RESUMO
BACKGROUND AND AIMS: Drugs resolving steatotic liver disease (SLD) could prevent the evolution of metabolic dysfunction associated SLD (MASLD) to more aggressive forms but must show not only efficacy, but also a high safety profile. Repurposing of drugs in clinical use, such as pemafibrate and mirabegron, could facilitate the finding of an effective and safe drug-treatment for SLD. APPROACH AND RESULTS: The SLD High Fat High Fructose (HFHFr) rat model develops steatosis without the influence of other metabolic disturbances, such as obesity, inflammation, or type 2 diabetes. Further, liver fatty acids are provided, as in human pathology, both from dietary origin and de novo lipid synthesis. We used the HFHFr model to evaluate the efficacy of pemafibrate and mirabegron, alone or in combination, in the resolution of SLD, analyzing zoometric, biochemical, histological, transcriptomic, fecal metabolomic and microbiome data. We provide evidence showing that pemafibrate, but not mirabegron, completely reverted liver steatosis, due to a direct effect on liver PPARα-driven fatty acid catabolism, without changes in total energy consumption, subcutaneous, perigonadal and brown fat, blood lipids and body weight. Moreover, pemafibrate treatment showed a neutral effect on whole-body glucose metabolism, but deeply modified fecal bile acid composition and microbiota. CONCLUSIONS: Pemafibrate administration reverts liver steatosis in the HFHFr dietary rat SLD model without altering parameters related to metabolic or organ toxicity. Our results strongly support further clinical research to reposition pemafibrate for the treatment of SLD/MASLD.
Assuntos
Benzoxazóis , Ácidos e Sais Biliares , Modelos Animais de Doenças , Fezes , Animais , Ácidos e Sais Biliares/metabolismo , Masculino , Ratos , Benzoxazóis/farmacologia , Fezes/microbiologia , Fezes/química , Microbioma Gastrointestinal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Acetanilidas/farmacologia , Butiratos/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Ratos Wistar , Tiazóis/farmacologia , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/patologia , Fígado Gorduroso/metabolismo , Frutose/efeitos adversosRESUMO
We previously demonstrated that treatment with BemA (bempedoic acid), an inhibitor of ATP citrate lyase, significantly reduces fatty liver in a model of liver steatosis (HFHFr-female Sprague-Dawley rat fed a high-fat high-fructose diet). Since the hepatic production of the gasotransmitter H2S is impaired in liver disorders, we were interested in determining if the production of H2S was altered in our HFHFr model and whether the administration of BemA reversed these changes. We used stored liver samples from a previous study to determine the total and enzymatic H2S production, as well as the expression of CBS (cystathionine ß-synthase), CSE (cystathionine γ-lyase), and 3MST (3-mercaptopiruvate sulfurtransferase), and the expression/activity of FXR (farnesoid X receptor), a transcription factor involved in regulating CSE expression. Our data show that the HFHFr diet reduces the total and enzymatic production of liver H2S, mainly by decreasing the expression of CBS and CSE. Furthermore, BemA treatment restored H2S production, increasing the expression of CBS and CSE, providing evidence for the involvement of FXR transcriptional activity and the mTORC1 (mammalian target of rapamycin1)/S6K1 (ribosomal protein S6 kinase beta-1)/PGC1α (peroxisome proliferator receptor gamma coactivator1α) pathway.
Assuntos
Sulfeto de Hidrogênio , Hepatopatia Gordurosa não Alcoólica , Animais , Feminino , Ratos , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Dieta Hiperlipídica/efeitos adversos , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To examine associations between intake of simple sugars and cancer incidence, cancer mortality, and total mortality in a prospective cohort study based on the PREDIMED trial conducted from 2003 to 2010. METHODS: Participants were older individuals at high cardiovascular risk. Exposures were total sugar, glucose and fructose from solid or liquid sources, and fructose from fruit and 100% fruit juice. Cancer incidence was the primary outcome; cancer mortality and all-cause mortality were secondary outcomes. Multivariable-adjusted, time-dependent Cox proportional hazard models were used. RESULTS: Of 7447 individuals enrolled, 7056 (94.7%) were included (57.6% women, aged 67.0 ± 6.2 years). 534 incident cancers with 152 cancer deaths and 409 all-cause deaths were recorded after a median follow-up of 6 years. Intake of simple sugars in solid form was unrelated to outcomes. Higher cancer incidence was found per 5 g/day increase in intake of liquid sugars, with multivariable-adjusted HR of 1.08 (95% CI, 1.03-1.13) for total liquid sugar, 1.19 (95% CI, 1.07-1.31) for liquid glucose, 1.14 (95% CI, 1.05-1.23) for liquid fructose, and 1.39 (95% CI, 1.10-1.74) for fructose from fruit juice. Cancer and all-cause mortality increased to a similar extent with intake of all sugars in liquid form. In categorical models, cancer risk was dose-related for all liquid sugars. CONCLUSIONS: Simple sugar intake in drinks and fruit juice was associated with an increased risk of overall cancer incidence and mortality and all-cause mortality. This suggests that sugary beverages are a modifiable risk factor for cancer and all-cause mortality.
Assuntos
Açúcares da Dieta/administração & dosagem , Monossacarídeos/administração & dosagem , Neoplasias/epidemiologia , Neoplasias/mortalidade , Idoso , Bebidas , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Estudos de Coortes , Dieta , Ingestão de Alimentos , Feminino , Frutose/administração & dosagem , Sucos de Frutas e Vegetais , Glucose/administração & dosagem , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mortalidade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sacarose/administração & dosagemRESUMO
Since the approval of immune checkpoint anti-programmed cell death protein 1 antibodies (pembrolizumab and nivolumab) and anti-cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) in combination or monotherapy, significant advances have been made in the treatment of metastatic melanoma. The nonspecific immune stimulation resulting from these drugs can case a wide range of side effects in many organs including the nervous system, named immune-related adverse events. Few immune-related encephalitis associated with these antibodies have been described in the literature. It is a rare complication (<1% of the total of immune-related adverse events) but it can be fatal if not diagnosed and treated on time. We describe 3 cases of patients with melanoma, which were treated with a combination of ipilimumab-nivolumab (case 1), ipilimumab monotherapy (case 2), and nivolumab monotherapy (case 3), who developed an encephalitis which was related to immune checkpoint therapy.
Assuntos
Encefalite/diagnóstico , Encefalite/etiologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Melanoma/complicações , Terapia de Alvo Molecular/efeitos adversos , Biomarcadores Tumorais , Tomada de Decisão Clínica , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Melanoma/diagnóstico , Melanoma/tratamento farmacológico , Melanoma/etiologia , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Mutação , Gradação de Tumores , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
Endoplasmic reticulum (ER) homeostasis is crucial to appropriate cell functioning, and when disturbed, a safeguard system called unfolded protein response (UPR) is activated. Fructose consumption modifies ER homeostasis and has been related to metabolic syndrome. However, fructose sweetened beverages intake is allowed during gestation. Therefore, we investigate whether maternal fructose intake affects the ER status and induces UPR. Thus, administrating liquid fructose (10% w/v) to pregnant rats partially activated the ER-stress in maternal and fetal liver and placenta. In fact, a fructose-induced increase in the levels of pIRE1 (phosphorylated inositol requiring enzyme-1) and its downstream effector, X-box binding protein-1 spliced form (XBP1s), was observed. XBP1s is a key transcription factor, however, XBP1s nuclear translocation and the expression of its target genes were reduced in the liver of the carbohydrate-fed mothers, and specifically diminished in the fetal liver and placenta in the fructose-fed mothers. These XBP1s target genes belong to the ER-associated protein degradation (ERAD) system, used to buffer ER-stress and to restore ER-homeostasis. It is known that XBP1s needs to form a complex with diverse proteins to migrate into the nucleus. Since methylglyoxal (MGO) content, a precursor of advanced glycation endproducts (AGE), was augmented in the three tissues in the fructose-fed mothers and has been related to interfere with the functioning of many proteins, the role of MGO in XBP1s migration should not be discarded. In conclusion, maternal fructose intake produces ER-stress, but without XBP1s nuclear migration. Therefore, a complete activation of UPR that would resolve ER-stress is lacking. A state of fructose-induced oxidative stress is probably involved.
Assuntos
Dieta , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Frutose/efeitos adversos , Fenômenos Fisiológicos da Nutrição Materna , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Proteína 1 de Ligação a X-Box/metabolismo , Animais , Transporte Biológico , Núcleo Celular , Açúcares da Dieta/efeitos adversos , Endorribonucleases/metabolismo , Feminino , Feto/efeitos dos fármacos , Fígado/efeitos dos fármacos , Placenta/efeitos dos fármacos , Gravidez , Proteínas Serina-Treonina Quinases/metabolismo , Aldeído Pirúvico/metabolismo , Ratos Sprague-DawleyRESUMO
We have recently shown that type of supplemented simple sugar, not merely calorie intake, determines adverse effects on metabolism and aortic endothelial function in female rats. The aim of the current study was to investigate and compare the effects of high consumption of glucose or fructose on mesenteric arterial reactivity and systolic blood pressure (SBP). Sprague-Dawley female rats were supplemented with 20% w/v glucose or fructose in drinking water for 8 weeks. Here, we show that both sugars alter insulin signaling in mesenteric arteries (MA), assessed by a reduction in phosphorylated Akt, and increase in SBP. Furthermore, ingestion of glucose or fructose enhances inducible nitric oxide synthase (iNOS) expression and contractile responses to endothelin and phenylephrine in MA of rats. The endothelium-dependent vasodilation to acetylcholine and bradykinin as well as the relaxation responses to the nitric oxide donor sodium nitroprusside are impaired in MA of fructose- but not glucose-supplemented rats. In contrast, only glucose supplementation increases the expression of phosphorylated endothelial NOS (eNOS) in MA of rats. In conclusion, this study reveals that supplementation with fructose or glucose in liquid form enhances vasocontractile responses and increases iNOS expression in MA, effects which are accompanied by increased SBP in those groups. On the other hand, the preserved vasodilatory responses in MA from glucose-supplemented rats could be attributed to the enhanced level of phosphorylated eNOS expression in this group.
Assuntos
Frutose/efeitos adversos , Glucose/efeitos adversos , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Acetilcolina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Bradicinina/farmacologia , Feminino , Insulina/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos Sprague-Dawley , Vasodilatação/efeitos dos fármacosRESUMO
High consumption of simple sugars causes adverse cardiometabolic effects. We investigated the mechanisms underlying the metabolic and vascular effects of glucose or fructose intake and determined whether these effects are exclusively related to increased calorie consumption. Female Sprague-Dawley rats were supplemented with 20% wt/vol glucose or fructose for 2 mo, and plasma analytes and aortic response to vasodilator and vasoconstrictor agents were determined. Expression of molecules associated with lipid metabolism, insulin signaling, and vascular response were evaluated in hepatic and/or aortic tissues. Caloric intake was increased in both sugar-supplemented groups vs. control and in glucose- vs. fructose-supplemented rats. Hepatic lipogenesis was induced in both groups. Plasma triglycerides were increased only in the fructose group, together with decreased expression of carnitine palmitoyltransferase-1A and increased microsomal triglyceride transfer protein expression in the liver. Plasma adiponectin and peroxisome proliferator-activated receptor (PPAR)-α expression was increased only by glucose supplementation. Insulin signaling in liver and aorta was impaired in both sugar-supplemented groups, but the effect was more pronounced in the fructose group. Fructose supplementation attenuated aortic relaxation response to a nitric oxide (NO) donor, whereas glucose potentiated it. Phenylephrine-induced maximal contractions were reduced in the glucose group, which could be related to increased endothelial NO synthase (eNOS) phosphorylation and subsequent elevated basal NO in the glucose group. In conclusion, despite higher caloric intake in glucose-supplemented rats, fructose caused worse metabolic and vascular responses. This may be because of the elevated adiponectin level and the subsequent enhancement of PPARα and eNOS phosphorylation in glucose-supplemented rats. NEW & NOTEWORTHY: This is the first study comparing the effects of glucose and fructose consumption on metabolic factors and aortic function in female rats. Our results show that, although total caloric consumption was higher in glucose-supplemented rats, fructose ingestion had a greater impact in inducing metabolic and aortic dysfunction.
Assuntos
Aorta/efeitos dos fármacos , Sacarose Alimentar/farmacologia , Ingestão de Energia , Frutose/farmacologia , Glucose/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Acetilcolina/farmacologia , Adiponectina/metabolismo , Animais , Aorta/metabolismo , Aorta/fisiopatologia , Western Blotting , Bradicinina/farmacologia , Carnitina O-Palmitoiltransferase/efeitos dos fármacos , Carnitina O-Palmitoiltransferase/metabolismo , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Feminino , Insulina/metabolismo , Lipogênese/efeitos dos fármacos , Fígado/metabolismo , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Nitroprussiato/farmacologia , PPAR alfa/efeitos dos fármacos , PPAR alfa/metabolismo , Fenilefrina/farmacologia , Fosforilação , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Triglicerídeos/metabolismo , Vasoconstritores/farmacologia , Vasodilatadores/farmacologiaRESUMO
SCOPE: One of the features of metabolic syndrome caused by liquid fructose intake is an impairment of redox status. We have investigated whether maternal fructose ingestion modifies the redox status in pregnant rats and their fetuses. METHODS AND RESULTS: Fructose (10% wt/vol) in the drinking water of rats throughout gestation, leads to maternal hepatic oxidative stress. However, this change was also observed in glucose-fed rats and, in fact, both carbohydrates produced a decrease in antioxidant enzyme activity. Surprisingly, mothers fed carbohydrates displayed low plasma lipid oxidation. In contrast, fetuses from fructose-fed mothers showed elevated levels of plasma lipoperoxides versus fetuses from control or glucose-fed mothers. Interestingly, a clearly augmented oxidative stress was observed in placenta of fructose-fed mothers, accompanied by a lower expression of the transcription factor Nuclear factor-erythroid 2-related factor-2 (Nrf2) and its target gene, heme oxygenase-1 (HO-1), a potent antioxidant molecule. Moreover, histone deacetylase 3 (HDAC3) that has been proposed to upregulate HO-1 expression by stabilizing Nrf2, exhibited a diminished expression in placenta of fructose-supplemented mothers. CONCLUSIONS: Maternal fructose intake provoked an imbalanced redox status in placenta and a clear diminution of HO-1 expression, which could be responsible for the augmented oxidative stress found in their fetuses.
Assuntos
Frutose/efeitos adversos , Heme Oxigenase (Desciclizante)/metabolismo , Exposição Materna/efeitos adversos , Estresse Oxidativo , Placenta/efeitos dos fármacos , Animais , Feminino , Feto/efeitos dos fármacos , Feto/metabolismo , Frutose/administração & dosagem , Heme Oxigenase (Desciclizante)/genética , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução/efeitos dos fármacos , Placenta/diagnóstico por imagem , Placenta/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Proteína 1 de Ligação a X-Box/genética , Proteína 1 de Ligação a X-Box/metabolismoRESUMO
Fructose intake from added sugars correlates with the epidemic rise in metabolic syndrome and related events. Nevertheless, consumption of beverages sweetened with fructose is not regulated in gestation. Previously, we found that maternal fructose intake produces in the progeny, when fetuses, impaired leptin signaling and hepatic steatosis and then impaired insulin signaling and hypoadiponectinemia in adult male rats. Interestingly, adult females from fructose-fed mothers did not exhibit any of these disturbances. However, we think that, actually, these animals keep a programmed phenotype hidden. Fed 240-day-old female progeny from control, fructose- and glucose-fed mothers were subjected for 3weeks to a fructose supplementation period (10% wt/vol in drinking water). Fructose intake provoked elevations in insulinemia and adiponectinemia in the female progeny independently of their maternal diet. In accordance, the hepatic mRNA levels of several insulin-responsive genes were similarly affected in the progeny after fructose intake. Interestingly, adult progeny of fructose-fed mothers displayed, in response to the fructose feeding, augmented plasma triglyceride and NEFA levels and hepatic steatosis versus the other two groups. In agreement, the expression and activity for carbohydrate response element binding protein (ChREBP), a lipogenic transcription factor, were higher after the fructose period in female descendants from fructose-fed mothers than in the other groups. Furthermore, liver fructokinase expression that has been indicated as one of those responsible for the deleterious effects of fructose ingestion was preferentially augmented in that group. Maternal fructose intake does influence the adult female offspring's response to liquid fructose and so exacerbates fructose-induced dyslipidemia and hepatic steatosis.
Assuntos
Bebidas/efeitos adversos , Dislipidemias/etiologia , Desenvolvimento Fetal , Frutose/efeitos adversos , Fenômenos Fisiológicos da Nutrição Materna , Hepatopatia Gordurosa não Alcoólica/etiologia , Adoçantes Calóricos/efeitos adversos , Adiponectina/agonistas , Adiponectina/sangue , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/agonistas , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Dislipidemias/sangue , Dislipidemias/metabolismo , Dislipidemias/fisiopatologia , Ácidos Graxos não Esterificados/agonistas , Ácidos Graxos não Esterificados/sangue , Feminino , Frutoquinases/química , Frutoquinases/genética , Frutoquinases/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Glucose/efeitos adversos , Hiperinsulinismo/sangue , Hiperinsulinismo/etiologia , Hiperinsulinismo/metabolismo , Hiperinsulinismo/fisiopatologia , Fígado/enzimologia , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Gravidez , Distribuição Aleatória , Ratos Sprague-Dawley , Triglicerídeos/agonistas , Triglicerídeos/sangueRESUMO
PURPOSE: Fructose intake from added sugars correlates with the epidemic rise in metabolic syndrome and cardiovascular diseases. However, consumption of beverages containing fructose is allowed during gestation. Recently, we found that an intake of fructose (10 % wt/vol) throughout gestation produces impaired fetal leptin signaling and hepatic steatosis. Therefore, we have investigated whether fructose intake during pregnancy produces subsequent changes in the progeny, when adult. METHODS: Fed 261-day-old male and female descendants from fructose-fed, control or glucose-fed mothers were used. Plasma was used to analyze glucose, insulin, leptin, and adiponectin. Hepatic expression of proteins related to insulin signaling was determined. RESULTS: Fructose intake throughout pregnancy did not produce alterations in the body weight of the progeny. Adult male progeny of fructose-fed mothers had elevated levels of insulin without a parallel increase in phosphorylation of protein kinase B. However, they displayed an augmented serine phosphorylation of insulin receptor substrate-2, indicating reduced insulin signal transduction. In agreement, adiponectin levels, which have been positively related to insulin sensitivity, were lower in male descendants from fructose-fed mothers than in the other two groups. Furthermore, mRNA levels for insulin-responsive genes were not affected (phosphoenolpyruvate carboxykinase, glucose-6-phosphatase) or they were decreased (sterol response element-binding protein-1c) in the livers of male progeny from fructose-supplemented rats. On the contrary, adult female rats from fructose-fed mothers did not exhibit any of these disturbances. CONCLUSION: Maternal fructose, but not glucose, intake confined to the prenatal stage provokes impaired insulin signal transduction, hyperinsulinemia, and hypoadiponectinemia in adult male, but not female, progeny.
Assuntos
Adiponectina/deficiência , Frutose/efeitos adversos , Hiperinsulinismo/etiologia , Resistência à Insulina , Fenômenos Fisiológicos da Nutrição Materna , Erros Inatos do Metabolismo/etiologia , Adiponectina/sangue , Animais , Animais Recém-Nascidos , Glicemia/metabolismo , Peso Corporal , Fígado Gorduroso/sangue , Fígado Gorduroso/etiologia , Feminino , Feto/efeitos dos fármacos , Feto/metabolismo , Frutose/administração & dosagem , Glucose-6-Fosfatase/genética , Glucose-6-Fosfatase/metabolismo , Hiperinsulinismo/sangue , Insulina/sangue , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Leptina/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Erros Inatos do Metabolismo/sangue , Fosfoenolpiruvato Carboxiquinase (ATP)/genética , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Fosforilação , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
Supplementation with 10% liquid fructose to female rats for 2weeks caused hepatic steatosis through increased lipogenesis and reduced peroxisome proliferator activated receptor (PPAR) α activity and fatty acid catabolism, together with increased expression of the spliced form of X-binding protein-1 (Rebollo et al., 2014). In the present study, we show that some of these effects are preserved after sub-chronic (8weeks) fructose supplementation, specifically increased hepatic expression of lipid synthesis-related genes (stearoyl-CoA desaturase, ×6.7-fold; acetyl-CoA carboxylase, ×1.6-fold; glycerol-3-phosphate acyltransferase, ×1.65-fold), and reduced fatty acid ß-oxidation (×0.77-fold), resulting in increased liver triglyceride content (×1.69-fold) and hepatic steatosis. However, hepatic expression of PPARα and its target genes was not modified and, further, livers of 8-week fructose-supplemented rats showed no sign of unfolded protein response activation, except for an increase in p-IRE1 levels. Hepatic mTOR phosphorylation was enhanced (×1.74-fold), causing an increase in the phosphorylation of UNC-51-like kinase 1 (ULK-1) (×2.8-fold), leading to a decrease in the ratio of LC3B-II/LC3B-I protein expression (×0.39-fold) and an increase in the amount of the autophagic substrate p62, indicative of decreased autophagy activity. A harmful cycle may be established in the liver of 8-week fructose-supplemented rats where lipid accumulation may cause defective autophagy, and reduced autophagy may result in decreased free fatty acid formation from triglyceride depots, thus reducing the substrates for ß-oxidation and further increasing hepatic steatosis. In summary, the length of supplementation is a key factor in the metabolic disturbances induced by fructose: in short-term studies, PPARα inhibition and ER stress induction are critical events, whereas after sub-chronic supplementation, mTOR activation and autophagy inhibition are crucial.
Assuntos
Autofagia , Estresse do Retículo Endoplasmático , Fígado Gorduroso/enzimologia , Frutose , Fígado/enzimologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Modelos Animais de Doenças , Ativação Enzimática , Ácidos Graxos/metabolismo , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Feminino , Regulação da Expressão Gênica , Glicólise/genética , Hipertrigliceridemia/induzido quimicamente , Hipertrigliceridemia/enzimologia , Hipertrigliceridemia/patologia , Lipogênese , Fígado/patologia , Oxirredução , PPAR alfa/metabolismo , Via de Pentose Fosfato/genética , Fosforilação , Ratos Sprague-Dawley , Transdução de Sinais , Fatores de Tempo , Triglicerídeos/metabolismoRESUMO
High consumption of fructose-sweetened beverages has been linked to a high prevalence of chronic metabolic diseases. We have previously shown that a short course of fructose supplementation as a liquid solution induces glucose intolerance in female rats. In the present work, we characterized the fructose-driven changes in the liver and the molecular pathways involved. To this end, female rats were supplemented or not with liquid fructose (10%, w/v) for 7 or 14 days. Glucose and pyruvate tolerance tests were performed, and the expression of genes related to insulin signaling, gluconeogenesis and nutrient sensing pathways was evaluated. Fructose-supplemented rats showed increased plasma glucose excursions in glucose and pyruvate tolerance tests and reduced hepatic expression of several genes related to insulin signaling, including insulin receptor substrate 2 (IRS-2). However, the expression of key gluconeogenic enzymes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, was reduced. These effects were caused by an inactivation of hepatic forkhead box O1 (FoxO1) due to an increase in its acetylation state driven by a reduced expression and activity of sirtuin 1 (SIRT1). Further contributing to FoxO1 inactivation, fructose consumption elevated liver expression of the spliced form of X-box-binding-protein-1 as a consequence of an increase in the activity of the mammalian target of rapamycin 1 and protein 38-mitogen activated protein kinase (p38-MAPK). Liquid fructose affects both insulin signaling (IRS-2 and FoxO1) and nutrient sensing pathways (p38-MAPK, mTOR and SIRT1), thus disrupting hepatic insulin signaling without increasing the expression of key gluconeogenic enzymes.
Assuntos
Regulação para Baixo , Frutose/metabolismo , Gluconeogênese , Proteínas Substratos do Receptor de Insulina/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Reação em Cadeia da Polimerase , RatosRESUMO
Fructose ingestion is associated with the production of hepatic steatosis and hypertriglyceridemia. For fructose to attain these effects in rats, simultaneous induction of fatty acid synthesis and inhibition of fatty acid oxidation is required. We aimed to determine the mechanism involved in the inhibition of fatty acid oxidation by fructose and whether this effect occurs also in human liver cells. Female rats were supplemented or not with liquid fructose (10% w/v) for 7 or 14 days; rat (FaO) and human (HepG2) hepatoma cells, and human hepatocytes were incubated with fructose 25mM for 24h. The expression and activity of the enzymes and transcription factors relating to fatty acid ß-oxidation were evaluated. Fructose inhibited the activity of fatty acid ß-oxidation only in livers of 14-day fructose-supplemented rats, as well as the expression and activity of peroxisome proliferator activated receptor α (PPARα). Similar results were observed in FaO and HepG2 cells and human hepatocytes. PPARα downregulation was not due to an osmotic effect or to an increase in protein-phosphatase 2A activity caused by fructose. Rather, it was related to increased content in liver of inactive and acetylated peroxisome proliferator activated receptor gamma coactivator 1α, due to a reduction in sirtuin 1 expression and activity. In conclusion, fructose inhibits liver fatty acid oxidation by reducing PPARα expression and activity, both in rat and human liver cells, by a mechanism involving sirtuin 1 down-regulation.
Assuntos
Ácidos Graxos/metabolismo , Frutose/farmacologia , Fígado/efeitos dos fármacos , Sirtuína 1/biossíntese , Animais , Ácidos Graxos/antagonistas & inibidores , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Fígado/patologia , Oxirredução , PPAR alfa/biossíntese , PPAR alfa/metabolismo , Ratos , Sirtuína 1/genéticaRESUMO
Fructose intake from added sugars correlates with the epidemic rise in obesity, metabolic syndrome and cardiovascular diseases. Fructose intake also causes features of metabolic syndrome in laboratory animals. Therefore, we have investigated whether fructose modifies lipidemia in pregnant rats and produces changes in their fetuses. Thus, fructose administration (10% wt/vol.) in the drinking water of rats throughout gestation leads to maternal hypertriglyceridemia. This change was not observed in glucose-fed rats, although both carbohydrates produced similar changes in liver triglycerides and in the expression of transcription factors and enzymes involved in lipogenesis. After fasting overnight, mothers fed with carbohydrates were found to be hyperleptinemic. However, after a bolus of glucose, leptinemia in fructose-fed mothers showed no response, whereas it increased in parallel in glucose-fed and control mothers. Fetuses from fructose-fed mothers showed hypotriglyceridemia and a higher hepatic triglyceride content than fetuses from control or glucose-fed mothers. A higher expression of genes related to lipogenesis and a lower expression of fatty acid catabolism genes were also found in fetuses from fructose-fed mothers. Moreover, although hyperleptinemic, these fetuses exhibited increased tyrosine phosphorylation of the signal transducer and activator of transcription-3 (STAT-3) protein, without a parallel increase in the serine phosphorylation of STAT-3 nor in the suppressor of cytokine signaling-3 protein levels whose expression is regulated by leptin through STAT-3 activation. Thus, fructose intake during gestation provoked a diminished maternal leptin response to fasting and refeeding and an impairment in the transduction of the leptin signal in the fetuses, which could be responsible for their hepatic steatosis.
Assuntos
Feto/metabolismo , Frutose/administração & dosagem , Leptina/fisiologia , Transdução de Sinais/efeitos dos fármacos , Animais , Glicemia/metabolismo , Jejum , Feminino , Alimentos , Glucose/metabolismo , Hipertrigliceridemia/etiologia , Gravidez , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Triglicerídeos/metabolismoRESUMO
The World Health Organization recommends that the daily intake of added sugars should make up no more than 10% of total energy. The consumption of sugar-sweetened beverages is the main source of added sugars. Fructose, together with glucose, as a component of high fructose corn syrups or as a component of the sucrose molecule, is one of the main sweeteners present in this kind of beverages. Data from prospective and intervention studies clearly point to high fructose consumption, mainly in the form of sweetened beverages, as a risk factor for several metabolic diseases in humans. The incidence of hypertension, nonalcoholic fatty liver disease (NAFLD), dyslipidemia (mainly hypertriglyceridemia), insulin resistance, type 2 diabetes mellitus, obesity, and the cluster of many of these pathologies in the form of metabolic syndrome is higher in human population segments that show high intake of fructose. Adolescent and young adults from low-income families are especially at risk. We recently reviewed evidence from experimental animals and human data that confirms the deleterious effect of fructose on lipid and glucose metabolism. In this present review we update the information generated in the past 2 years about high consumption of fructose-enriched beverages and the occurrence of metabolic disturbances, especially NAFLD, type 2 diabetes mellitus, and metabolic syndrome. We have explored recent data from observational and experimental human studies, as well as experimental data from animal and cell models. Finally, using information generated in our laboratory and others, we provide a view of the molecular mechanisms that may be specifically involved in the development of liver lipid and glucose metabolic alterations after fructose consumption in liquid form.
Assuntos
Frutose/metabolismo , Fígado/metabolismo , Animais , Bebidas , Pesquisa Biomédica , Dieta , Dislipidemias/etiologia , Fígado Gorduroso/etiologia , Humanos , Síndrome Metabólica/complicações , Camundongos , Hepatopatia Gordurosa não Alcoólica , Obesidade/complicações , Fosforilação , RatosRESUMO
Although metabolic syndrome (MS) and systemic lupus erythematosus (SLE) are often associated, a common link has not been identified. Using the BWF1 mouse, which develops MS and SLE, we sought a molecular connection to explain the prevalence of these two diseases in the same individuals. We determined SLE- markers (plasma anti-ds-DNA antibodies, splenic regulatory T cells (Tregs) and cytokines, proteinuria and renal histology) and MS-markers (plasma glucose, non-esterified fatty acids, triglycerides, insulin and leptin, liver triglycerides, visceral adipose tissue, liver and adipose tissue expression of 86 insulin signaling-related genes) in 8-, 16-, 24-, and 36-week old BWF1 and control New-Zealand-White female mice. Up to week 16, BWF1 mice showed MS-markers (hyperleptinemia, hyperinsulinemia, fatty liver and visceral adipose tissue) that disappeared at week 36, when plasma anti-dsDNA antibodies, lupus nephritis and a pro-autoimmune cytokine profile were detected. BWF1 mice had hyperleptinemia and high splenic Tregs till week 16, thereby pointing to leptin resistance, as confirmed by the lack of increased liver P-Tyr-STAT-3. Hyperinsulinemia was associated with a down-regulation of insulin related-genes only in adipose tissue, whereas expression of liver mammalian target of rapamicyn (mTOR) was increased. Although leptin resistance presented early in BWF1 mice can slow-down the progression of autoimmunity, our results suggest that sustained insulin stimulation of organs, such as liver and probably kidneys, facilitates the over-expression and activity of mTOR and the development of SLE.
Assuntos
Fígado/enzimologia , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Anticorpos Antinucleares/sangue , Biomarcadores/metabolismo , Peso Corporal , Citocinas/metabolismo , Modelos Animais de Doenças , Comportamento Alimentar , Feminino , Regulação da Expressão Gênica , Humanos , Insulina/sangue , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Leptina/sangue , Fígado/patologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Síndrome Metabólica/metabolismo , Camundongos , Proteinúria/sangue , Proteinúria/complicações , Proteinúria/metabolismo , Triglicerídeos/metabolismoRESUMO
This short review comments on the recently published work of Ishimoto et al regarding the opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice. The framework for the commentary is the preexisting background of epidemiological and experimental data regarding the association between ingestion of fructose, as present in sweetened beverages, and the development of metabolic syndrome. The work of Ishimoto et al clearly confirms the negative effect of fructose on lipid and glucose metabolism, independently from the amount of energy provided by the ingested sugar. It also confirms the absolute requirement of liver fructose metabolism, driven by fructokinase activity, in order to develop the full spectrum of metabolic syndrome alterations.
RESUMO
Aging is associated with a loss of cellular homeostasis, a decline in physiological function and an increase in various pathologies. Employing a meta-analysis, hepatic gene expression profiles from four independent mouse aging studies were interrogated. There was little overlap in the number of genes or canonical pathways perturbed, suggesting that independent study-specific factors may play a significant role in determining age-dependent gene expression. However, 43 genes were consistently altered during aging in three or four of these studies, including those that (1) exhibited progressively increased expression starting from 12 months of age, (2) exhibited similar expression changes in models of progeria at young ages and dampened or no changes in old longevity mouse models, (3) were associated with inflammatory tertiary lymphoid neogenesis (TLN) associated with formation of ectopic lymphoid structures observed in chronically inflamed tissues, and (4) overlapped with genes perturbed by aging in brain, muscle, and lung. Surprisingly, around half of the genes altered by aging in wild-type mice exhibited similar expression changes in adult long-lived mice compared to wild-type controls, including those associated with intermediary metabolism and feminization of the male-dependent gene expression pattern. Genes unique to aging in wild-type mice included those linked to TLN.
Assuntos
Envelhecimento/fisiologia , Regulação da Expressão Gênica/fisiologia , Fígado/metabolismo , Transcriptoma/fisiologia , Animais , Biomarcadores/metabolismo , Inflamação/metabolismo , Masculino , CamundongosRESUMO
Atherosclerosis is a pathological phenomenon in which the walls of large arteries thicken and lose elasticity as a result of the growth of atheromatous lesions. It is a complex, multifactorial disease that involves several cell types and various pathobiological processes. Its genetic basis has not yet been deciphered, but it is related to complex multigene patterns influenced by environmental interactions. In this review, we focus specifically on the application of microarrays to atherosclerosis research using monocytes and monocyte-derived macrophages, as these are key cells in all phases of atherosclerosis, from the formation of foam cells to the destabilization and rupture of the atherosclerotic plaque. These studies have provided relevant information on genes involved in atherosclerosis development, contributing to our understanding of the molecular mechanisms that underlie this complex disease.