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2.
Nat Med ; 22(7): 771-9, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27270587

RESUMO

The discovery of genetic mechanisms for resistance to obesity and diabetes may illuminate new therapeutic strategies for the treatment of this global health challenge. We used the polygenic 'lean' mouse model, which has been selected for low adiposity over 60 generations, to identify mitochondrial thiosulfate sulfurtransferase (Tst; also known as rhodanese) as a candidate obesity-resistance gene with selectively increased expression in adipocytes. Elevated adipose Tst expression correlated with indices of metabolic health across diverse mouse strains. Transgenic overexpression of Tst in adipocytes protected mice from diet-induced obesity and insulin-resistant diabetes. Tst-deficient mice showed markedly exacerbated diabetes, whereas pharmacological activation of TST ameliorated diabetes in mice. Mechanistically, TST selectively augmented mitochondrial function combined with degradation of reactive oxygen species and sulfide. In humans, TST mRNA expression in adipose tissue correlated positively with insulin sensitivity in adipose tissue and negatively with fat mass. Thus, the genetic identification of Tst as a beneficial regulator of adipocyte mitochondrial function may have therapeutic significance for individuals with type 2 diabetes.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/genética , Resistência à Insulina/genética , Mitocôndrias/metabolismo , Obesidade/genética , Tiossulfato Sulfurtransferase/genética , Animais , Diferenciação Celular , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Técnicas de Introdução de Genes , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Humanos , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Modelos Animais , Terapia de Alvo Molecular , Obesidade/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Tiossulfato Sulfurtransferase/metabolismo
3.
Psychoneuroendocrinology ; 63: 135-43, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26444587

RESUMO

BACKGROUND: The maternal hypothalamic-pituitary-adrenal-axis (HPAA) undergoes dramatic activation during pregnancy. Increased cortisol and corticotrophin-releasing-hormone (CRH) associate with low birthweight and preterm labor. In non-pregnant obesity, the HPAA is activated but circulating cortisol levels are normal or lower than in lean women. We hypothesized that maternal cortisol levels would be lower in obese pregnancy, and would associate with increased fetal size and length of gestation. METHOD: Fasting serum cortisol was measured at 16, 28 and 36 weeks gestation and at 3-6 months postpartum in 276 severely obese and 135 lean women. In a subset of obese (n=20) and lean (n=20) we measured CRH, hormones that regulate bioavailable cortisol (corticosteroid-binding-globulin, estradiol, estriol, and progesterone). Urinary glucocorticoid metabolites were measured in pregnant (obese n=6, lean n=5) and non-pregnant (obese n=7, lean n=7) subjects. RESULTS: Maternal cortisol and HPAA hormones were lower in obese pregnancy. Total urinary glucocorticoid metabolites increased significantly in lean pregnancy, but not in obese. Lower maternal cortisol in obese tended to be associated with increased birthweight (r=-0.13, p=0.066). In obese, CRH at 28 weeks correlated inversely with gestational length (r=-0.49, p=0.04), and independently predicted gestational length after adjustment for confounding factors (mean decrease in CRH of -0.25 pmol/L (95% CI -0.45 to -0.043 pmol/L) per/day increase in gestation). CONCLUSION: In obese pregnancy, lower maternal cortisol without an increase in urinary glucocorticoid clearance may indicate a lesser activation of the HPAA than in lean pregnancy. This may offer a novel mechanism underlying increased birthweight and longer gestation in obese pregnancy.


Assuntos
Peso ao Nascer , Idade Gestacional , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Obesidade Mórbida/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Complicações na Gravidez/metabolismo , Adulto , Estudos de Casos e Controles , Hormônio Liberador da Corticotropina/metabolismo , Cortisona/urina , Estradiol/metabolismo , Estriol/metabolismo , Feminino , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Masculino , Gravidez , Pregnanos/urina , Progesterona/metabolismo , Tetra-Hidrocortisol/urina , Transcortina/metabolismo
4.
Food Chem ; 133(2): 300-7, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25683399

RESUMO

Dietary isothiocyanates and selenium are chemopreventive agents and potent inducers of antioxidant enzymes. It has been previously shown that sulforaphane and selenium have a synergistic effect on the upregulation of thioredoxin reductase-1 (TrxR-1) in human hepatoma HepG2 cells. In this paper, further evidence is presented to show that sulforaphane and selenium synergistically induce TrxR-1 expression in immortalised human hepatocytes. Sulforaphane was found to be more toxic toward hepatocytes than HepG2 cells with IC50=25.1 and 56.4 µM, respectively. Sulforaphane can protect against hydrogen peroxide-induced cell death and this protection was enhanced by co-treatment with selenium. Using siRNA to knock down TrxR-1 or Nrf2, sulforaphane (5 µM)-protected cell viability was reduced from 73% to 46% and 34%, respectively, suggesting that TrxR-1 is an important enzyme in protection against hydrogen peroxide-induced cell death. Sulforaphane-induced TrxR-1 expression was positively associated with significant levels of Nrf2 translocation into the nucleus, but co-treatment with selenium showed no significant increase in Nrf2 translocation. Moreover, MAPK (ERK, JNK and p38) and PI3K/Akt signalling pathways were found to play no significant role in sulforaphane-induced Nrf2 translocation into the nucleus. However, blocking ERK and JNK signalling pathways decreased sulforaphane-induced TrxR-1 mRNA by about 20%; whereas blocking p38 and PI3K/AKT increased TrxR-1 transcription. In summary, a combination of sulforaphane and selenium resulted in a synergistic upregulation of TrxR-1 that contributed to the enhanced protection against free radical-mediated oxidative damage in human hepatocytes.


Assuntos
Hepatócitos/efeitos dos fármacos , Isotiocianatos/farmacologia , Selênio/farmacologia , Tiorredoxina Dissulfeto Redutase/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sinergismo Farmacológico , Células Hep G2 , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Peróxido de Hidrogênio/toxicidade , Isotiocianatos/metabolismo , Sulfóxidos , Regulação para Cima/efeitos dos fármacos
5.
Biochim Biophys Acta ; 1800(6): 611-8, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20188144

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance and hepatic steatosis. Non-alcoholic steatohepatitis (NASH) is a serious consequence of NAFLD where chronic tissue damage and inflammation result in fibrosis which may progress to cirrhosis. Transforming growth factor beta1 (TGFbeta1), proinflammatory cytokines and oxidative stress are thought to play crucial roles in the pathogenesis of these conditions. The contributions of individual liver cell types to fibrogenesis remain controversial and the influence of selenium status has not been investigated. METHODS: In this study we have used a cell culture model of fat-loading using oleate-treated human hepatoblastoma (C3A) cells to investigate how fat-loading and selenium status might influence the production of collagen in response to TGFbeta1. The secretion of inflammatory cytokines was also investigated, together with the epithelial character of the treated cells. RESULTS: We found that in response to treatment with TGFbeta1, C3A cells produced mRNA encoding the pro-alphaI chain of procollagen I, secreted procollagen I peptide, up-regulated production of the proinflammatory cytokine interleukin-8 (IL-8) and the mesenchymal marker vimentin, and down-regulated albumin production. Most of these responses were considerably enhanced when cells were fat-loaded with oleate and were attenuated by selenium addition at a dose that optimised the expression of thioredoxin reductase and glutathione peroxidase. CONCLUSIONS: Our data establish that both fat-loading and suboptimal selenium status enhance collagen and IL-8 production by C3A hepatocytes in response to TGFbeta1, possibly as part of an epithelial to mesenchymal transition. GENERAL SIGNIFICANCE: These findings suggest that the hepatocyte may be an important contributor to the pathogenesis of fibrosis associated with NAFLD.


Assuntos
Gorduras/análise , Hepatoblastoma/metabolismo , Interleucina-8/biossíntese , Neoplasias Hepáticas/metabolismo , Pró-Colágeno/biossíntese , Selênio/administração & dosagem , Fator de Crescimento Transformador beta1/farmacologia , Sequência de Bases , Linhagem Celular Tumoral , Primers do DNA , Células Epiteliais/citologia , Hepatoblastoma/patologia , Humanos , Neoplasias Hepáticas/patologia , Mesoderma/citologia , Reação em Cadeia da Polimerase , Selênio/farmacologia
6.
Biochim Biophys Acta ; 1790(10): 1191-7, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19595745

RESUMO

BACKGROUND: We examined the expression of the mitochondrial selenoenzyme TrxR2 in the endothelial cell line EAhy926 under conditions known to modify its cytoplasmic counterpart TrxR1. METHODS: Cells were cultured with varying concentrations of selenite, sulforaphane or the Ca2+ ionophore A23187 for 72-h, prior to assay of TrxR concentration and activity. Further cultures underwent prolonged (7-day) Se-depletion before selenoprotein measurement. RESULTS: In Se-deficient cultures, neither Se, A23187 or sulforaphane affected TrxR2 concentration, while these treatments induced TrxR1 concentration (p<0.05). When co-incubated, optimal concentrations of Se (40 nM) and sulforaphane (4 microM) only modestly increased TrxR2 protein (approximately 1.3-fold), compared with TrxR1 (approximately 4-fold). In Se-deficient cells, TrxR activity was unaffected by sulforaphane or A23187. Prolonged Se-depletion caused a comparatively small reduction in TrxR2 (66% TrxR2 retained) against TrxR1 and glutathione peroxidase-1 activity (38% and 17% retained, respectively). CONCLUSIONS: The relative resistance of TrxR2 to Se-deprivation and induction by sulforaphane and A23187 suggests TrxR2 lies near the top of the selenoprotein hierarchy in EAhy926 cells and exhibits near maximum expression under a range of culture conditions. In Se deficiency an inactive (possibly truncated) TrxR1 is produced in response to stimulus by sulforaphane and A23187. GENERAL SIGNIFICANCE: These observations underpin a likely critical antioxidant role for TrxR2 and TrxR1 in the endothelium.


Assuntos
Células Endoteliais/metabolismo , Selenoproteínas/metabolismo , Tiorredoxina Redutase 1/biossíntese , Tiorredoxina Redutase 2/biossíntese , Calcimicina/farmacologia , Linhagem Celular , Sinergismo Farmacológico , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Humanos , Ionóforos/farmacologia , Isotiocianatos , Selenito de Sódio/farmacologia , Sulfóxidos , Tiocianatos/farmacologia , Fatores de Tempo
7.
FASEB J ; 21(12): 3063-74, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17536041

RESUMO

Selenium (Se), a micronutrient essential for human health, is incorporated into at least 25 selenoproteins including selenoprotein P (SePP), which transports Se within the body. This research identified two single nucleotide polymorphisms (SNPs) in the SePP gene, one in the coding region (position 24731, causing an Ala to Thr change) and one in the 3'untranslated region (position 25191). Their frequency was similar in Caucasian, Chinese, and South Asian populations. Prospectively genotyped volunteers were supplemented for 6 wk with 100 microg sodium selenite/day. Blood samples were analyzed for plasma Se and selenoprotein biomarkers at baseline, after supplementation, and during a washout period. Plasma Se, SePP, and glutathione peroxidase 3 (GPx3) levels increased with supplementation. Baseline plasma Se content depended on both SePP genotypes and body mass index. Presupplementation SePP concentration was associated with gender and genotype at SNP 24731 and postsupplementation concentration with SNP 25191. Both SNPs and gender were associated with differences in GPx3 activity, plasma, and erythrocyte thioredoxin reductase 1 concentrations and lymphocyte glutathione peroxidase 1 and 4 activities and concentrations. In conclusion, the data reveal two common functional SNPs within the human SePP gene that may predict behavior of biomarkers of Se status and response to supplementation and thus susceptibility to disease.


Assuntos
Biomarcadores/metabolismo , Suplementos Nutricionais , Etnicidade/genética , Polimorfismo de Nucleotídeo Único , Selênio , Selenoproteína P/genética , Adulto , Células Sanguíneas/metabolismo , Suscetibilidade a Doenças , Feminino , Genótipo , Glutationa Peroxidase/sangue , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Distribuição Aleatória , Selênio/administração & dosagem , Selênio/metabolismo , Selenoproteína P/metabolismo , Fatores Sexuais , Reino Unido , Glutationa Peroxidase GPX1
8.
Biochim Biophys Acta ; 1593(1): 85-92, 2002 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-12431787

RESUMO

The human endothelial cell line EAhy926 was used to determine the importance of selenium in preventing oxidative damage induced by tert-butyl hydroperoxide (tert-BuOOH) or oxidised low density lipoprotein (LDLox). In cells grown in a low selenium medium, tert-BuOOH and LDLox killed cells in a dose-dependent manner. At 555 mg/l LDLox or 300 microM tert-BuOOH, >80% of cells were killed after 20 h. No significant cell kill was achieved by these agents if cells were pre-incubated for 48 h with 40 nM sodium selenite, a concentration that maximally induced the activities of cytoplasmic glutathione peroxidase (cyGPX; 5.1-fold), phospholipid hydroperoxide glutathione peroxidase (PHGPX;1.9-fold) and thioredoxin reductase (TR; 3.1-fold). Selenium-deficient cells pre-treated with 1 microM gold thioglucose (GTG) (a concentration that inhibited 25% of TR activity but had no inhibitory effect on cyGPX or PHGPX activity) were significantly (P<0.05) more susceptible to tert-BuOOH toxicity (LC(50) 110 microM) than selenium-deficient cells (LC(50) 175 microM). This was also the case for LDLox. In contrast, cells pre-treated with 40 nM selenite prior to exposure to GTG were significantly more resistant to damage from tert-BuOOH and LDLox than Se-deficient cells. Treatment with GTG or selenite had no significant effect on intracellular total glutathione concentrations. These results suggest that selenium supplementation, acting through induction of TR and GPX, has the potential to protect the human endothelium from oxidative damage.


Assuntos
Glutationa Peroxidase/biossíntese , Peróxidos Lipídicos/metabolismo , Selenito de Sódio/metabolismo , Tiorredoxina Dissulfeto Redutase/biossíntese , Aurotioglucose/administração & dosagem , Aurotioglucose/farmacologia , Endotélio Vascular/fisiologia , Indução Enzimática/fisiologia , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Humanos , Peróxidos Lipídicos/efeitos adversos , Selenito de Sódio/administração & dosagem , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , terc-Butil Hidroperóxido/efeitos adversos , terc-Butil Hidroperóxido/metabolismo
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