RESUMO
Metabolic reprogramming is recognized as a hallmark of cancer, enabling cancer cells to acquire essential biomolecules for cell growth, often characterized by upregulated glycolysis and/or fatty acid synthesis-related genes. The transcription factor forkhead box M1 (FOXM1) has been implicated in various cancers, contributing significantly to their development, including colorectal cancer (CRC), a major global health concern. Despite FOXM1's established role in cancer, its specific involvement in the Warburg effect and fatty acid biosynthesis in CRC remains unclear. We analyzed The Cancer Genome Atlas (TCGA) Colonic Adenocarcinoma and Rectal Adenocarcinoma (COADREAD) datasets to derive the correlation of the expression levels between FOXM1 and multiple genes and the survival prognosis based on FOXM1 expression. Using two human CRC cell lines, HT29 and HCT116, we conducted RNAi or plasmid transfection procedures, followed by a series of assays, including RNA extraction, quantitative real-time polymerase chain reaction, Western blot analysis, cell metabolic assay, glucose uptake assay, Oil Red O staining, cell viability assay, and immunofluorescence analysis. Higher expression levels of FOXM1 correlated with a poorer survival prognosis, and the expression of FOXM1 was positively correlated with glycolysis-related genes SLC2A1 and LDHA, de novo lipogenesis-related genes ACACA and FASN, and MYC. FOXM1 appeared to modulate AKT/mammalian target of rapamycin (mTOR) signaling, the expression of c-Myc, proteins related to glycolysis and fatty acid biosynthesis, and glucose uptake, as well as extracellular acidification rate in HT29 and HCT116 cells. In summary, FOXM1 plays a regulatory role in glycolysis, fatty acid biosynthesis, and cellular energy consumption, thereby influencing CRC cell growth and patient prognosis.NEW & NOTEWORTHY Transcription factor forkhead box M1 (FOXM1) regulates glycolysis, fatty acid biosynthesis, and cellular energy consumption, which, together, controls cell growth and patient prognosis in colorectal cancer (CRC).
Assuntos
Neoplasias Colorretais , Proteína Forkhead Box M1 , Humanos , Proteína Forkhead Box M1/metabolismo , Proteína Forkhead Box M1/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Células HT29 , Células HCT116 , Glicólise , Regulação Neoplásica da Expressão Gênica , Efeito Warburg em Oncologia , Transdução de Sinais , Proliferação de Células , Reprogramação Celular/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Reprogramação MetabólicaRESUMO
BACKGROUND: Dietary frying oil may have endocrine-disrupting effects, as a feminization effect was observed in cohorts of C57BL/6J male mice fetuses from dams consuming oxidized frying oil (OFO) during pregnancy. OBJECTIVE: The aim of present study was to test the hypothesis that OFO is an anti-androgen. METHODS: In experiment 1, male progeny of Sprague Dawley female rats fed fresh oil or an OFO diet (10 g fat/100 g, from fresh or 24-h-fried soybean oil; [control diet (C) and OFO groups, respectively] from midgestation through lactation were studied. Pups were weaned at 3 wk of age and then consumed their mothers' diet until 9 wk of age. In addition, a group of dams and pups that consumed a high-fat diet (HF; 10 g fried and 20 g fresh soybean oil/100 g) was included to counteract body-weight loss associated with OFO ingestion. Indices of male reproductive development and testosterone homeostasis were measured. In experiment 2, male rats were allocated to C and OFO groups (treated as above) and indices of male fertility compared at 9-10 wk of age. RESULTS: In experiment 1, final body weights of the HF group were lower (17%) than the C group but higher (14%) than the OFO group (P < 0.0001 for each). In addition to abnormalities in seminiferous tubules, HF and OFO groups did not differ from one another, but, compared with the C group, had delayed preputial separation (4.9 d) and reductions in serum testosterone concentrations (17-74%), anogenital distance (8-20%), weights of androgen-dependent tissues (8-30%), testicular testosterone and cholesterol concentrations (30-40%), and mRNA levels of genes involved in steroidogenesis and cholesterol homeostasis (30-70%). In experiment 2, OFO-exposed males had 20% lower sperm motility (P < 0.05); however, when mated to normal females, pregnancy rates and litter sizes did not differ between OFO and C groups. CONCLUSIONS: The anti-androgenic effect of OFO in Sprague Dawley rats was attributed to decreased testicular concentrations of cholesterol (testosterone precursor) and not body-weight loss.
Assuntos
Colesterol/metabolismo , Homeostase/efeitos dos fármacos , Óleo de Soja/toxicidade , Testículo/efeitos dos fármacos , Testosterona/metabolismo , Fenômenos Fisiológicos da Nutrição Animal , Animais , Culinária , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/toxicidade , Feminino , Masculino , Oxirredução , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Fenômenos Fisiológicos da Nutrição Pré-Natal , Ratos , Ratos Sprague-Dawley , Testículo/metabolismoRESUMO
The objective was to investigate endocrine-disrupting effects of polar compounds from oxidized frying oil. Estrogenicity of polar compounds was tested with a rat uterotrophic bioassay. Dietary oxidized frying oil (containing 51% polar compounds) or polar compounds isolated from it were incorporated into feed (in lieu of fresh soybean oil) and fed to ovariectomized rats, with or without treatment with exogenous ethynyl estradiol. Exogenous estrogen restored uterine weight, and caused histological abnormalities (stratified epithelia and conglomerate glands) as well as proliferation of uterine epithelial cells. However, tamoxifen or polar compounds reduced these effects. Furthermore, tamoxifen or polar compounds down-regulated uterine mRNA expression of estrogen receptor (ER)-target genes, implicating reduced ER activity in this hypo-uterotrophic effect. Inhibition of ER signaling and mitosis by polar compounds were attributed to reduced MAPK and AKT activation, as well as a reduced ligand binding domain-transactivity of ERα/ß. We concluded polar compounds from frying oil are potential endocrine-disrupting chemicals, with implications for food and environmental safety.
Assuntos
Disruptores Endócrinos/toxicidade , Antagonistas de Estrogênios/toxicidade , Animais , Culinária , Dieta , Estrogênios/farmacologia , Etinilestradiol/farmacologia , Feminino , Oxirredução , Ratos , Receptores de Estrogênio/antagonistas & inibidores , Receptores de Estrogênio/metabolismo , Óleo de Soja , Tamoxifeno/toxicidade , Útero/efeitos dos fármacos , Útero/metabolismo , Útero/patologiaRESUMO
We previously reported that polar compounds (PO) in cooking oil are teratogenic and perturbed retinoic acid (RA) metabolism. Considering PO as a potent peroxisome proliferator-activated receptor α (PPARα) activator, this study aimed to investigate the role of PPARα in PO-induced teratogenesis and disturbance of RA metabolism. Female PPARα knockout or wild type mice were mated with males of the same genotype. Pregnant mice were fed a diet containing 10% fat from either fresh oil (FO) or PO from gestational day1 to day18, and killed at day18. The PO diet significantly increased the incidence of teratogenesis and fetal RA concentrations, regardless of genotype. Though PPARα deficiency disturbed maternal RA homeostasis, itself did not contribute to teratogenesis as long as FO diet was given. The mRNA profile of genes involved in RA metabolism was differentially affected by diet or genotype in mothers and fetuses. Based on hepatic mRNA levels of genes involved in xenobiotic metabolism, we inferred that PO not only activated PPARα, but also altered transactivity of other xenobiotic receptors. We concluded that PO-induced fetal anomalies and RA accumulation were independent of PPARα activation.
Assuntos
Gorduras Insaturadas na Dieta/farmacologia , Óxidos , PPAR alfa/metabolismo , Teratogênese , Animais , Gorduras Insaturadas na Dieta/efeitos adversos , Feminino , Expressão Gênica , Camundongos , Camundongos Knockout , Óxidos/química , PPAR alfa/deficiência , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodução/efeitos dos fármacos , Teratogênese/efeitos dos fármacos , Teratogênese/genética , Teratogênicos/química , Teratogênicos/farmacologia , Vitamina A/farmacologiaRESUMO
The aim of this study was to investigate whether maternal ingestion of oxidized frying oil (OFO) during pregnancy influences the susceptibility to diet-induced obesity (DIO) of the adult offspring. Pregnant C57BL/6J mice were fed either a control diet [10% fresh soybean oil (SO)] or an OFO-containing diet (10% OFO) throughout the entire gestational period. After parturition, all pups were nursed by SO-fed dams for 3 wk, weaned onto a nonpurified standard diet for 4 wk, and shifted to a high-fat diet (29% butter + 1% SO) for 5 wk. Consequently, 4 groups of offspring were obtained, consisting of the male (m) or female (f) offspring of dams fed the OFO diet (OFO-m and OFO-f) or the SO diet (SO-m and SO-f). At pregnancy d 18, higher amounts (P < 0.05) of mRNA for PPARα target genes were found in the liver of the OFO-fed dams and their fetuses than in their SO controls. Although all pups were raised under the same conditions in postnatal life, a comparison based on the gender of pups from dams fed the different diets showed that adult OFO-f mice were prone to DIO, whereas adult OFO-m mice were resistant. The adult OFO-m mice also had higher expression of PPARα target genes in the liver and white adipose tissue (WAT) and of thermogenic genes in the WAT than adult SO-m mice, whereas adult OFO-f and SO-f mice did not differ. We conclude that uterine PPARα activation caused by maternal OFO ingestion affects hepatic PPARα activity and adipose thermogenic capacity and contributes to the differential susceptibility to DIO in the male and female offspring in adulthood.
Assuntos
Culinária/métodos , Dieta/efeitos adversos , Gorduras na Dieta/farmacologia , Obesidade/etiologia , Efeitos Tardios da Exposição Pré-Natal , Fatores Sexuais , Óleo de Soja/farmacologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Gorduras na Dieta/metabolismo , Feminino , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Oxirredução , PPAR alfa/genética , PPAR alfa/metabolismo , Gravidez , RNA Mensageiro/metabolismo , Óleo de Soja/metabolismo , Termogênese/efeitos dos fármacos , Termogênese/genéticaRESUMO
Few studies on humans have comprehensively evaluated the intake composition of methyl-donor nutrients (MDNs: choline, betaine, and folate) in relation to visceral obesity (VOB)-related hepatic steatosis (HS), the hallmark of non-alcoholic fatty liver diseases. In this case-control study, we recruited 105 patients with HS and 104 without HS (controls). HS was diagnosed through ultrasound examination. VOB was measured using a whole-body analyzer. MDN intake was assessed using a validated quantitative food frequency questionnaire. After adjustment for multiple HS risk factors, total choline intake was the most significant dietary determinant of HS in patients with VOB (Beta: -0.41, p = 0.01). Low intake of choline (<6.9 mg/kg body weight), betaine (<3.1 mg/kg body weight), and folate (<8.8 µg/kg body weight) predicted increased odds ratios (ORs) of VOB-related HS (choline: OR: 22, 95% confidence interval [CI]: 6.5-80; betaine: OR: 14, 95% CI: 4.4-50; and folate: OR: 19, 95% CI: 5.2-74). Combined high intake of choline and betaine, but not folate, was associated with an 81% reduction in VOB-related HS (OR: 0.19, 95% CI: 0.05-0.69). Our data suggest that the optimal intake of choline and betaine can minimize the risk of VOB-related HS in a threshold-dependent manner.
Assuntos
Betaína/administração & dosagem , Colina/administração & dosagem , Fígado Gorduroso/prevenção & controle , Ácido Fólico/administração & dosagem , Obesidade Abdominal/complicações , Adiposidade , Idoso , Biomarcadores/sangue , Composição Corporal , Estudos de Casos e Controles , Registros de Dieta , Ingestão de Alimentos , Fígado Gorduroso/sangue , Fígado Gorduroso/diagnóstico por imagem , Fígado Gorduroso/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade Abdominal/sangue , Obesidade Abdominal/diagnóstico , Razão de Chances , Taiwan , UltrassonografiaRESUMO
Tumour metabolomics and transcriptomics co-expression network as related to biological folate alteration and cancer malignancy remains unexplored in human non-small cell lung cancers (NSCLC). To probe the diagnostic biomarkers, tumour and pair lung tissue samples (n = 56) from 97 NSCLC patients were profiled for ultra-performance liquid chromatography tandem mass spectrometry (UPLC/MS/MS)-analysed metabolomics, targeted transcriptionomics, and clinical folate traits. Weighted Gene Co-expression Network Analysis (WGCNA) was performed. Tumour lactate was identified as the top VIP marker to predict advance NSCLC (AUC = 0.765, Sig = 0.017, CI 0.58-0.95). Low folate (LF)-tumours vs. adjacent lungs displayed higher glycolytic index of lactate and glutamine-associated amino acids in enriched biological pathways of amino sugar and glutathione metabolism specific to advance NSCLCs. WGCNA classified the green module for hub serine-navigated glutamine metabolites inversely associated with tumour and RBC folate, which module metabolites co-expressed with a predominant up-regulation of LF-responsive metabolic genes in glucose transport (GLUT1), de no serine synthesis (PHGDH, PSPH, and PSAT1), folate cycle (SHMT1/2 and PCFR), and down-regulation in glutaminolysis (SLC1A5, SLC7A5, GLS, and GLUD1). The LF-responsive WGCNA markers predicted poor survival rates in lung cancer patients, which could aid in optimizing folate intervention for better prognosis of NSCLCs susceptible to folate malnutrition.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Ácido Fólico , Glutamina/metabolismo , Espectrometria de Massas em Tandem , Prognóstico , Metabolômica/métodos , Antígenos de Histocompatibilidade Menor , Sistema ASC de Transporte de AminoácidosRESUMO
Microglia are the resident macrophages in the central nervous system. Brain injuries, such as traumatic brain injury, hypoxia, and stroke, can induce inflammatory responses accompanying microglial activation. The morphology of microglia is notably diverse and is one of the prominent manifestations during activation. In this study, we proposed to detect the activated microglia in immunohistochemistry images by convolutional neural networks (CNN). 2D Iba1 images (40µm) were acquired from a control and a cardiac arrest treated Sprague-Dawley rat brain by a scanning microscope using a 20X objective. The training data were a collection of 54,333 single-cell images obtained from the cortex and midbrain areas, and curated by experienced neuroscientists. Results were compared between CNNs with different architectures, including Resnet18, Resnet50, Resnet101, and support vector machine (SVM) classifiers. The highest model performance was found by Resnet18, trained after 120 epochs with a classification accuracy of 95.5%. The findings indicate a potential application for using CNN in quantitative analysis of microglial morphology over regional difference in a large brain section.
RESUMO
With regards to cardiovascular health, frequent consumption of fried foods is discouraged, despite a lack of clear evidence of a direct link between eating oxidative frying oil (OFO) and cardiovascular diseases. In this study, male Sprague Dawley rats were exposed to diets containing fresh or fried soybean oil (groups C and O, respectively) from in utero to 28 weeks of age. A subset of rats in group O was supplemented with vitamin E (500 mg/kg of DL-α-tocopherol acetate; group OE) from 8 week of age onward to mitigate oxidative stress associated with OFO ingestion. Echocardiography, cardiac histology and indices associated with ATP production and calcium cycling in cardiac tissues were measured. Compared to group C, there was cardiac hypertrophy, fibrosis and diastolic dysfunction, in groups O and OE, with no differences between the latter two groups. Although cardiac mRNA levels of genes associated with mitochondrial biogenesis and function were increased, there were lower ATP concentrations and higher transcripts of uncoupling proteins in groups O and OE than in group C. In addition, decreases in phosphorylation of phospholamban and Ca2+/calmodulin-dependent protein kinase II activity, plus increased protein phosphatase 2A activity in groups O and OE, implied calcium cycling required for cardiac function was disrupted by OFO consumption. We concluded that long-term OFO exposure resulted in cardiac hypertrophy, fibrosis and diastolic dysfunction that was not mitigated by vitamin E supplementation. Underlying mechanisms were partly attributed to inefficient energy production via uncoupled phosphorylation and disrupted calcium cycling.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Cálcio/metabolismo , Cardiomegalia/etiologia , Óleo de Soja/efeitos adversos , Vitamina E/farmacologia , Animais , Antioxidantes/farmacologia , Proteínas de Ligação ao Cálcio/metabolismo , Culinária/métodos , Dieta/métodos , Feminino , Fibrose/etiologia , Masculino , Miocárdio/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Óleo de Soja/farmacologiaRESUMO
BACKGROUND: Establishing animal models with metabolic disorders similar to human metabolic syndrome (MS) is important. In terms of eliciting a full array of MS, we have previously shown that Wistar rats are more responsive to sucrose water drinking than are C57BL/6J mice. This study was aimed at investigating the underlying molecular mechanism of sucrose water-induced MS in Wistar rats. METHODS: Male Wistar rats were divided into 2 groups (n = 8 for each group) which were given plain water (C group) or 30% sucrose water (SW group) to drink ad libitum. After 20 weeks, the transcriptional levels and protein translocation of hepatic sterol regulatory element-binding protein-1c (SREBP-1c) and carbohydrate response element-binding protein (ChREBP) as well as the protein levels of protein tyrosine phosphatase-1B (PTP-1B) in insulin-responsive tissues (liver, muscle, and adipose tissue) were measured. RESULTS: The sucrose water regimen successfully elicited visceral obesity, hypertriglyceridemia, insulin resistance, and high blood pressure. The upregulation of de novo lipogenesis in the liver of the sucrose water-treated rats was demonstrated by an increased activity of enzymes, mRNA levels of lipogenic proteins, and nuclear levels of SREBP-1c and ChREBP. Moreover, in the sucrose water-treated rats, protein levels of PTP-1B were significantly increased in liver and skeletal muscle but decreased in adipose tissue. CONCLUSION: The susceptibility of Wistar rats to sucrose water-induced MS is associated with the transactivation of SREBP-1c and ChREBP in the liver, and PTP-1B is involved in the upregulation of de novo lipogenesis in the liver and the pathology of systemic insulin resistance in rats with MS chronically induced by drinking sucrose water.
Assuntos
Lipogênese/genética , Fígado/metabolismo , Síndrome Metabólica/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Regulação para Cima , Animais , Glicemia/metabolismo , Sacarose Alimentar/administração & dosagem , Sacarose Alimentar/efeitos adversos , Sacarose Alimentar/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Resistência à Insulina , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
Some candidate genes have been robustly reported to be associated with complex traits, such as the fat mass and obesity-associated (FTO) gene on body mass index (BMI), and the fibroblast growth factor 5 (FGF5) gene on blood pressure levels. It is of interest to know whether an environmental factor (E) can attenuate or exacerbate the adverse influence of a candidate gene. To this end, we here evaluate the performance of "genetic risk score" (GRS) approaches to detect "gene-environment interactions" (G × E). In the first stage, a GRS is calculated according to the genotypes of variants in a candidate gene. In the second stage, we test whether E can significantly modify this GRS effect. This two-stage procedure can not only provide a p-value for a G × E test but also guide inferences on how E modifies the adverse effect of a gene. With systematic simulations, we compared several ways to construct a GRS. If E exacerbates the adverse influence of a gene, GRS formed by the elastic net (ENET) or the least absolute shrinkage and selection operator (LASSO) is recommended. However, the performance of ENET or LASSO will be compromised if E attenuates the adverse influence of a gene, and using the ridge regression (RIDGE) can be more powerful in this situation. Applying RIDGE to 18,424 subjects in the Taiwan Biobank, we showed that performing regular exercise can attenuate the adverse influence of the FTO gene on four obesity measures: BMI (p = 0.0009), body fat percentage (p = 0.0031), waist circumference (p = 0.0052), and hip circumference (p = 0.0001). As another example, we used RIDGE and found the FGF5 gene has a stronger effect on blood pressure in Han Chinese with a higher waist-to-hip ratio [p = 0.0013 for diastolic blood pressure (DBP) and p = 0.0027 for systolic blood pressure (SBP)]. This study provides an evaluation on the GRS approaches, which is important to infer whether E attenuates or exacerbates the adverse influence of a candidate gene.
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Antidiabetic properties of red yeast rice, bitter gourd, and chromium have gained scientific support. This study aimed to test whether a nutraceutical combination of these 3 materials prevented dedifferentiation of pancreatic ß cells. Male db/db mice (8 weeks of age) were allocated into four groups (DB, DB/L, DB/M, and DB/H; n = 8-10) and fed a high-fat diet containing 0%, 0.2%, 0.4%, or 1% nutraceutical, respectively, whereas wild-type mice receiving a standard diet served as a healthy control (C; n = 10). The nutraceutical contained 10 mg/g monacolin K, 165 µg/g chromium, and 300 mg/g bitter gourd. After 8-weeks dietary treatment, diabetic syndromes (including hyperglycemia, hyperphagia, excessive drinking, polyuria, glucosuria, albuminuria, and glucose intolerance), were improved by the nutraceutical in a dose-dependent fashion. Decreased insulin and increased glucagon in serum and pancreatic islets in db/db mice were abolished in the DB/H group. Furthermore, supplementation curtailed dedifferentiation of ß cells, as evidenced by decreasing the dedifferentiation marker (Aldh1a3) and increasing ß-cell-enriched genes and transcription factors (Ins1, Ins2, FOXO1, and NKX6.1), as well as nuclear localization of NKX6.1 in pancreatic islets when compared to the DB group. We concluded that this nutraceutical, a combination of Monascus purpureus, Momordica charantia, and chromium, could be used as an adjunct for type 2 diabetes treatment and delay disease progression by sustaining ß-cell function.
RESUMO
The phase behavior and morphological characteristics of monolayers composed of equimolar mixed cationic-anionic surfactants at the air/water interface were investigated by measurements of surface pressure-area per alkyl chain (pi-A) and surface potential-area per alkyl chain (DeltaV-A) isotherms with Brewster angle microscope (BAM) observations. Cationic single-alkyl ammonium bromides and anionic sodium single-alkyl sulfates with alkyl chain length ranging from C(12) to C(16) were used to form mixed surfactant monolayers on the water subphase at 21 degrees C by a co-spreading approach. The results demonstrated that when the monolayers were at states with larger areas per alkyl chain during the monolayer compression process, the DeltaV-A isotherms were generally more sensitive than the pi-A isotherms to the molecular orientation variations. For the mixed monolayer components with longer alkyl chains, a close-packed monolayer with condensed monolayer characteristics resulted apparently due to the stronger dispersion interaction between the molecules. BAM images also revealed that with the increase in the alkyl chain length of the surfactants in the mixed monolayers, the condensed/collapse phase formation of the monolayers during the interface compression stage became pronounced. In addition, the variations in the condensed monolayer morphology of the equimolar mixed cationic-anionic surfactants were closely related to the alkyl chain lengths of the components.
RESUMO
α-Eleostearic acid (α-ESA), or the cis-9, trans-11, trans-13 isomer of conjugated linolenic acid, is a special fatty acid present at high levels in bitter melon seed oil. The aim of this study was to examine the effect of α-ESA on hepatic lipid metabolism. Using H4IIEC3 hepatoma cell line, we showed that α-ESA significantly lowered intracellular triglyceride accumulation compared to α-linolenic acid (LN), used as a fatty acid control, in a dose- and time-dependent manner. The effects of α-ESA on enzyme activities and mRNA profiles in H4IIEC3 cells suggested that enhanced fatty acid oxidation and lowered lipogenesis were involved in α-ESA-mediated triglyceride lowering effects. In addition, α-ESA triggered AMP-activated protein kinase (AMPK) activation without altering sirtuin 1 (SIRT1) protein levels. When cells were treated with vehicle control (VC), LN alone (LN; 100µmol/L) or in combination with α-ESA (LN+α-ESA; 75+25µmol/L) for 24h, acetylation of forkhead box protein O1 was decreased, while the NAD(+)/NADH ratio, mRNA levels of NAMPT and PTGR1 and enzyme activity of nicotinamide phosphoribosyltransferase were increased by LN+α-ESA treatment compared to treatment with LN alone, suggesting that α-ESA activates SIRT1 by increasing NAD(+) synthesis and NAD(P)H consumption. The antisteatosis effect of α-ESA was confirmed in mice treated with a high-sucrose diet supplemented with 1% α-ESA for 5weeks. We conclude that α-ESA favorably affects hepatic lipid metabolism by increasing cellular NAD(+)/NADH ratio and activating PPARα, AMPK and SIRT1 signaling pathways.
Assuntos
Suplementos Nutricionais , Regulação Enzimológica da Expressão Gênica , Hepatócitos/metabolismo , Hipolipemiantes/uso terapêutico , Ácidos Linoleicos Conjugados/uso terapêutico , Ácidos Linolênicos/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Proteínas Quinases Ativadas por AMP/química , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Ativação Enzimática , Hepatócitos/enzimologia , Hipertrigliceridemia/sangue , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/prevenção & controle , Hipolipemiantes/metabolismo , Ácidos Linoleicos Conjugados/metabolismo , Ácidos Linolênicos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Momordica charantia/química , NAD/química , NAD/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Oxirredução , PPAR alfa/agonistas , PPAR alfa/metabolismo , Ratos , Sementes/química , Transdução de Sinais , Sirtuína 1/química , Sirtuína 1/metabolismo , Células Tumorais CultivadasRESUMO
We previously observed a higher incidence of congenital malformations in the fetuses of dams fed an oxidized frying oil (OFO)-containing diet during pregnancy. In this study, we hypothesized that, during pregnancy, maternal ingestion of OFO, specifically the oxidized components (i.e. the polar fraction), modulates peroxisome proliferator-activated receptor (PPARα) or aryl hydrocarbon receptor (AhR) transactivity, altering the metabolism of retinoic acid (RA), a well-characterized morphogen, resulting in teratogenesis. Pregnant C57BL/6J mice were divided into four groups which, from d1 (conception) to d18, were fed a diet containing 10 g/100 g of fresh soybean oil (SO), OFO or the non-polar (NP) or polar (PO) fraction of OFO. Reporter assays testing the transactivity of PPARα and AhR showed that free fatty acids from OFO, specifically the PO fraction, up-regulated PPARα transactivity and down-regulated AhR transactivity. In vivo study showed that the PO fraction group had a significantly higher number of dead fetuses and resorptions per litter than the SO and NP fraction groups. The incidence of abnormalities in terms of gross morphology and skeletal ossification of the fetus was greatest in the PO fraction group, followed by the OFO group, both values being significantly higher than in the other two groups. Hepatic expression of genes encoding enzymes associated with RA synthesis and catabolism in dams and fetuses was differentially affected by PO fraction assault. We conclude that OFO-mediated teratogenesis is associated with disturbed RA metabolism in the dams and fetuses caused, at least in part, by modulation of PPARα and AhR transactivity by the oxidized components in OFO.
Assuntos
Culinária/métodos , Gorduras Insaturadas na Dieta/toxicidade , Fígado/embriologia , Fígado/metabolismo , Teratogênicos/toxicidade , Vitamina A/metabolismo , Animais , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Camundongos Endogâmicos C57BL , Oxirredução , PPAR alfa/genética , PPAR alfa/metabolismo , Gravidez , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Vitamina A/genéticaRESUMO
Inhibition of acetyl-CoA carboxylase (ACC) is one approach used for treating metabolic syndrome. Using partially purified ACC to screen herbs commonly used in Taiwanese folk medicine, we previously showed that an ethanol extract of Polygonum hypoleucum Ohwi (EP) had potent ACC inhibitory activity and partially alleviated metabolic disorders induced by a high fat diet. Since ACC plays a crucial role in de novo lipogenesis, the favorable effects of EP on metabolism were tested under lipogenic conditions in the present study. On incubating high glucose (30 mM)-stimulated HepG2 cells with EP (72.5 or 145 microg/mL), ACC and fatty acid synthase activity, triacylglycerol content, and microsomal triacylglycerol transfer protein mRNA levels were all significantly reduced (P < 0.05, vs vehicle). When EP was given at low, medium, and high dosages (94, 188, and 470 mg/kg) to sucrose water-treated Wistar rats for four weeks, alleviation of symptoms associated with metabolic syndrome, including obesity, insulin resistance, hypertriglyceridemia, and hypertension, accompanied by hepatic ACC inactivation, was seen in the low dosage group. Four compounds (emodin, emodin-8-O-beta-D-glucopyranoside, (+)-catechin, and (-)-epicatechin) isolated from EP were identified as ACC inhibitors. These results confirm that P. hypoleucum Ohwi, acting partly through ACC inhibition, has favorable effects in alleviating metabolic disturbances occurring under lipogenic conditions.