RESUMEN
Background: Rosa mosqueta (RM) oil is characterized by high concentrations of antioxidants and α-linolenic acid (ALA; 18:3n-3). We have previously demonstrated in male C57BL/6J mice that RM decreases hepatic steatosis, a condition strongly associated with oxidative stress and inflammation.Objective: We studied the molecular mechanisms that underlie the role of RM in preventing high-fat diet (HFD)-induced oxidative stress and inflammation.Methods: Male C57BL/6J mice aged 28 d and weighing 12-14 g were divided into the following groups and fed for 12 wk: control diet (CD; 10% fat, 20% protein, and 70% carbohydrates); CD + RM (1.94 mg ALA â g body weight-1 â d-1 administered by oral gavage); HFD (60% fat, 20% protein, and 20% carbohydrates); and HFD + RM. General parameters (body weight, visceral fat, and histology); glucose metabolism [homeostasis model assessment and blood glucose area under the curve (AUC)]; oxidative stress [hepatic nuclear factor (erythroid-derived 2)-like-2 (NRF2) and heme oxygenase 1 (HO-1) concentrations]; and inflammation [hepatic peroxisome proliferator-activated receptor α (PPAR-α) and acyl-coenzyme A oxidase 1 (ACOX1) concentrations, blood tumor necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß) concentrations, and Tnfa and Il1b mRNA expression in liver and visceral adipose tissue] were evaluated.Results: In the HFD + RM mice, the final body weight (24.8 ± 1.1 g) was 19% lower than in the HFD mice (30.6 ± 2.8 g) (P < 0.05). Visceral fat was 34% lower in the HFD + RM mice than in the HFD mice (P < 0.05). The blood glucose AUC was 29% lower and Tnfa and Il1b expression levels were 47% and 59% lower, respectively, in the HFD + RM mice than in the HFD mice (P < 0.05). HFD + RM mice had 40% less hepatic steatosis (P < 0.05) and lower upregulation of PPAR-α (33%), ACOX1 (50%), NRF2 (39%), and HO-1 (68%) protein concentrations than did the HFD mice (P < 0.05).Conclusions: Our findings suggest that RM supplementation prevents the obese phenotype observed in HFD-fed mice by downregulating inflammatory cytokine expression and secretion and stimulating hepatic antioxidant and fatty acid oxidation markers.
Asunto(s)
Inflamación/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , PPAR alfa/metabolismo , Aceites de Plantas/farmacología , Rosa/química , Animales , Glucemia , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/efectos adversos , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Insulina/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , PPAR alfa/genética , Aceites de Plantas/química , Regulación hacia ArribaRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is triggered by a nutritional-metabolic alteration characterized by triacylglicerides acumulation, insulin resistance (IR), oxidative stress and depletion of polyunsaturated fatty acid (PUFA). The n-3 PUFA, such as eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, would be hepatoprotective against the development of NAFLD by stimulating lipolysis and inhibit lipogenesis. So, fish oil supplementation (EPA + DHA) prevents HFD-induced NAFLD. In this context, the aim of this study is to evaluate the correlation between liver oxidative stress with IR and levels of PUFA in supplemented mice. Male mice C57BL/6J (n = 9) were fed for 12th week: a) control diet (20% protein, 70% carbohydrate, 10% lipids), b) control diet and fish oil supplementation (200 mg EPA+DHA/kg/day), c) high fat diet (20% protein, 20% carbohydrate, 60% lipids), and d) high fat diet and fish oil supplementation. Liver steatosis (histology), insulin resistance (HOMA), liver oxidative stress (GSH/GSSG, carbonyl protein and 8-isoprostanes) and liver fatty acid content were evaluated. The significant decrease in liver oxidative stress parameters (p < 0.05, ANOVA followed by Newman Keuls test) were correlated (Pearson test) with HOMA and levels of PUFA, along with the hepatoprotection observed. It concludes that prevention of NAFLD by supplementation with fish oil (EPA+DHA) is dependent of the prevention of liver oxidative stress, IR and PUFA depletion.
Asunto(s)
Grasas Insaturadas en la Dieta/administración & dosificación , Suplementos Dietéticos , Hígado Graso/prevención & control , Aceites de Pescado/administración & dosificación , Resistencia a la Insulina/fisiología , Estrés Oxidativo/fisiología , Animales , Hígado Graso/metabolismo , Hígado Graso/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no AlcohólicoRESUMEN
OBJECTIVES: The aim of this study was to evaluate the effect of the dietary supplementation of an alpha- and gamma-tocopherol mixture (1:5 ratio) in the adipose tissue expansion, hepatic steatosis, and expression of inflammatory markers induced by consumption of a high-fat diet (HFD) in mice. METHODS: Male C57BL/6 J mice were fed for 12 wk and divided into the following: 1) control diet (CD; 10% fat, 20% protein, 70% carbohydrates); 2) CD + TF (CD plus alpha-tocopherol: 0.7 mg/kg/d, gamma-tocopherol: 3.5 mg/kg/d); 3) HFD (60% fat, 20% protein, 20% carbohydrates); and 4) HFD + TF (HFD plus alpha-tocopherol: 0.7 mg/kg/d, gamma-tocopherol: 3.5 mg/kg/d). General parameters, adipocyte size, liver steatosis, adipose and hepatic tumor necrosis factor-α (TNF-α) and interleukin-1 ß (IL-1ß) expression, hepatic nuclear factor kappa B (NF-κB), and peroxisome proliferator-activated receptor α (PPAR-α) levels were evaluated. RESULTS: Tocopherol supplementation in HFD-fed mice showed a significant decrease in the body weight (19%) and adipose tissue weight (52%), adipose tissue/body weight ratio (36%), and serum triacylglycerols (56%); a 42% decrease (P < 0.05) of adipocyte size compared to HFD; attenuation of liver steatosis by decreasing (P < 0.05) lipid vesicles presence (90%) and total lipid content (75%); and downregulation of inflammatory markers (TNF-α and IL-1ß), along with an upregulation of hepatic PPAR-α expression and its downstream-regulated genes (ACOX and CAT-1), and an inhibition of hepatic NF-κB activation. CONCLUSION: The present study suggests that alpha- and gamma-tocopherol (1:5 ratio) supplementation attenuates the adipocyte enlargement, hepatic steatosis, and metabolic inflammation induced by HFD in association with PPAR-α/NF-κB modulation.
Asunto(s)
Dieta Alta en Grasa , Hígado Graso , Tejido Adiposo , Animales , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos , Modelos Animales de Enfermedad , Hígado Graso/etiología , Hígado Graso/prevención & control , Hígado , Masculino , Ratones , Ratones Endogámicos C57BL , Expansión de Tejido , gamma-Tocoferol/farmacologíaRESUMEN
The administration of iron induces liver oxidative stress and depletion of long-chain polyunsaturated fatty acids (LCPUFAs), n-6/n-3 LCPUFA ratio enhancement and fat accumulation, which may be prevented by antioxidant-rich extra virgin olive oil (AR-EVOO) supplementation. Male Wistar rats were subjected to a control diet (50 mg iron/kg diet) or iron-rich diet (IRD; 200 mg/kg diet) with alternate AR-EVOO for 21 days. Liver fatty acid (FA) analysis was performed by gas-liquid chromatography (GLC) after lipid extraction and fractionation, besides Δ-5 desaturase (Δ-5 D) and Δ6-D mRNA expression (qPCR) and activity (GLC) measurements. The IRD significantly (p < 0.05) increased hepatic total fat, triacylglycerols, free FA contents and serum transaminases levels, with diminution in those of n-6 and n-3 LCPUFAs, higher n-6/n-3 ratios, lower unsaturation index and Δ5-D and Δ6-D activities, whereas the mRNA expression of both desaturases was enhanced over control values, changes that were prevented by concomitant AR-EVOO supplementation. N-6 and n-3 LCPUFAs were also decreased by IRD in extrahepatic tissues and normalized by AR-EVOO. In conclusion, AR-EVOO supplementation prevents IRD-induced changes in parameters related to liver FA metabolism and steatosis, an effect that may have a significant impact in the treatment of iron-related pathologies or metabolic disorders such as non-alcoholic fatty liver disease.
Asunto(s)
Antioxidantes/administración & dosificación , Ácido Graso Desaturasas/genética , Hígado Graso/prevención & control , Hierro/efectos adversos , Linoleoil-CoA Desaturasa/genética , Aceite de Oliva/administración & dosificación , Animales , Antioxidantes/química , Antioxidantes/farmacología , Cromatografía de Gases , delta-5 Desaturasa de Ácido Graso , Modelos Animales de Enfermedad , Ácidos Grasos/análisis , Hígado Graso/inducido químicamente , Hígado Graso/epidemiología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Masculino , Aceite de Oliva/química , Aceite de Oliva/farmacología , Ratas , Ratas WistarRESUMEN
High-fat-diet (HFD) feeding is associated with liver oxidative stress (OS), n-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) depletion, hepatic steatosis and mitochondrial dysfunction. Our hypothesis is that the HFD-induced liver injury can be attenuated by the combined supplementation of n-3 LCPUFA eicosapentaenoic acid (EPA) and the antioxidant hydroxytyrosol (HT). The C57BL/6J mice were administered an HFD (60% fat, 20% protein, 20% carbohydrates) or control diet (CD; 10% fat, 20% protein, 70% carbohydrates), with or without EPA (50 mg kg-1 day-1), HT (5 mg kg-1 day-1), or EPA + HT (50 and 5 mg kg-1 day-1, respectively) for 12 weeks. We measured the body and liver weights and dietary and energy intakes along with liver histology, FA composition, steatosis score and associated transcription factors, mitochondrial functions and metabolic factors related to energy sensing through the AMP-activated protein kinase (AMPK) and PPAR-γ coactivator-1α (PGC-1α) cascade. It was found that the HFD significantly induced liver steatosis, with a 66% depletion of n-3 LCPUFAs and a 100% increase in n-6/n-3 LCPUFA ratio as compared to the case of CD (p < 0.05). These changes were concomitant with (i) a 95% higher lipogenic and 70% lower FA oxidation signaling, (ii) a 40% diminution in mitochondrial respiratory capacity and (iii) a 56% lower ATP content. HFD-induced liver steatosis was also associated with (iv) a depressed mRNA expression of AMPK-PGC-1α signaling components, nuclear respiratory factor-2 (NRF-2) and ß-ATP synthase. These HFD effects were significantly attenuated by the combined EPA + HT supplementation in an additive manner. These results suggested that EPA and HT co-administration partly prevented HFD-induced liver steatosis, thus strengthening the importance of combined interventions in hepatoprotection in non-alcoholic fatty liver disease.
Asunto(s)
Ácido Eicosapentaenoico , Metabolismo Energético , Enfermedad del Hígado Graso no Alcohólico , Alcohol Feniletílico , Animales , Humanos , Masculino , Ratones , Adenosina Trifosfato/metabolismo , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos/análisis , Sinergismo Farmacológico , Ácido Eicosapentaenoico/administración & dosificación , Metabolismo Energético/efectos de los fármacos , Ácidos Grasos Omega-3/metabolismo , Lipogénesis/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Alcohol Feniletílico/administración & dosificación , Alcohol Feniletílico/análogos & derivadosRESUMEN
Attenuation of high-fat diet (HFD)-induced liver steatosis is accomplished by different nutritional interventions. Considering that the n-3 PUFA docosahexaenoic acid (DHA) modulates lipid metabolism and the antioxidant hydroxytyrosol (HT) diminishes oxidative stress underlying fatty liver, it is hypothesized that HFD-induced steatosis is suppressed by DHA and HT co-administration. Male C57BL/6J mice were fed a control diet (CD; 10% fat, 20% protein, 70% carbohydrates) or a HFD (60% fat, 20% protein, 20% carbohydrates) for 12 weeks, without and with supplementation of DHA (50 mg/kg/day), HT (5 mg/kg/day) or both. The combined DHA + HT protocol fully prevented liver steatosis and the concomitant pro-inflammatory state induced by HFD, with suppression of lipogenic and oxidative stress signaling, recovery of fatty acid oxidation capacity and enhancement in resolvin availability affording higher inflammation resolution capability. Abrogation of HFD-induced hepatic steatosis by DHA and HT co-administration represents a crucial therapeutic strategy eluding disease progression into stages lacking efficacious handling at present time.
Asunto(s)
Ácidos Docosahexaenoicos/farmacología , Hígado Graso/dietoterapia , Inflamación/dietoterapia , Alcohol Feniletílico/análogos & derivados , Animales , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Hígado Graso/etiología , Hígado Graso/genética , Hígado Graso/patología , Humanos , Inflamación/genética , Inflamación/patología , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/patología , Ratones , Estrés Oxidativo/efectos de los fármacos , PPAR alfa/genética , Alcohol Feniletílico/farmacologíaRESUMEN
Ischemia-reperfusion (IR) is a deleterious condition associated with liver transplantation or resection that involves pro-oxidant and pro-inflammatory mechanisms. Considering that Rosa Mosqueta (RM) oil composition is rich in protective components such as α-linolenic acid (ALA) and tocopherols, we studied the effects of RM oil supplementation given prior to an IR protocol. Male Sprague-Dawley rats receiving RM oil (0.4 mL d-1) for 21 days were subjected to 1 h of ischemia followed by 20 h reperfusion. Parameters of liver injury (serum transaminases, histology), oxidative stress [liver contents of protein carbonyls, thiobarbituric acid reactants, Nrf2 activity and its target mRNA expression of heme oxygenase-1 (HO-1) and NADPH-quinone oxidoreductase-1 (NQO-1)] and inflammation [nuclear factor-κB (NF-κB) and its target mRNA expression of tumor necrosis factor-α (TNF-α) and interleukine-1ß (IL-1ß)] were studied. RM oil increased liver ALA and its derived EPA and DHA fatty acids' contents, with enhancement in those of α- and γ-tocopherols. IR induced inflammatory liver injury, with enhancement in serum transaminases, oxidative stress-related parameters with reduced Nrf2 signaling, and higher pro-inflammatory cytokines, indexes that were attenuated or abrogated by RM oil pretreatment. It is concluded that RM oil supplementation represents a novel non-invasive preconditioning strategy against liver injury induced by IR that has potential clinical applications in metabolic stress conditions.
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Antiinflamatorios no Esteroideos/uso terapéutico , Antioxidantes/uso terapéutico , Suplementos Dietéticos , Hígado/metabolismo , Aceites Volátiles/uso terapéutico , Daño por Reperfusión/prevención & control , Rosa/química , Animales , Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Regulación de la Expresión Génica , Hígado/irrigación sanguínea , Hígado/inmunología , Hígado/patología , Masculino , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Distribución Aleatoria , Ratas Sprague-Dawley , Daño por Reperfusión/inmunología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Semillas/química , Transducción de Señal , Destete , Ácido alfa-Linolénico/metabolismo , Ácido alfa-Linolénico/uso terapéutico , alfa-Tocoferol/metabolismo , alfa-Tocoferol/uso terapéutico , gamma-Tocoferol/metabolismo , gamma-Tocoferol/uso terapéuticoRESUMEN
Enhanced iron levels in liver are associated with oxidative stress development and damage with increased fat accumulation. The aim of this work was to assess the hypothesis that antioxidant-rich extra virgin olive oil (AR-EVOO) counteracts iron-rich diet (IRD)-induced oxidative stress hindering hepatic steatosis. Male Wistar rats were fed and IRD (200â¯mg iron/kg diet) versus a control diet (CD; 50â¯mg iron/kg diet) with alternate AR-EVOO supplementation (100â¯mg/day) for 21 days. IRD induced liver steatosis and oxidative stress (higher levels of protein oxidation and lipid peroxidation with glutathione depletion), mitochondrial dysfunction (decreased citrate synthase and complex I and II activities) and loss of polyunsaturated fatty acids (PUFAs), with a drastic enhancement in the sterol regulatory element-binding protein-1c (SREBP-1c)/peroxisome proliferator-activated receptor-α (PPAR-α) ratio upregulating the expression of lipogenic enzymes (acetyl-CoA carboxylase, fatty acid (FA) synthase and stearoyl desaturase 2) and downregulating those involved in FA oxidation (carnitine palmitoyl transferase and acyl-CoA oxidase) over values in the CD group. IRD also upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and its target genes. AR-EVOO supplementation alone did not modify the studied parameters, however, IRD combined with AR-EVOO administration returned IRD-induced changes to baseline levels of the CD group. It is concluded that IRD-induced non-alcoholic fatty liver disease (NAFLD) is prevented by AR-EVOO supplementation, which might be related to the protective effects of its components such as hydroxytyrosol, oleic acid, tocopherols and/or PUFAs, thus representing a suitable anti-steatotic strategy to avoid progression into more severe stages of the disease, underlying NAFLD associated with iron overloading pathologies or obesity.
Asunto(s)
Antioxidantes/administración & dosificación , Suplementos Dietéticos , Enfermedad del Hígado Graso no Alcohólico/dietoterapia , Aceite de Oliva/administración & dosificación , Animales , Dieta Alta en Grasa/efectos adversos , Ácidos Grasos Omega-3/metabolismo , Humanos , Hierro/administración & dosificación , Hierro/metabolismo , Sobrecarga de Hierro/dietoterapia , Sobrecarga de Hierro/metabolismo , Sobrecarga de Hierro/patología , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , RatasRESUMEN
OBJECTIVE: The aim of this study was to evaluate the contribution of tocopherols present in Rosa mosqueta oil (RM) in the prevention of high-fat diet (HFD)-induced alterations. METHODS: Male C57 BL/6 J mice (n = 9/group) were fed for 12 wk and divided into four groups: control (CD; 10% kcal fat, 20% kcal protein, 70% kcal carbohydrates); HFD (60% as fat, 20% kcal protein, 20% kcal carbohydrates); HFD + RM (0.01 mL/g body weight/d); and HFD + RM- without tocopherols (0.01 mL/g body weight/d). Parameters of obesity, liver steatosis (histology, triacylglycerols content), inflammation (adipose NLRP3 inflammasome, tumor necrosis factor-α and interleukin-1 ß expression, hepatic nuclear factor-κB) and oxidative stress (hepatic Nrf2 activation, carbonylated proteins) were evaluated. RESULTS: Liver steatosis, inflammatory, and oxidative stress parameters were significantly (P < 0.05) increased in the HFD + RM- compared with the HFD + RM, with no differences between HFD and HFD + RM-. CONCLUSION: The present study suggests that α- and γ-tocopherols from RM may have an important role in the prevention of alterations induced by HFD.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Inflamación/prevención & control , Estrés Oxidativo/efectos de los fármacos , Aceites de Plantas/farmacología , Rosa , alfa-Tocoferol/farmacología , gamma-Tocoferol/farmacología , Animales , Modelos Animales de Enfermedad , Hígado Graso/prevención & control , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Rosa mosqueta (RM) oil is rich in α-linolenic acid (ALA) - a precursor of eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), and it has a high antioxidant activity due to its abundant content of tocopherols. Additionally, it has been observed that RM oil administration prevents hepatic steatosis. Thus, the aim of this study was to demonstrate the antilipogenic mechanism related to RM oil administration in a high-fat diet (HFD) fed mice model by evaluating markers associated with the regulation of lipid droplet metabolism (PLIN2, PLIN5 and PPAR-γ), and proteins associated with lipogenesis (FAS and SREBP-1c). C57BL/6J mice were fed either a control diet or a HFD, with and without RM oil supplementation for 12 weeks. The results showed that RM oil supplementation decreases hepatic PLIN2 and PPAR-γ mRNA expression and SREBP-1c, FAS and PLIN2 protein levels, whereas we did not find changes in the level of PLIN5 among the groups. These results suggest that modulation of lipogenic markers could be one of the mechanisms, through which RM oil supplementation prevents the hepatic steatosis induced by HFD consumption in a mice model.
Asunto(s)
Hígado Graso/prevención & control , Aceites de Plantas/administración & dosificación , Rosa/química , Animales , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos/análisis , Hígado Graso/genética , Hígado Graso/metabolismo , Humanos , Lipogénesis , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , PPAR gamma/genética , PPAR gamma/metabolismo , Perilipina-2/genética , Perilipina-2/metabolismo , Perilipina-5/genética , Perilipina-5/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismoRESUMEN
SCOPE: Nonalcoholic fatty liver disease is the most common cause of liver disease, for which there is no validated drug therapy at present time. In this respect, the PUFA docosahexaenoic acid (DHA; C22:6 n-3) modulate lipid metabolism in the liver, and extra virgin olive oil (EVOO) has hepatoprotective effects. METHODS AND RESULTS: The effect of combined DHA (C22:6 n-3) and EVOO administration to mice on oxidative stress and metabolic disturbances induced by high-fat diet (HFD) is evaluated. Male C57BL/6J mice are fed with a control diet (10% fat, 20% protein, and 70% carbohydrates) or an HFD (60% fat, 20% protein, and 20% carbohydrates) for 12 weeks. Animals are supplemented with DHA (50 mg/kg/day), EVOO (50 mg/kg/day), or DHA + EVOO through oral route. DHA + EVOO cosupplementation results in greater protection (p < 0.05) over that elicited by DHA or EVOO supply alone, when compared to the damage induced by HFD. DHA + EVOO significantly reduces hepatic steatosis, oxidative stress, systemic inflammation, and insulin resistance. CONCLUSION: Synergistic beneficial effects of DHA + EVOO supplementation are associated with the activation/inactivation of key transcription factors involved in the above-mentioned processes. Data presented indicate that dietary supplementation with DHA + EVOO drastically reduces the development of nonalcoholic fatty liver disease.
Asunto(s)
Ácidos Docosahexaenoicos/farmacología , Hígado/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Aceite de Oliva/farmacología , Grasa Abdominal/efectos de los fármacos , Animales , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos , Regulación hacia Abajo/efectos de los fármacos , Ácidos Grasos/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Estrés Oxidativo/efectos de los fármacos , PPAR alfa/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismoRESUMEN
Maternal obesity during pregnancy has been related with several pathological states in offspring. However, the impact of maternal obesity on reproductive system on the progeny is beginning to be elucidated. In this work, we characterize the effect of maternal obesity on puberty onset and follicular development in adult offspring in rats. We also propose that alterations in ovarian physiology observed in offspring of obese mothers are due to increased levels of estradiol during early development. Offspring of control dams and offspring of dams exposed to a high-fat diet (HF) were studied at postnatal days (PND) 1, 7, 14, 30, 60, and 120. Body weight and onset of puberty were measured. Counting of ovarian follicles was performed at PND 60 and 120. Serum estradiol, estriol, androstenedione, FSH, LH, and insulin levels were measured by ELISA. Hepatic CYP3A2 expression was determined by Western blot. HF rats had a higher weight than controls at all ages and they also had a precocious puberty. Estradiol levels were increased while CYP3A2 expression was reduced from PND 1 until PND 60 in HF rats compared to controls. Estriol was decreased at PND60 in HF rats. Ovaries from HF rats had a decrease in antral follicles at PND60 and PND120 and an increase in follicular cysts at PND60 and PND120. In this work, we demonstrated that maternal obesity in rats alters follicular development and induces follicular cysts generation in the adult offspring. We observed that maternal obesity produces an endocrine disruption through increasing endogenous estradiol in early life. A programmed failure in hepatic metabolism of estradiol is probably the cause of its increase.
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Citocromo P-450 CYP3A/metabolismo , Estradiol/sangre , Hígado/metabolismo , Obesidad/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Androstenodiona/sangre , Animales , Peso Corporal/fisiología , Dieta Alta en Grasa , Estriol/sangre , Femenino , Hormona Folículo Estimulante/sangre , Insulina/sangre , Hormona Luteinizante/sangre , Fenómenos Fisiologicos Nutricionales Maternos , Obesidad/sangre , Embarazo , Efectos Tardíos de la Exposición Prenatal/sangre , Ratas , Ratas Sprague-Dawley , Maduración Sexual/fisiologíaRESUMEN
The effects of dietary Rosa mosqueta (RM, Rosa rubiginosa) oil, rich in α-linolenic acid, in the prevention of liver steatosis were studied in mice fed a high fat diet (HFD). C57BL/6j mice were fed either a control diet or HFD with or without RM oil for 12 weeks. The results indicate that RM oil supplementation decreases fat infiltration of the liver from 43.8% to 6.2%, improving the hepatic oxidative state, insulin levels, HOMA index, and both body weight and adipose tissue weight of HFD plus RM treated animals compared to HFD without supplementation. In addition, the DHA concentration in the liver was significantly increased in HFD fed mice with RM oil compared to HFD (3 vs. 1.6 g per 100 g FAME). The n-6/n-3 ratio was not significantly modified by treatment with RM. Our findings suggest that RM oil supplementation prevents the development of hepatic steatosis and the obese phenotype observed in HFD fed mice.
Asunto(s)
Hígado Graso/prevención & control , Aceites de Plantas/metabolismo , Rosa/química , Animales , Glucemia/metabolismo , Dieta Alta en Grasa/efectos adversos , Hígado Graso/dietoterapia , Hígado Graso/metabolismo , Humanos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo , Rosa/metabolismoRESUMEN
SCOPE: Dietary n-3 long-chain PUFAs (n-3 LCPUFAs) supplementation was studied in an HFD-induced (HFD is high-fat diet) steatosis and inflammation in relation to peroxisome proliferator-activated receptor alpha (PPAR-α) and nuclear factor κB (NF-κB) signaling. METHODS AND RESULTS: Male C57BL/6J mice received (i) control diet (10% fat, 20% protein, 70% carbohydrate), (ii) control diet plus n-3 LCPUFAs (daily doses of 108 mg/kg body weight of eicosapentaenoic acid plus 92 mg/kg body weight of docosahexaenoic acid), (iii) HFD (60% fat, 20% protein, 20% carbohydrate), or (iv) HFD plus n-3 LCPUFAs for 12 wk. PPAR-α, tumor necrosis factor alpha (TNF-α), and IL-1ß mRNA expression, acyl-CoA oxidase 1 (ACOX1), and carnitine-acyl-CoA transferase 1 (CAT-I) protein contents, and NF-κB DNA binding activity were measured. HFD significantly decreased liver PPAR-α, ACOX1, and CAT-I levels with NF-κB activation, higher TNF-α and IL-1ß expression, and steatosis development. These changes were either reduced or normalized to control values in animals subjected to HFD plus n-3 LCPUFAs, with establishment of an inverse association between NF-κB activation and PPAR-α mRNA expression (r = -0.66, p < 0.0001). CONCLUSION: Data presented indicate that n-3 LCPUFAs supplementation prevents liver steatosis and inflammation induced by HFD, with underlying mechanisms involving enhanced PPAR-α signaling and diminished NF-κB activation.
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Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos , Ácidos Grasos Omega-3/administración & dosificación , Hígado Graso/prevención & control , FN-kappa B/metabolismo , PPAR alfa/metabolismo , Acil-CoA Oxidasa/genética , Acil-CoA Oxidasa/metabolismo , Animales , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Hígado Graso/etiología , Inflamación/etiología , Inflamación/prevención & control , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Hígado/enzimología , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , Tamaño de los Órganos , PPAR alfa/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia ArribaRESUMEN
Omega-3 (n-3) long-chain polyunsaturated fatty acids (n-3 LCPUFA) are associated with several physiological functions, suggesting that their administration may prevent non transmissible chronic diseases. Therefore, we investigate whether dietary n-3 LCPUFA supplementation triggers an antioxidant response preventing liver steatosis in mice fed a high fat diet (HFD) in relation to n-3 LCPUFA levels. Male C57BL/6J mice received (a) control diet (10% fat, 20% protein, 70% carbohydrate), (b) control diet plus n-3 LCPUFA (108 mg/kg/day eicosapentaenoic acid plus 92 mg/kg/day docosahexaenoic acid), (c) HFD (60% fat, 20% protein, 20% carbohydrate), or (d) HFD plus n-3 LCPUFA for 12 weeks. Parameters of liver steatosis, glutathione status, protein carbonylation, and fatty acid analysis were determined, concomitantly with insulin resistance and serum tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6 levels. HFD significantly increased total fat and triacylglyceride contents with macrovesicular steatosis, concomitantly with higher fasting serum glucose and insulin levels, HOMA, and serum TNF-α, IL-1ß, and IL-6. Reduced and total liver glutathione contents were diminished by HFD, with higher GSSG/GSH ratio and protein carbonylation, n-3 LCPUFA depletion and elevated n-6/n-3 ratio over control values. These changes were either reduced or normalized to control values in animals subjected to HFD and n-3 LCPUFA, with significant increased hepatic total n-3 LCPUFA content and reduced n-6/n-3 ratio being observed after n-3 LCPUFA supplementation alone. So, repletion of liver n-3 LCPUFA levels by n-3 LCPUFA dietary supplementation in HFD obese mice reduces hepatic lipid content, with concomitant antioxidant and anti-inflammatory responses favouring insulin sensitivity.
Asunto(s)
Suplementos Dietéticos , Ácidos Grasos Omega-3/uso terapéutico , Hígado Graso/tratamiento farmacológico , Hígado Graso/patología , Hígado/patología , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Citocinas/sangre , Dieta Alta en Grasa , Ácidos Grasos/metabolismo , Ácidos Grasos Omega-3/farmacología , Hígado Graso/sangre , Hígado Graso/inducido químicamente , Insulina/sangre , Resistencia a la Insulina , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Tamaño de los Órganos/efectos de los fármacos , Estrés Oxidativo , Triglicéridos/metabolismoRESUMEN
High dietary intake of n-6 fatty acids in relation to n-3 fatty acids may generate health disorders, such as cardiovascular and other chronic diseases. Fish consumption rich in n-3 fatty acids is low in Latin America, it being necessary to seek other alternatives to provide α-linolenic acid (ALA), precursor of n-3 LCPUFA (EPA and DHA). Two innovative oils were assayed, chia (Salvia hispanica) and rosa mosqueta (Rosa rubiginosa). This study evaluated hepatic bioconversion of ALA to EPA and DHA, expression of PPAR-α, acyl-Coenzyme A oxidase 1 (ACOX1) and carnitine acyltransferase I (CAT-I), and accumulation of EPA and DHA in plasma and adipose tissue in Sprague-Dawley rats. Three experimental groups were fed 21 days: sunflower oil (SFO, control); chia oil (CO); rosa mosqueta oil (RMO). Fatty acid composition of total lipids and phospholipids from plasma, hepatic and adipose tissue was assessed by gas-liquid chromatography and TLC. Expression of PPAR-α (RT-PCR) and ACOX1 and CAT-I (Western blot). CO and RMO increased plasma, hepatic and adipose tissue levels of ALA, EPA and DHA and decreased n-6:n-3 ratio compared to SFO (p < 0.05, One-way ANOVA and Newman-Keuls test). CO increased levels of ALA and EPA compared to RMO (p < 0.05). No significant differences were observed for DHA levels. CO also increased the expression of PPAR-α, ACOX1 and CAT-I. Only CAT-I levels were increased by RO. CO and RMO may be a nutritional alternative to provide ALA for its bioconversion to EPA and DHA, and to increase the expression of PPAR-α, ACOX1 and CAT-I, especially CO-oil.
Asunto(s)
Acil-CoA Oxidasa/genética , Carnitina O-Palmitoiltransferasa/genética , Ácidos Grasos Omega-3/metabolismo , PPAR alfa/genética , Aceites de Plantas/metabolismo , Rosa/química , Salvia/química , Ácido alfa-Linolénico/metabolismo , Acil-CoA Oxidasa/metabolismo , Animales , Biotransformación , Carnitina O-Palmitoiltransferasa/metabolismo , Humanos , PPAR alfa/metabolismo , Aceites de Plantas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Regulación hacia Arriba , Ácido alfa-Linolénico/administración & dosificaciónRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is triggered by a nutritional-metabolic alteration characterized by triacylglicerides acumulation, insulin resistance (IR), oxidative stress and depletion of polyunsaturated fatty acid (PUFA). The n-3 PUFA, such as eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, would be hepatoprotective against the development of NAFLD by stimulating lipolysis and inhibit lipogenesis. So, fish oil supplementation (EPA + DHA) prevents HFDinduced NAFLD. In this context, the aim of this study is to evaluate the correlation between liver oxidative stress with IR and levels of PUFA in supplemented mice. Male mice C57BL/6J (n=9) were fed for 12th week: a) control diet (20% protein, 70% carbohydrate, 10% lipids), b) control diet and fish oil supplementation (200 mg EPA+DHA/kg/day), c) high fat diet (20% protein, 20% carbohydrate, 60% lipids), and d) high fat diet and fish oil supplementation. Liver steatosis (histology), insulin resistance (HOMA), liver oxidative stress (GSH/GSSG, carbonyl protein and 8-isoprostanes) and liver fatty acid content were evaluated. The significant decrease in liver oxidative stress parameters (p<0.05, ANOVA followed by Newman Keuls test) were correlated (Pearson test) with HOMA and levels of PUFA, along with the hepatoprotection observed. It concludes that prevention of NAFLD by supplementation with fish oil (EPA+DHA) is dependent of the prevention of liver oxidative stress, IR and PUFA depletion.
La enfermedad por hígado graso no alcohólica (EHGNA) está provocada por una alteración metabólico- nutricional caracterizada por la acumulación de triacilglicéridos, resistencia a la insulina, estrés oxidativo y disminución de ácidos grasos poliinsaturados (AGPI). Los AGPI ω-3, como los ácidos eicosapentaenoico (EPA) y docosahexaenoico (DHA), serían hepatoprotectores contra la EHGNA al estimular la lipolisis e inhibir la lipogénesis hepática. La suplementación con aceite de pescado (EPA + DHA) previene la esteatosis hepática inducida por una dieta alta en grasas. En este contexto, el objetivo de este estudio es evaluar la correlación entre el estrés oxidativo hepático, la resistencia a la insulina y los niveles de AGPI ω-3 en ratones suplementados. Ratones machos C57BL/6J (n=9) alimentados durante 12 semanas con: a) dieta control (20% proteína, 70% hidratos de carbono, 10% lípidos), b) dieta control y suplementación con 200 mg de EPA+DHA/kg/día, c) dieta alta en grasa (20% proteína, 20% hidratos de carbono, 60% lípidos), y d) dieta alta en grasas más EPA+DHA. Se evaluaron la esteatosis hepática (histología), resistencia a la insulina (HOMA), estrés oxidativo hepático (GSH/GSSG, proteínas carboniladas y 8-isoprostanos) y el contenido de ácidos grasos hepáticos. La disminución significativa en los parámetros hepáticos de estrés oxidativo (p <0,05, ANOVA seguido de Newman-Keuls) se correlacionó positivamente (test de Pearson) con el HOMA y los niveles de AGPI ω-3, junto con la hepatoprotección observada. Se concluye que la prevención de EHGNA por suplementación con EPA+DHA, se acompaña de una correlación inversa entre el estrés oxidativo y la resistencia a la insulina y la disminución de AGPI ω-3 hepáticos.