RESUMEN
PURPOSE: Excessive exposure of glucocorticoids activates adipose lipolysis, increases circulating free fatty acids, and contributes to ectopic lipid deposition in liver and skeletal muscle. Our previous study demonstrated that maternal betaine supplementation attenuates glucocorticoid-induced hepatic lipid accumulation in rat offspring. However, it is unclear whether maternal betaine supplementation is effective in preventing glucocorticoid-induced lipolysis in the adipose tissue of offspring. METHODS: In this study, 20 pregnant rats were fed with basal or betaine-supplemented (10 g/kg) diets throughout gestation and lactation, and the offspring rats were raised on the basal diet from weaning till 3 months of age followed by daily intraperitoneal injection of saline or 0.1 mg/kg dexamethasone (DEX) for 3 weeks. RESULTS: Chronic DEX treatment significantly (P < 0.05) decreased serum corticosterone level and increased proinflammatory cytokines, such as TNFα, IL-1ß, and IL-6. Meanwhile, GR protein content in adipose tissue was increased in response to DEX treatment, which was associated with a significant (P < 0.05) up-regulation of ATGL and HSL expression at both mRNA and protein levels. All these DEX-induced changes were significantly (P < 0.05) attenuated in progeny rats derived from betaine-supplemented dams. Furthermore, DEX-induced hypomethylation of ATGL and HSL gene promoters was reversed by maternal betaine supplementation. CONCLUSIONS: Taken together, these results suggest that maternal betaine supplementation is effective in alleviating glucocorticoid-induced lipolysis in adipose tissue with modification of DNA methylation on the promoter of lipolytic genes.
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Tejido Adiposo/efectos de los fármacos , Betaína/farmacología , Metilación de ADN/efectos de los fármacos , Lipólisis/efectos de los fármacos , Lipotrópicos/farmacología , Fenómenos Fisiologicos Nutricionales Maternos/fisiología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Tejido Adiposo/metabolismo , Animales , Betaína/metabolismo , Suplementos Dietéticos , Femenino , Glucocorticoides , Lipotrópicos/metabolismo , Masculino , Embarazo , Sustancias Protectoras/metabolismo , Sustancias Protectoras/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: We have recently shown that binge or heavy levels of alcohol drinking increase deoxyribonucleic acid (DNA) methylation and reduce gene expression of proopiomelanocortin (POMC) and period 2 (PER2) in adult human subjects (Gangisetty et al., Alcohol Clin Exp Res, 43, 2019, 212). One hypothesis would be that methylation of these 2 genes is consistently associated with alcohol exposure and could be used as biomarkers to predict risk of prenatal alcohol exposure (PAE). Results of the present study provided some support for this hypothesis. METHODS: We conducted a series of studies to determine DNA methylation changes in stress regulatory genes proopiomelanocortin (POMC) and period 2 (PER2) using biological samples from 3 separate cohorts of patients: (i) pregnant women who consumed moderate-to-high levels of alcohol or low/unexposed controls, (ii) children with PAE and non-alcohol-exposed controls, and (iii) children with PAE treated with or without choline. RESULTS: We found pregnant women who consumed moderate-to-high levels of alcohol and gave birth to PAE children had higher DNA methylation of POMC and PER2. PAE children also had increased methylation of POMC and PER2. The differences in the gene methylation of PER2 and POMC between PAE and controls did not differ by maternal smoking status. PAE children had increased levels of stress hormone cortisol and adrenocorticotropic hormone. Choline supplementation reduced DNA hypermethylation and increased expression of POMC and PER2 in children with PAE. CONCLUSIONS: These data suggest that PAE significantly elevates DNA methylation of POMC and PER2 and increases levels of stress hormones. Furthermore, these results suggest the possibility that measuring DNA methylation levels of PER2 and POMC in biological samples from pregnant women or from children may be useful for identification of a woman or a child with PAE.
Asunto(s)
Depresores del Sistema Nervioso Central/efectos adversos , Etanol/efectos adversos , Proteínas Circadianas Period/metabolismo , Efectos Tardíos de la Exposición Prenatal , Proopiomelanocortina/metabolismo , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Colina/farmacología , Colina/uso terapéutico , Metilación de ADN/efectos de los fármacos , Suplementos Dietéticos , Epigénesis Genética/efectos de los fármacos , Femenino , Trastornos del Espectro Alcohólico Fetal/metabolismo , Trastornos del Espectro Alcohólico Fetal/prevención & control , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Lipotrópicos/farmacología , Lipotrópicos/uso terapéutico , Masculino , EmbarazoRESUMEN
Dietary supplementation with the major lipotrope myo-inositol (MI) potently reduces triglyceride (TG) content and expression levels of the fatty acid synthesis genes, for example, fatty acid synthase (FASN), in rat nonalcoholic fatty liver induced by high-fructose diet. Fatty acid synthesis genes are regulated by the carbohydrate-responsive element-binding protein (ChREBP) that exists in 2 isoforms: ChREBP-α and ChREBP-ß. The gene encoding the latter isoform is more responsive to fructose. Because MI repressed the induction of fatty acid synthesis gene expression by high-fructose diet, we hypothesized that MI may reduce binding of ChREBP to the carbohydrate response elements (ChoREs) in the ChREBP-ß gene as well as in fatty acid synthesis genes in the liver. Rats were fed high-glucose, high-fructose, or high-fructose diets supplemented with MI (0.05% and 0.25%) for 2â¯weeks. Hepatic TG content and expression levels of the glucose-6-phosphate dehydrogenase, malic enzyme 1, FASN, acetyl-CoA carboxylase alpha, S14, and ChREBP-ß were remarkably elevated in rats fed with high fructose compared with the corresponding levels in high-glucose group. Notably, elevated values of these parameters in high-fructose group were reduced by MI. Similarly, high-fructose-induced ChREBP binding to the ChoREs of the ChREBP-ß and FASN genes was nominally decreased by MI. This study showed that treatment with MI reduced elevated TG content and expression of genes related to fatty acid synthesis, such as FASN and ChREBP-ß, in rat nonalcoholic fatty liver induced by high-fructose diet. Furthermore, MI treatment nominally decreased increased binding of ChREBP to the ChoREs of ChREBP-ß and FASN genes.
Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Acido Graso Sintasa Tipo I/metabolismo , Fructosa/metabolismo , Inositol/farmacología , Hígado/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Triglicéridos/metabolismo , Acetil-CoA Carboxilasa/metabolismo , Animales , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Dieta/efectos adversos , Azúcares de la Dieta/administración & dosificación , Azúcares de la Dieta/efectos adversos , Azúcares de la Dieta/metabolismo , Suplementos Dietéticos , Acido Graso Sintasa Tipo I/genética , Fructosa/administración & dosificación , Fructosa/efectos adversos , Expresión Génica , Glucosafosfato Deshidrogenasa/metabolismo , Inositol/uso terapéutico , Lipogénesis/efectos de los fármacos , Lipotrópicos/farmacología , Lipotrópicos/uso terapéutico , Hígado/metabolismo , Malato Deshidrogenasa/metabolismo , Masculino , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/genética , Proteínas Nucleares/metabolismo , Ratas Wistar , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Leptin acts via its receptor (LepRb) to modulate gene expression in hypothalamic LepRb-expressing neurons, thereby controlling energy balance and glucose homeostasis. Despite the importance of the control of gene expression in hypothalamic LepRb neurons for leptin action, the transcriptional targets of LepRb signaling have remained undefined because LepRb cells contribute a small fraction to the aggregate transcriptome of the brain regions in which they reside. We thus employed translating ribosome affinity purification followed by RNA sequencing to isolate and analyze mRNA from the hypothalamic LepRb neurons of wild-type or leptin-deficient (Lepob/ob) mice treated with vehicle or exogenous leptin. Although the expression of most of the genes encoding the neuropeptides commonly considered to represent the main targets of leptin action were altered only following chronic leptin deprivation, our analysis revealed other transcripts that were coordinately regulated by leptin under multiple treatment conditions. Among these, acute leptin treatment increased expression of the transcription factor Atf3 in LepRb neurons. Furthermore, ablation of Atf3 from LepRb neurons (Atf3LepRbKO mice) decreased leptin efficacy and promoted positive energy balance in mice. Thus, this analysis revealed the gene targets of leptin action, including Atf3, which represents a cellular mediator of leptin action.
Asunto(s)
Factor de Transcripción Activador 3/agonistas , Regulación de la Expresión Génica , Hipotálamo/metabolismo , Leptina/metabolismo , Neuronas/metabolismo , Receptores de Leptina/agonistas , Transducción de Señal , Factor de Transcripción Activador 3/química , Factor de Transcripción Activador 3/genética , Factor de Transcripción Activador 3/metabolismo , Animales , Cruzamientos Genéticos , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patología , Metabolismo Energético/efectos de los fármacos , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Hipotálamo/citología , Hipotálamo/efectos de los fármacos , Hipotálamo/patología , Leptina/análogos & derivados , Leptina/farmacología , Leptina/uso terapéutico , Lipotrópicos/farmacología , Lipotrópicos/uso terapéutico , Masculino , Ratones Noqueados , Ratones Mutantes , Ratones Transgénicos , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/patología , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Obesidad/patología , ARN Mensajero/química , ARN Mensajero/metabolismo , Receptores de Leptina/genética , Receptores de Leptina/metabolismo , Análisis de Secuencia de ARN , Transducción de Señal/efectos de los fármacosRESUMEN
Hyperlipidemia is a chronic disorder which plays an important role in the development of cardiovascular diseases, type 2 diabetes, atherosclerosis, hypertension, and nonalcoholic fatty liver disease. Genipin (GNP) is a metabolite from genipioside, which is an active component of the traditional Chinese medicine Gardenia jasminoides Ellis, and has been recognized as a beneficial compound against metabolic disorders. However, whether it can correct overnutrition-induced dyslipidemia is still unknown. In this study, the effects of GNP on attenuating hyperlipidemia and hepatic lipid accumulation were investigated using normal and obese mice induced with a high-fat diet (HFD) and primary hepatocytes treated with free fatty acids. We also sought to identify potential targets of GNP to mediate its effects in the liver. We found that obese mice treated with GNP showed a decrease in the body weight, serum lipid levels, as well as hepatic lipid accumulation. Besides, GNP regulated hepatic expression levels of lipid metabolic genes, which are important in maintaining systemic lipid homeostasis. At the molecular level, GNP increased the expression levels of miR-142a-5p, which bound to 3' untranslated region of Srebp-1c, an important regulator of lipogenesis, which thus led to the inhibition of lipogenesis. Collectively, our data demonstrated that GNP effectively antagonized HFD-induced hyperlipidemia and hepatic lipid accumulation in mice. Such effects were achieved by regulating miR-142a-5p/SREBP-1c axis.
Asunto(s)
Hiperlipidemias/tratamiento farmacológico , Iridoides/uso terapéutico , Metabolismo de los Lípidos/efectos de los fármacos , Lipotrópicos/uso terapéutico , Hígado/efectos de los fármacos , MicroARNs/agonistas , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Animales , Fármacos Antiobesidad/administración & dosificación , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/uso terapéutico , Células Cultivadas , Biología Computacional , Dieta Alta en Grasa/efectos adversos , Relación Dosis-Respuesta a Droga , Ácidos Grasos no Esterificados/efectos adversos , Ácidos Grasos no Esterificados/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Genes Reporteros/efectos de los fármacos , Hiperlipidemias/etiología , Hiperlipidemias/metabolismo , Hiperlipidemias/patología , Resistencia a la Insulina , Iridoides/administración & dosificación , Iridoides/farmacología , Lipotrópicos/administración & dosificación , Lipotrópicos/farmacología , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/tratamiento farmacológico , Obesidad/etiología , Obesidad/metabolismo , Obesidad/patología , Distribución Aleatoria , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/agonistas , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismoRESUMEN
BACKGROUND: Deficiency of choline, a required nutrient, is related to intestinal failure-associated liver disease (IFALD). Therefore, we aimed to investigate the effects of choline supplementation on IFALD and the underlying mechanisms. METHODS: Male Sprague-Dawley rats (4 weeks old) were fed AIN-93G chow and administered intravenous 0.9% saline (control), parenteral nutrition (PN), or PN plus intravenous choline (600 mg/kg) for 7 days. We evaluated body weight, hepatic histology, biochemical indicators, triglycerides, oxidative status, methylation levels of peroxisomal proliferator-activated receptor alpha (PPARα) gene promoter, expression of PPARα and carnitine palmitoyltransferase 1 (CPT1), and levels of choline metabolites. RESULTS: The PN + choline group exhibited improved body weight compared with the PN group. PN impaired hepatic function, increased hepatic triglycerides, induced dyslipidemia, enhanced reactive oxygen species and malondialdehyde, and reduced total antioxidant capacity. The PN group had higher pathologic scores than the control group. These results were prevented by choline administration. Compared with the control group, PN increased PPARα promoter methylation and hepatic betaine concentration, reduced hepatic choline and phosphatidylcholine (PC) levels, decreased plasma choline and betaine concentrations, and downregulated PPARα and CPT1 mRNA and protein expression. Choline supplementation elevated hepatic choline and PC levels and enhanced plasma choline, betaine, and PC concentrations but reduced hepatic betaine level, reversed PPARα promoter hypermethylation, and upregulated PPARα and CPT1 mRNA and protein expression in PN-fed rats, compared with rats receiving PN alone. CONCLUSION: Choline addition to PN may prevent IFALD by reducing oxidative stress, enhancing hepatic fat export, and promoting fatty acid catabolism in immature rats receiving PN.
Asunto(s)
Colina/farmacología , Enfermedades Intestinales/prevención & control , Lipotrópicos/farmacología , Nutrición Parenteral/métodos , Animales , Colina/administración & dosificación , Modelos Animales de Enfermedad , Intestinos/efectos de los fármacos , Lipotrópicos/administración & dosificación , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
PURPOSE: We aim to study the effect of neurodegeneration on the brain of rat pups caused by prenatal and postnatal ethanol exposure with modified liquid diet to elucidate protective effects of betaine and omega-3 supplementation. When ethanol is consumed during prenatal and postnatal periods, it may result in fetal alcohol syndrome (FAS) in the offspring. METHODS: Rats were divided into control, ethanol, ethanol + betaine, ethanol + omega-3, ethanol + omega-3 + betaine groups. The effect of betaine and omega-3 in response to ethanol-induced changes on the brain, by biochemical analyses cytochrome c, caspase-3, calpain, cathepsin B and L, DNA fragmentation, histological and morfometric methods were evaluated. RESULTS: Caspase-3, calpain, cathepsin B, and cytochrome c levels in ethanol group were significantly higher than control. Caspase-3, calpain levels were decreased in ethanol + betaine, ethanol + omega-3, and ethanol + omega-3 + betaine groups compared to ethanol group. Cathepsin B in ethanol + omega-3 + betaine group was decreased compared to ethanol, ethanol + betaine groups. Cathepsin L and DNA fragmentation were found not statistically significant. We found similar results in histological and morfometric parameters. CONCLUSION: We found that pre- and postnatal ethanol exposure is capable of triggering necrotic cell death in rat brains, omega-3, and betaine reduce neurodegeneration. Omega-3 and betaine may prove beneficial for neurodegeneration, particularly in preventing FAS.
Asunto(s)
Betaína/farmacología , Depresores del Sistema Nervioso Central/toxicidad , Etanol/toxicidad , Ácidos Grasos Omega-3/farmacología , Degeneración Nerviosa/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Animales , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Lipotrópicos/farmacología , Degeneración Nerviosa/prevención & control , Embarazo , Efectos Tardíos de la Exposición Prenatal/prevención & control , Ratas , Ratas Sprague-DawleyRESUMEN
Choline is a water-soluble essential nutrient included as a member of the vitamin B12 group owing to its structural similarities with that of the other members of the group. Its roles and functions, however, extend much wider than that of the vitamins with which it is grouped. Choline is vital for maintenance of various key metabolic processes which play a role in the prevention or progression of various health impairments. The occurrence of diseases like neural tube defect (NTD) and Alzheimer's is prevented by the metabolic role of choline. It is also indispensable for mitigation of various forms of toxic contamination. While adequate level of choline in the body is essential, an excess of choline can result in various forms of disorder. To maintain the optimal level of choline in the body can be a challenge. The vital roles played by choline together with the range of contradictions and problems that choline presents make choline an interesting area of study. This paper attempts to summarize and review some recent publications on choline that have opened up new prospect in understanding the multiple role played by choline and in throwing light on the role played by this wonder essential nutrient in mitigating various forms of toxic contamination.
Asunto(s)
Colina/farmacología , Suplementos Dietéticos , Enfermedades Metabólicas/prevención & control , Necesidades Nutricionales/fisiología , Humanos , Lipotrópicos/farmacologíaRESUMEN
Respiratory allergic disease is an inflammatory condition accompanied by oxidative stress. Supplementation of an anti-inflammatory agent with antioxidants may have a therapeutic effect. In this study, the effects of choline chloride in combination with antioxidants were evaluated via the intranasal route in a mouse model of allergic airway disease. Balb/c mice were sensitized on days 0, 7, and 14 and challenged on days 25-30 with cockroach extract (CE) and with a booster challenge on day 38. They were treated with choline chloride (ChCl; 1mg/kg), vitamin C (Vit C; 308.33 mg/kg), and selenium (Se; 1mg/kg) alone or in combination via the intranasal route on days 31, 33, 35, 37, and 39. The mice were sacrificed on day 40 to collect blood, bronchoalveolar lavage fluid, lungs, and spleen. Mice immunized with CE showed a significant increase in airway hyperresponsiveness (AHR), lung inflammation, Th2 cytokines, and the oxidative stress markers intracellular reactive oxygen species and 8-isoprostanes compared to the phosphate-buffered saline control group. A significant decrease was observed in these parameters with all the treatments (p<0.01). The highest decrease was noticed in the ChCl+Vit C+Se-treated group, with AHR decreased to the normal level. This group also showed the highest decrease in airway inflammation (p<0.001), IL-4 and IL-5 (p<0.001), IgE and IgG1 (p<0.001), NF-κB (p<0.001), and 8-isoprostane levels (p<0.001). Glutathione peroxidase activity, which was decreased significantly in CE-immunized mice, was restored to normal levels in this group (p<0.001). IL-10 level was decreased in CE-immunized mice and was restored to normal by combination treatment. The combination treatment induced FOXP3(+) cells in splenocyte culture, responsible for the upregulation of IL-10. In conclusion, the combination of choline chloride, vitamin C, and selenium via the intranasal route reduces AHR, inflammation, and oxidative stress, probably by causing IL-10 production by FOXP3(+) cells, and possesses therapeutic potential against allergic airway disease.
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Ácido Ascórbico/farmacología , Asma/tratamiento farmacológico , Colina/farmacología , Hipersensibilidad Respiratoria/tratamiento farmacológico , Selenio/farmacología , Administración Intranasal , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Asma/inmunología , Líquido del Lavado Bronquioalveolar/química , Cucarachas/inmunología , Dinoprost/análogos & derivados , Dinoprost/metabolismo , Combinación de Medicamentos , Peroxidasa del Eosinófilo/metabolismo , Glutatión Peroxidasa/metabolismo , Inmunoglobulina E/inmunología , Inmunoglobulina G/inmunología , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Interleucina-10/inmunología , Interleucina-4/inmunología , Interleucina-5/inmunología , Lipotrópicos/farmacología , Pulmón/enzimología , Ratones , Ratones Endogámicos BALB C , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Hipersensibilidad Respiratoria/inmunología , Bazo/enzimología , Células Th2/inmunología , Factor de Transcripción ReIA/metabolismoRESUMEN
UNLABELLED: Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various PPAR agonists, i.e. fenofibrate, bezafibrate, troglitazone, rosiglitazone, muraglitazar and tesaglitazar on oleic acid-induced steatotic HepaRG cells were investigated after a single 24-hour or 2-week repeat treatment. Lipid vesicles stained by Oil-Red O and triglycerides accumulation caused by oleic acid overload, were decreased, by up to 50%, while fatty acid oxidation was induced after 2-week co-treatment with PPAR agonists. The greatest effects on reduction of steatosis were obtained with the dual PPARα/γ agonist muraglitazar. Such improvement of steatosis was associated with up-regulation of genes related to fatty acid oxidation activity and down-regulation of many genes involved in lipogenesis. Moreover, modulation of expression of some nuclear receptor genes, such as FXR, LXRα and CAR, which are potent actors in the control of lipogenesis, was observed and might explain repression of de novo lipogenesis. CONCLUSION: Altogether, our in vitro data on steatotic HepaRG cells treated with PPAR agonists correlated well with clinical investigations, bringing a proof of concept that drug-induced reversal of steatosis in human can be evaluated in in vitro before conducting long-term and costly in vivo studies in animals and patients.
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Hígado Graso/tratamiento farmacológico , Metabolismo de los Lípidos/efectos de los fármacos , Lipotrópicos/farmacología , Hígado/efectos de los fármacos , Receptores Activados del Proliferador del Peroxisoma/agonistas , Línea Celular , Receptor de Androstano Constitutivo , Evaluación Preclínica de Medicamentos , Ácidos Grasos no Esterificados/efectos adversos , Hígado Graso/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Glicina/análogos & derivados , Glicina/farmacología , Humanos , Lipogénesis/efectos de los fármacos , Hígado/metabolismo , Receptores X del Hígado , Enfermedad del Hígado Graso no Alcohólico , Ácido Oléico/efectos adversos , Receptores Nucleares Huérfanos/antagonistas & inhibidores , Receptores Nucleares Huérfanos/genética , Receptores Nucleares Huérfanos/metabolismo , Oxazoles/farmacología , Oxidación-Reducción , PPAR alfa/agonistas , PPAR alfa/metabolismo , PPAR gamma/agonistas , PPAR gamma/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Triglicéridos/metabolismoRESUMEN
An experiment was conducted to evaluate the role of different lipotropes in modulating immunity and biochemical plasticity under conditions of sublethal low-dose pesticide-induced stress in fish. Labeo rohita fish fingerlings were divided in two sets with one set of fish continuously exposed to low-dose endosulfan (1/10th of 96-h LC50) for 21 days, the other was unexposed, and both sets of fish were fed with practical diets supplemented with either 2 % lecithin, 0.5 % betaine, or 0.1 % choline and compared against unsupplemented diet. Low-dose endosulfan exposure had adverse effects (P < 0.05/P < 0.01) on hematological profile (erythrocyte count, hemoglobin, and hematocrit), serum protein (total protein, albumin, and globulin) and lipid profile (cholesterol and triglyceride), anti-oxidative status (ascorbic acid content of muscle, liver, brain, and kidney and activity of anti-oxidative enzymes: catalase and superoxide dismutase), neurotransmission (acetylcholinesterase activity in muscle and brain), immunological attributes (WBC count, albumin to globulin ratio, phagocytic activity, and serum cortisol), and metabolic plasticity as revealed from enzyme activities (muscle lactate dehydrogenase, liver and kidney glucose-6-phosphatase dehydrogenase-G6PDH activity). Dietary lipotropes prevented these effects completely or partially and the effects were lipotrope dependent. Kinetics (maximum velocity value V max, catalytic efficiency and Michaelis constant K m) of G6PDH enzyme from crude extracts of liver and kidney indicated inhibition due to endosulfan but lipotropes could protect enzyme and showed a stabilizing effect. The supplements also helped maintain integrity of histoarchitecture of the hepatocytes in endosulfan-exposed fish to a great extent. Feeding lipotropes to fish reared in endosulfan-free water also improved hematological and serum protein and lipid profiles and were immunostimulatory. In conclusion, dietary lipotropes, especially betaine and lecithin at the levels used, improve erythropoiesis, serum protein and lipid profile, anti-oxidant status, immunocompetence, neurotransmission, and protect the livers of L. rohita fingerlings even when continuously exposed to low-dose endosulfan.
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Endosulfano/toxicidad , Peces/fisiología , Lipotrópicos/farmacología , Estrés Oxidativo/efectos de los fármacos , Plaguicidas/toxicidad , Animales , Proteínas Sanguíneas/metabolismo , Suplementos Dietéticos , Peces/metabolismo , Glucosafosfato Deshidrogenasa/metabolismo , Cinética , Hígado/enzimología , Hígado/metabolismo , Hígado/patologíaRESUMEN
Increased consumption of plant products is associated with lower chronic disease prevalence. This is attributed to the great diversity of healthy phytochemicals present in these foods. The most investigated physiological effects have been their antioxidant, anti-carcinogenic, hypolipidemic, and hypoglycemic properties. Although less studied in humans, some compounds were very early on shown to be lipotropic in animals, i.e., the capacity to hasten the removal of fat from liver and/or reduce hepatic lipid synthesis or deposits by mainly increasing phospholipid synthesis via the transmethylation pathway for triglyceride-rich lipoprotein exportation from the liver and enhanced fatty acid ß-oxidation and/or down- and up-regulation of genes involved in lipogenic and fatty acid oxidation enzyme synthesis, respectively. The main plant lipotropes are choline, betaine, myo-inositol, methionine, and carnitine. Magnesium, niacin, pantothenate, and folates also indirectly support the overall lipotropic effect. The exhaustive review of rat studies investigating phytochemical effect on hepatic lipid metabolism suggests that some fatty acids, acetic acid, melatonin, phytic acid, some fiber compounds, oligofructose, resistant starch, some phenolic acids, flavonoids, lignans, stilbenes, curcumin, saponins, coumarin, some plant extracts, and some solid foods may be lipotropic. However, this remains to be confirmed in humans, for whom intervention studies are practically non-existent. Supplemental materials are available for this article. Go to the publisher's online edition of Critical Reviews in Food Science and Nutrition® to view the free supplemental file.
Asunto(s)
Lipotrópicos/farmacología , Extractos Vegetales/farmacología , Plantas Comestibles/química , Animales , Enfermedad Crónica/prevención & control , Bases de Datos Factuales , Dieta Vegetariana , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , MetabolómicaRESUMEN
BACKGROUND: Phosphatidylcholine (PC) produced via the S-adenosylmethionine-dependent phosphatidylethanolamine (PE) N-methyltransferase (PEMT) pathway is enriched with docosahexaenoic acid (DHA). DHA plays a critical role in fetal development and is linked to health endpoints in adulthood. It is unknown whether choline, which can serve as a source of S-adenosylmethionine methyl groups, influences PC-DHA or the PC:PE ratio in pregnant and nonpregnant women. OBJECTIVE: This study tested whether choline intake affects indicators of choline-related lipid metabolism, including erythrocyte and plasma PC-DHA and PC:PE ratios, in pregnant women in the third trimester and nonpregnant women. DESIGN: Pregnant (n = 26) and nonpregnant (n = 21) women consumed 480 or 930 mg choline/d and a daily DHA supplement for 12 wk. Blood was collected at baseline and at the midpoint and end of the study. PC-DHA was analyzed as the proportion of total PC fatty acids. RESULTS: Pregnant women had greater (P = 0.002) PC-DHA concentrations than did nonpregnant women at baseline. The proportion of erythrocyte and plasma PC-DHA increased (P ≤ 0.002) in pregnant and nonpregnant women regardless of choline intake. However, in nonpregnant women, consumption of 930 mg choline/d led to greater (P < 0.001) erythrocyte PC-DHA and a more rapid increase (P < 0.001) in plasma PC-DHA. Lower (P = 0.001-0.024) erythrocyte and plasma PC:PE in pregnant women was not modified by choline intake. CONCLUSIONS: A higher choline intake may increase PEMT activity, resulting in greater PC-DHA enrichment of the PC molecule in nonpregnant women. Increased production of PC-DHA during pregnancy indicates elevated PEMT activity and a higher demand for methyl donors. This trial was registered at clinicaltrials.gov as NCT01127022.
Asunto(s)
Colina/farmacología , Suplementos Dietéticos , Ácidos Docosahexaenoicos/sangre , Metabolismo de los Lípidos/efectos de los fármacos , Lipotrópicos/farmacología , Fosfatidilcolinas/sangre , Embarazo/sangre , Eritrocitos/metabolismo , Femenino , Humanos , Fosfatidiletanolamina N-Metiltransferasa/metabolismo , Fosfatidiletanolaminas/sangre , Embarazo/metabolismo , Tercer Trimestre del EmbarazoRESUMEN
BACKGROUND: Betaine is a methyl donor and has been considered as a lipotropic effect substance. But its mechanism remains unclear. Hepatic steatosis is associated with abnormal expression of genes involved in hepatic lipid metabolism. DNA methylation contributes to the disregulation of gene expression. Here we hypothesized that betaine supplement and subsequent DNA methylation modifications alter the expression of genes that are involved in hepatic lipid metabolism and hence alleviate hepatic triglyceride accumulation. METHODS: Male wild-type (WT) C57BL/6 mice (n = 6) were fed with the AIN-93 G diet. ApoE-/- mice (n = 12), weight-matched with the WT mice, were divided into two groups (n = 6 per group), and fed with the AIN-93 G diet and AIN-93 G supplemented with 2% betaine/100 g diet. Seven weeks after the intervention, mice were sacrificed. Liver betaine, choline, homocysteine concentration were measured by HPLC. Liver oxidants activity and triglyceride level were assessed by ultraviolet spectrophotometry. Finally, hepatic PPAR alpha gene and its target genes expression levels and the methylation status of the PPAR alpha gene were determined. RESULTS: ApoE-/- mice had higher hepatic triglyceride and lower GSH-Px activity when compared with the WT mice. Betaine intervention reversed triglyceride deposit, enhanced SOD and GSH-Px activity in the liver. Interestingly, mice fed on betaine-supplemented diet showed a dramatic increase of hepatic choline concentration and a decrease of betaine and homocysteine concentration relative to the WT mice and the ApoE-/- mice absent with betaine intervention. Expression of PPAR alpha and CPT1 were decreased and expression of FAS was markedly increased in ApoE-/- mice. In parallel, PPAR alpha promoter methylation level were slightly increased in ApoE-/- mice though without significance. Betaine supplement upregulated expression of PPAR alpha and its target genes (CPT1, CYP2E1) and reversed hypermethylation of PPAR alpha promoter of ApoE-/- mice. Furthermore, PPAR alpha methylation was positively correlated with hepatic betaine concentration. CONCLUSIONS: Our findings indicate that betaine supplement could alleviate hepatic triglyceride accumulation and improve antioxidant capacity by decreasing PPAR alpha promoter methylation and upregulating PPAR alpha and its target genes mRNA expression.
Asunto(s)
Betaína/farmacología , Metilación de ADN/efectos de los fármacos , Metabolismo de los Lípidos/genética , Lipotrópicos/farmacología , Hígado/efectos de los fármacos , PPAR alfa/genética , Triglicéridos/metabolismo , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Colina/metabolismo , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Acido Graso Sintasa Tipo I/genética , Acido Graso Sintasa Tipo I/metabolismo , Alimentos Formulados , Regulación de la Expresión Génica/efectos de los fármacos , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Homocisteína/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , PPAR alfa/antagonistas & inhibidores , PPAR alfa/metabolismo , Regiones Promotoras Genéticas/efectos de los fármacos , Transducción de Señal , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismoRESUMEN
In two experiments adult rats were maintained on a diet enriched with added choline for 12 weeks prior to behavioral testing; control rats remained on the standard diet during this time. In Experiment 1 all rats received training in the Hall-Pearce negative transfer paradigm in which prior training with a conditioned stimulus (CS) paired with a small reinforcer retards further learning when the size of the reinforcer is increased. This effect, which has been attributed to a loss of associability by the CS, was obtained in control subjects but not in those given the supplement. Experiment 2 investigated the effect of prior nonreinforced exposure of the to-be-CS (latent inhibition). Such exposure retarded subsequent learning in control subjects, but latent inhibition was not obtained in those given the supplement. We conclude that the mechanism that reduces the attention paid to a stimulus that accurately predicts its consequences does not operate effectively after choline supplementation. These results are consistent with a role for the cholinergic system of the basal forebrain in modulation of attention.
Asunto(s)
Atención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Colina/farmacología , Condicionamiento Clásico/efectos de los fármacos , Lipotrópicos/farmacología , Animales , Colina/administración & dosificación , Inhibición Psicológica , Lipotrópicos/administración & dosificación , Masculino , Pruebas Psicológicas , Ratas , Ratas WistarRESUMEN
Hyperhomocysteinemia (Hhcy) may induce memory deficits with ß-amyloid (Aß) accumulation and tau hyperphosphorylation. Simultaneous supplement of folate and vitamin B12 partially restored the plasma homocysteine level and attenuated tau hyperphosphorylation, Aß accumulation and memory impairments induced by Hhcy. However, folate and vitamin B12 treatment have no effects on Hhcy which has the methylenetetrahydrofolate reductase genotype mutation. In this study, we investigated the effects of simultaneous supplement of betaine on Alzheimer-like pathological changes and memory deficits in hyperhomocysteinemic rats after a 2-week induction by vena caudalis injection of homocysteine (Hcy). We found that supplementation of betaine could ameliorate the Hcy-induced memory deficits, enhance long-term potentiation (LTP) and increase dendritic branches numbers and the density of the dendritic spines, with up-regulation of NR1, NR2A, synaptotagmin, synaptophysin, and phosphorylated synapsin I protein levels. Supplementation of betaine also attenuated the Hcy-induced tau hyperphosphorylation at multiple AD-related sites through activation protein phosphatase-2A (PP2A) with decreased inhibitory demethylated PP2A(C) at Leu309 and phosphorylated PP2A(C) at Tyr307. In addition, supplementation of betaine also decreased Aß production with decreased presenilin-1 protein levels. Our data suggest that betaine could be a promising candidate for arresting Hcy-induced AD-like pathological changes and memory deficits.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Betaína/toxicidad , Homocisteína/toxicidad , Hiperhomocisteinemia/tratamiento farmacológico , Trastornos de la Memoria/tratamiento farmacológico , Enfermedad de Alzheimer/sangre , Animales , Modelos Animales de Enfermedad , Homocisteína/sangre , Hiperhomocisteinemia/inducido químicamente , Lipotrópicos/farmacología , Masculino , Trastornos de la Memoria/inducido químicamente , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: The use of betaine as a dietary supplement to reduce fat deposition and increase lean muscle mass in pigs is increasing. However, there is no available information on its effect on the physical and chemical (i.e. fatty acid (FA) profile) characteristics of pork. RESULTS: The effects of long-term betaine intake (1 g betaine kg(-1) diet for 20 weeks) on the chemical and physical characteristics of Musculus longissimus dorsi, M. biceps femoris and M. semimembranosus from the Alentejano pig were investigated. The contents of total protein, intramuscular lipids (neutral and polar), myoglobin and total collagen as well as the water-holding capacity, physical colour characteristics and FA profile of the three muscles were determined. With the exception of a significant increase in the intramuscular lipid content of M. longissimus dorsi and M. biceps femoris, betaine supplementation did not influence muscle chemical and colour characteristics or body fat deposition. CONCLUSION: These data suggest that long-term betaine supplementation selectively increases intramuscular lipid deposition (a trait related to meat quality) while not affecting other chemical (including the atheroprotective FA profile) and physical characteristics of the Alentejano pig muscles studied.
Asunto(s)
Betaína/farmacología , Suplementos Dietéticos , Lipotrópicos/farmacología , Carne/análisis , Músculo Esquelético/efectos de los fármacos , Tejido Adiposo/efectos de los fármacos , Animales , Cruzamiento , Color , Ácidos Grasos/metabolismo , Músculo Esquelético/metabolismo , PorcinosRESUMEN
BACKGROUND: To elucidate whether rice protein can possess a vital function in improving lipids level and adiposity, the effects of rice proteins extracted by alkaline (RP-A) and α-amylase (RP-E) on triglyceride metabolism were investigated in 7-week-old male Wistar rats fed cholesterol-enriched diets for 2 weeks, as compared with casein (CAS). RESULTS: Compared with CAS, plasma concentrations of glucose and lipids were significantly reduced by RP-feeding (P < 0.05), as well as hepatic accumulation of lipids (P < 0.05). RP-A and RP-E significantly depressed the hepatic activities of fatty acid synthase (FAS), glucose 6-phosphate dehydrogenase (G6PD) and malate dehydrogenase (MDH) (P < 0.05), whereas the activities of lipoprotein lipase (PL) and hepatic lipase (HL) were significantly stimulated (P < 0.05), as compared to CAS. Neither lipids level nor activities of enzymes were different between RP-A and RP-E (P > 0.05). There was a significant positive correlation between protein digestibility and deposit fat (r = 0.8567, P < 0.05), as well as the plasma TG concentration (r = 0.8627, P < 0.05). CONCLUSIONS: The present study demonstrates that rice protein can modify triglyceride metabolism, leading to an improvement of body weight and adiposity. Results suggest that the triglyceride-lowering action as well as the potential of anti-adiposity induced by rice protein is attributed to upregulation of lipolysis and downregulation of lipogenesis, and the lower digestibility of rice protein may be the main modulator responsible for the lipid-lowering action.
Asunto(s)
Adiposidad/efectos de los fármacos , Fármacos Antiobesidad/farmacología , Lípidos/sangre , Lipotrópicos/farmacología , Oryza/química , Extractos Vegetales/farmacología , Proteínas de Plantas/farmacología , Triglicéridos/metabolismo , Pérdida de Peso/efectos de los fármacos , Alanina Transaminasa/sangre , Aminoácidos/sangre , Animales , Fármacos Antiobesidad/aislamiento & purificación , Aspartato Aminotransferasas/sangre , Dieta Alta en Grasa , Heces/química , Lipogénesis/efectos de los fármacos , Lipólisis/efectos de los fármacos , Lipotrópicos/aislamiento & purificación , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Masculino , Extractos Vegetales/aislamiento & purificación , Proteínas de Plantas/aislamiento & purificación , Ratas , Ratas WistarRESUMEN
The weight loss observed in consumers of extracts of Citrus aurantium (bitter orange) has been tentatively attributed to the lipolytic and thermogenic effects of the alkaloids abundant in the unripe fruit. Synephrine, octopamine, tyramine, and other alkaloids have been repeatedly identified and quantified in Citrus members of the Rutaceae family or in their extracts incorporated in dietary supplements for weight management. However, there are only scarce reports on their lipolytic action. This study aimed at comparing the acute lipolytic activity of synephrine, octopamine, tyramine, and N-methyltyramine in rat and human adipocytes. Maximal response to the prototypical ß-adrenergic agonist isoprenaline was taken as reference in both species. In rat, octopamine was slightly more active than synephrine while tyramine and N-methyl tyramine did not stimulate-and even inhibited-lipolysis. In human adipocytes, none of these amines stimulated lipolysis when tested up to 10 µg/ml. At higher doses (≥100 µg/ml), tyramine and N-methyl tyramine induced only 20% of the maximal lipolysis and exhibited antilipolytic properties. Synephrine and octopamine were partially stimulatory at high doses. Since synephrine is more abundant than octopamine in C. aurantium, it should be the main responsible for the putative lipolytic action of the extracts claimed to mitigate obesity. Noteworthy, their common isopropyl derivative, isopropylnorsynephrine (also named isopropyloctopamine or betaphrine), was clearly lipolytic: active at 1 µg/ml and reproducing more than 60% of isoprenaline maximal effect in human adipocytes. This compound, not detected in C. aurantium, and which has few reported adverse effects to date, might be useful for in vivo triglyceride breakdown.
Asunto(s)
Adipocitos Blancos/efectos de los fármacos , Citrus/química , Lipólisis/efectos de los fármacos , Lipotrópicos/farmacología , Octopamina/análogos & derivados , Extractos Vegetales/farmacología , Sinefrina/farmacología , Adipocitos Blancos/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Animales , Epinefrina/farmacología , Femenino , Glucosa/metabolismo , Humanos , Isoproterenol/farmacología , Monoaminooxidasa/metabolismo , Octopamina/química , Octopamina/farmacología , Oxidación-Reducción , Ratas , Ratas Wistar , Tiramina/análogos & derivados , Tiramina/farmacologíaRESUMEN
Our previous studies, demonstrating ethanol-induced alterations in phosphatidylcholine (PC) synthesis via the phosphatidylethanolamine methyltransferase (PEMT) pathway, implicated a defect in very low-density lipoprotein (VLDL) secretion in the pathogenesis of hepatic steatosis. The objective of this study was to determine whether VLDL secretion was reduced by chronic ethanol consumption and whether betaine supplementation, that restores PEMT activity and prevents the development of alcoholic steatosis, could normalize VLDL secretion. The VLDL secretion in rats fed with control, ethanol and the betaine supplemented diets was determined using Triton WR-1339 to inhibit plasma VLDL metabolism. We observed reduced VLDL production rates in chronic alcohol-fed rats compared to control animals. Supplementation of betaine in the ethanol diet increased VLDL production rate to values significantly higher than those observed in the control diet-fed rats. To conclude, chronic ethanol consumption impairs PC generation via the PEMT pathway resulting in diminished VLDL secretion which contributes to the development of hepatic steatosis. By increasing PEMT-mediated PC generation, betaine results in increased fat export from the liver and attenuates the development of alcoholic fatty liver.