínas de Plantas/química , Receptores Citoplasmáticos y Nucleares/metabolismo , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/metabolismo , Absorción , Animales , Colesterol/metabolismo , Humanos , Receptores X del Hígado , Proteínas de Transporte de Membrana/metabolismo , Ratones , Modelos Biológicos , Receptores Nucleares Huérfanos , Fitosteroles/metabolismo , Extractos Vegetales , ARN Mensajero/metabolismoRESUMEN
Folic acid is a vitamin that when used as a dietary supplementation can improve endothelial function. To assess the effect of folic acid on the development of atherosclerosis, male apolipoprotein E-deficient mice fed a standard chow diet received either water (control group) or an aqueous solution of folic acid that provided a dose of 75 microg/kg/day, for ten weeks. At the time of sacrifice, blood was drawn and the heart removed. The study measured plasma homocysteine, lipids, lipoproteins, low-density lipoprotein (LDL) oxidation, isoprostane, paraoxonase, and apolipoproteins, and aortic atherosclerotic areas. In folic acid-treated animals, total cholesterol, mainly carried in very low-density and low-density lipoproteins, increased significantly, and homocysteine, HDL cholesterol, paraoxonase, and triglyceride levels did not change significantly. Plasma isoprostane and apolipoprotein (apo) B levels decreased. The resistance of LDL to oxidization and plasma apoA-I and apoA-IV levels increased with a concomitant decrease in the area of atherosclerotic lesions. The administration of folic acid decreased atherosclerotic lesions independently of plasma homocysteine and cholesterol levels, but was associated with plasma levels of apolipoproteins A-I, A-IV and B, and decreased oxidative stress.
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Apolipoproteínas E/deficiencia , Aterosclerosis/prevención & control , Suplementos Dietéticos , Ácido Fólico/administración & dosificación , Complejo Vitamínico B/administración & dosificación , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/patología , Apolipoproteínas/genética , Apolipoproteínas/metabolismo , Apolipoproteínas E/genética , Aterosclerosis/metabolismo , Homocisteína/sangre , Lípidos/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Noqueados , Estrés Oxidativo/efectos de los fármacosRESUMEN
An increased activity of ATP-binding cassette transporter (ABC) A1 has been proposed as a mechanism underlying the hypocholesterolaemic effect of phytosterols. In the present study, ABCA1-deficient mice (ABCA1-/- mice) were used to examine the involvement of the ABCA1 in the reduction of intestinal cholesterol absorption in response to a phytosterol-enriched diet. A decrease in intestinal cholesterol absorption of 39 and 35 % was observed after phytosterol treatment in ABCA1+/+ mice and in ABCA1-/- mice, respectively. No statistically significant changes in plasma lipoprotein profile or in intestinal ABCG5, ABCG8 and Niemann-Pick C1-Like 1 gene expression levels were found when phytosterol-treated ABCA1-/- mice and untreated ABCA1-/- mice were compared. We conclude that phytosterol inhibition of cholesterol absorption in mice is independent of ABCA1.