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1.
Gastroenterology ; 160(5): 1694-1708.e3, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33388316

RESUMO

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) demonstrate nutritional selenium deficiencies and are at greater risk of developing colon cancer. Previously, we determined that global reduction of the secreted antioxidant selenium-containing protein, selenoprotein P (SELENOP), substantially increased tumor development in an experimental colitis-associated cancer (CAC) model. We next sought to delineate tissue-specific contributions of SELENOP to intestinal inflammatory carcinogenesis and define clinical context. METHODS: Selenop floxed mice crossed with Cre driver lines to delete Selenop from the liver, myeloid lineages, or intestinal epithelium were placed on an azoxymethane/dextran sodium sulfate experimental CAC protocol. SELENOP loss was assessed in human ulcerative colitis (UC) organoids, and expression was queried in human and adult UC samples. RESULTS: Although large sources of SELENOP, both liver- and myeloid-specific Selenop deletion failed to modify azoxymethane/dextran sodium sulfate-mediated tumorigenesis. Instead, epithelial-specific deletion increased CAC tumorigenesis, likely due to elevated oxidative stress with a resulting increase in genomic instability and augmented tumor initiation. SELENOP was down-regulated in UC colon biopsies and levels were inversely correlated with endoscopic disease severity and tissue S100A8 (calprotectin) gene expression. CONCLUSIONS: Although global selenium status is typically assessed by measuring liver-derived plasma SELENOP levels, our results indicate that the peripheral SELENOP pool is dispensable for CAC. Colonic epithelial SELENOP is the main contributor to local antioxidant capabilities. Thus, colonic SELENOP is the most informative means to assess selenium levels and activity in IBD patients and may serve as a novel biomarker for UC disease severity and identify patients most predisposed to CAC development.


Assuntos
Colite Ulcerativa/metabolismo , Neoplasias Associadas a Colite/prevenção & controle , Colite/metabolismo , Colo/metabolismo , Mucosa Intestinal/metabolismo , Estresse Oxidativo , Selenoproteína P/metabolismo , Adolescente , Animais , Azoximetano , Estudos de Casos e Controles , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Criança , Pré-Escolar , Colite/induzido quimicamente , Colite/genética , Colite Ulcerativa/genética , Neoplasias Associadas a Colite/induzido quimicamente , Neoplasias Associadas a Colite/genética , Neoplasias Associadas a Colite/metabolismo , Colo/patologia , Dano ao DNA , Sulfato de Dextrana , Modelos Animais de Doenças , Feminino , Instabilidade Genômica , Humanos , Mucosa Intestinal/patologia , Fígado/metabolismo , Masculino , Camundongos Knockout , Células Mieloides/metabolismo , Selenoproteína P/genética
2.
Carcinogenesis ; 39(11): 1352-1358, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30084959

RESUMO

Selenoprotein P (SELENOP) is a major selenoenzyme in plasma and linked to antioxidant properties and possibly to lung cancer; however, supporting evidence is limited. We investigated the association between pre-diagnostic plasma SELENOP concentration and lung cancer risk in a case-control study of 403 cases and 403 individually matched controls nested within the Shanghai Men's Health Study. SELENOP concentration in pre-diagnostic plasma samples was measured by a sandwich enzyme-linked immunosorbent assay. Cases were diagnosed with lung cancer between 2003 and 2010. Multivariate conditional logistic regression was used to estimate odds ratios (OR) and the corresponding 95% confidence intervals (CI) for studying the association between plasma SELENOP concentration and lung cancer risk. Cases had slightly lower plasma SELENOP concentration than controls (4.3 ± 1.2 versus 4.4 ± 1.1 mg/l, P difference = 0.09). However, the multivariate analysis showed no association between plasma SELENOP concentration and lung cancer risk among all participants (OR = 1.08, 95% CI = 0.54-2.14 for quartile 4 versus quartile 1), or by smoking status or tumor aggressiveness. In contrast, although the number of cases was limited, plasma SELENOP concentration was positively associated with lung adenocarcinoma risk (OR = 5.38, 95% CI = 1.89-15.35 for tertile 3 versus tertile 1), but not with squamous cell lung carcinoma (OR = 1.69, 95% CI = 0.43-6.70). Our study of adult men living in selenium non-deficient areas in China provides little support for the inverse association between pre-diagnostic plasma SELENOP concentration and lung cancer risk. Our finding of a positive association with risk of lung adenocarcinoma needs to be interpreted with caution.


Assuntos
Adenocarcinoma de Pulmão/sangue , Neoplasias Pulmonares/sangue , Saúde do Homem/estatística & dados numéricos , Neoplasias de Células Escamosas/sangue , Selênio/sangue , Selenoproteína P/sangue , Adenocarcinoma de Pulmão/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , China/epidemiologia , Ensaio de Imunoadsorção Enzimática , Humanos , Modelos Logísticos , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias de Células Escamosas/epidemiologia , Estudos Prospectivos , Risco , Fumar/efeitos adversos
3.
J Biol Chem ; 291(46): 24036-24040, 2016 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-27645994

RESUMO

The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4, and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine sulfoxide reductase B1), and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15-kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV), and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing, and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates.


Assuntos
Selenoproteínas/classificação , Selenoproteínas/genética , Humanos , Terminologia como Assunto
4.
Annu Rev Nutr ; 35: 109-34, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25974694

RESUMO

Selenium is regulated in the body to maintain vital selenoproteins and to avoid toxicity. When selenium is limiting, cells utilize it to synthesize the selenoproteins most important to them, creating a selenoprotein hierarchy in the cell. The liver is the central organ for selenium regulation and produces excretory selenium forms to regulate whole-body selenium. It responds to selenium deficiency by curtailing excretion and secreting selenoprotein P (Sepp1) into the plasma at the expense of its intracellular selenoproteins. Plasma Sepp1 is distributed to tissues in relation to their expression of the Sepp1 receptor apolipoprotein E receptor-2, creating a tissue selenium hierarchy. N-terminal Sepp1 forms are taken up in the renal proximal tubule by another receptor, megalin. Thus, the regulated whole-body pool of selenium is shifted to needy cells and then to vital selenoproteins in them to supply selenium where it is needed, creating a whole-body selenoprotein hierarchy.


Assuntos
Homeostase/fisiologia , Selênio/metabolismo , Animais , Disponibilidade Biológica , Transporte Biológico , Biomarcadores , Dieta , Suplementos Nutricionais , Nível de Saúde , Humanos , Túbulos Renais Proximais/metabolismo , Proteínas Relacionadas a Receptor de LDL/fisiologia , Fígado/fisiologia , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/fisiologia , Necessidades Nutricionais , Especificidade de Órgãos , Selênio/deficiência , Selênio/farmacocinética , Selenocisteína/metabolismo , Selenometionina/metabolismo , Selenoproteína P/análise , Selenoproteína P/sangue , Selenoproteínas/biossíntese , Selenoproteínas/metabolismo
5.
J Biol Chem ; 289(13): 9195-207, 2014 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-24532792

RESUMO

Sepp1 supplies selenium to tissues via receptor-mediated endocytosis. Mice, rats, and humans have 10 selenocysteines in Sepp1, which are incorporated via recoding of the stop codon, UGA. Four isoforms of rat Sepp1 have been identified, including full-length Sepp1 and three others, which terminate at the second, third, and seventh UGA codons. Previous studies have shown that the longer Sepp1 isoforms bind to the low density lipoprotein receptor apoER2, but the mechanism remains unclear. To identify the essential residues for apoER2 binding, an in vitro Sepp1 binding assay was developed using different Sec to Cys substituted variants of Sepp1 produced in HEK293T cells. ApoER2 was found to bind the two longest isoforms. These results suggest that Sepp1 isoforms with six or more selenocysteines are taken up by apoER2. Furthermore, the C-terminal domain of Sepp1 alone can bind to apoER2. These results indicate that apoER2 binds to the Sepp1 C-terminal domain and does not require the heparin-binding site, which is located in the N-terminal domain. Site-directed mutagenesis identified three residues of Sepp1 that are necessary for apoER2 binding. Sequential deletion of extracellular domains of apoER2 surprisingly identified the YWTD ß-propeller domain as the Sepp1 binding site. Finally, we show that apoER2 missing the ligand-binding repeat region, which can result from cleavage at a furin cleavage site present in some apoER2 isoforms, can act as a receptor for Sepp1. Thus, longer isoforms of Sepp1 with high selenium content interact with a binding site distinct from the ligand-binding domain of apoER2 for selenium delivery.


Assuntos
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Selênio/metabolismo , Selenoproteína P/metabolismo , Sequência de Aminoácidos , Animais , Endocitose , Feminino , Células HEK293 , Humanos , Ligantes , Masculino , Camundongos , Dados de Sequência Molecular , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Selenocisteína/metabolismo , Selenoproteína P/química , Alinhamento de Sequência , Especificidade por Substrato
6.
FASEB J ; 28(8): 3579-88, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24760755

RESUMO

Selenoprotein P (Sepp1) and its receptor, apolipoprotein E receptor 2 (apoER2), account for brain retaining selenium better than other tissues. The primary sources of Sepp1 in plasma and brain are hepatocytes and astrocytes, respectively. ApoER2 is expressed in varying amounts by tissues; within the brain it is expressed primarily by neurons. Knockout of Sepp1 or apoER2 lowers brain selenium from ∼120 to ∼50 ng/g and leads to severe neurodegeneration and death in mild selenium deficiency. Interactions of Sepp1 and apoER2 that protect against this injury have not been characterized. We studied Sepp1, apoER2, and brain selenium in knockout mice. Immunocytochemistry showed that apoER2 mediates Sepp1 uptake at the blood-brain barrier. When Sepp1(-/-) or apoER2(-/-) mice developed severe neurodegeneration caused by mild selenium deficiency, brain selenium was ∼35 ng/g. In extreme selenium deficiency, however, brain selenium of ∼12 ng/g was tolerated when both Sepp1 and apoER2 were intact in the brain. These findings indicate that tandem Sepp1-apoER2 interactions supply selenium for maintenance of brain neurons. One interaction is at the blood-brain barrier, and the other is within the brain. We postulate that Sepp1 inside the blood-brain barrier is taken up by neurons via apoER2, concentrating brain selenium in them.


Assuntos
Barreira Hematoencefálica/fisiologia , Encéfalo/metabolismo , Proteínas Relacionadas a Receptor de LDL/fisiologia , Degeneração Neural/prevenção & controle , Selênio/metabolismo , Selenoproteína P/fisiologia , Animais , Animais Congênicos , Transporte Biológico , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Capilares/metabolismo , Plexo Corióideo/embriologia , Plexo Corióideo/crescimento & desenvolvimento , Plexo Corióideo/metabolismo , Endocitose , Células Endoteliais/metabolismo , Feminino , Proteínas Relacionadas a Receptor de LDL/deficiência , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Degeneração Neural/etiologia , Degeneração Neural/metabolismo , Neurônios/metabolismo , Gravidez , Selênio/administração & dosagem , Selênio/deficiência , Selênio/farmacocinética , Selenoproteína P/deficiência
7.
FASEB J ; 27(8): 3249-56, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23651543

RESUMO

Selenoprotein P (Sepp1) is taken up by receptor-mediated endocytosis for its selenium. The other extracellular selenoprotein, glutathione peroxidase-3 (Gpx3), has not been shown to transport selenium. Mice with genetic alterations of Sepp1, the Sepp1 receptors apolipoprotein E receptor-2 (apoER2) and megalin, and Gpx3 were used to investigate maternal-fetal selenium transfer. Immunocytochemistry (ICC) showed receptor-independent uptake of Sepp1 and Gpx3 in the same vesicles of d-13 visceral yolk sac cells, suggesting uptake by pinocytosis. ICC also showed apoER2-mediated uptake of maternal Sepp1 in the d-18 placenta. Thus, two selenoprotein-dependent maternal-fetal selenium transfer mechanisms were identified. Selenium was quantified in d-18 fetuses with the mechanisms disrupted. Maternal Sepp1 deletion, which lowers maternal whole-body selenium, decreased fetal selenium under selenium-adequate conditions but deletion of fetal apoER2 did not. Fetal apoER2 deletion did decrease fetal selenium, by 51%, under selenium-deficient conditions, verifying function of the placental Sepp1-apoER2 mechanism. Maternal Gpx3 deletion decreased fetal selenium, by 13%, but only under selenium-deficient conditions. These findings indicate that the selenoprotein uptake mechanisms ensure selenium transfer to the fetus under selenium-deficient conditions. The failure of their disruptions (apoER2 deletion, Gpx3 deletion) to affect fetal selenium under selenium-adequate conditions indicates the existence of an additional maternal-fetal selenium transfer mechanism.


Assuntos
Glutationa Peroxidase/metabolismo , Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Troca Materno-Fetal/fisiologia , Selênio/metabolismo , Selenoproteína P/metabolismo , Animais , Transporte Biológico , Feminino , Glutationa Peroxidase/genética , Imuno-Histoquímica , Proteínas Relacionadas a Receptor de LDL/genética , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Masculino , Troca Materno-Fetal/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Fluorescência , Placenta/embriologia , Placenta/metabolismo , Gravidez , Selenoproteína P/genética , Fatores de Tempo , Saco Vitelino/embriologia , Saco Vitelino/metabolismo
8.
J Biol Chem ; 287(34): 28717-26, 2012 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-22761431

RESUMO

In vivo studies have shown that selenium is supplied to testis and brain by apoER2-mediated endocytosis of Sepp1. Although cultured cell lines have been shown to utilize selenium from Sepp1 added to the medium, the mechanism of uptake and utilization has not been characterized. Rat L8 myoblast cells were studied. They took up mouse Sepp1 from the medium and used its selenium to increase their glutathione peroxidase (Gpx) activity. L8 cells did not utilize selenium from Gpx3, the other plasma selenoprotein. Neither did they utilize it from Sepp1(Δ240-361), the isoform of Sepp1 that lacks the selenium-rich C-terminal domain. To identify Sepp1 receptors, a solubilized membrane fraction was passed over a Sepp1 column. The receptors apoER2 and Lrp1 were identified in the eluate by mass spectrometry. siRNA experiments showed that knockdown of apoER2, but not of Lrp1, inhibited (75)Se uptake from (75)Se-labeled Sepp1. The addition of protamine to the medium or treatment of the cells with chlorate also inhibited (75)Se uptake. Blockage of lysosome acidification did not inhibit uptake of Sepp1 but did prevent its digestion and thereby utilization of its selenium. These results indicate that L8 cells take up Sepp1 by an apoER2-mediated mechanism requiring binding to heparin sulfate proteoglycans. The presence of at least part of the selenium-rich C-terminal domain of Sepp1 is required for uptake. RT-PCR showed that mouse tissues express apoER2 in varying amounts. It is postulated that apoER2-mediated uptake of long isoform Sepp1 is responsible for selenium distribution to tissues throughout the body.


Assuntos
Endocitose/fisiologia , Proteínas Relacionadas a Receptor de LDL/metabolismo , Lisossomos/metabolismo , Mioblastos/metabolismo , Selenoproteínas/metabolismo , Animais , Linhagem Celular , Cloratos/farmacologia , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Proteínas Relacionadas a Receptor de LDL/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Lisossomos/genética , Camundongos , Camundongos Knockout , Mioblastos/citologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratos , Receptores de LDL/genética , Receptores de LDL/metabolismo , Selenoproteínas/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
9.
J Biol Chem ; 287(48): 40414-24, 2012 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-23038251

RESUMO

BACKGROUND: Sepp1 transports selenium, but its complete role in selenium homeostasis is not known. RESULTS: Deletion of Sepp1 in hepatocytes increases liver selenium at the expense of other tissues and decreases whole-body selenium by increasing excretion. CONCLUSION: Sepp1 production by hepatocytes retains selenium in the organism and distributes it from the liver to peripheral tissues. SIGNIFICANCE: Sepp1 is central to selenium homeostasis. Sepp1 is a widely expressed extracellular protein that in humans and mice contains 10 selenocysteine residues in its primary structure. Extra-hepatic tissues take up plasma Sepp1 for its selenium via apolipoprotein E receptor-2 (apoER2)-mediated endocytosis. The role of Sepp1 in the transport of selenium from liver, a rich source of the element, to peripheral tissues was studied using mice with selective deletion of Sepp1 in hepatocytes (Sepp1(c/c)/alb-cre(+/-) mice). Deletion of Sepp1 in hepatocytes lowered plasma Sepp1 concentration to 10% of that in Sepp1(c/c) mice (controls) and increased urinary selenium excretion, decreasing whole-body and tissue selenium concentrations. Under selenium-deficient conditions, Sepp1(c/c)/alb-cre(+/-) mice accumulated selenium in the liver at the expense of extra-hepatic tissues, severely worsening clinical manifestations of dietary selenium deficiency. These findings are consistent with there being competition for metabolically available hepatocyte selenium between the synthesis of selenoproteins and the synthesis of selenium excretory metabolites. In addition, selenium deficiency down-regulated the mRNA of the most abundant hepatic selenoprotein, glutathione peroxidase-1 (Gpx1), to 15% of the selenium-replete value, while reducing Sepp1 mRNA, the most abundant hepatic selenoprotein mRNA, only to 61%. This strongly suggests that Sepp1 synthesis is favored in the liver over Gpx1 synthesis when selenium supply is limited, directing hepatocyte selenium to peripheral tissues in selenium deficiency. We conclude that production of Sepp1 by hepatocytes is central to selenium homeostasis in the organism because it promotes retention of selenium in the body and effects selenium distribution from the liver to extra-hepatic tissues, especially under selenium-deficient conditions.


Assuntos
Hepatócitos/metabolismo , Selênio/metabolismo , Selenoproteína P/metabolismo , Animais , Transporte Biológico , Feminino , Homeostase , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Selenoproteína P/genética
11.
J Nutr ; 142(3): 419-26, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22259188

RESUMO

Previous studies suggest some effects of selenium on risk of several chronic diseases, which may be mediated through a small number of selenoenzymes with antioxidant properties. In this cross-sectional analysis of 195 participants from the Seattle Barrett's Esophagus Study who were free of esophageal cancer at the time of blood draw, we examined whether the number of the minor alleles in 26 tagging single nucleotide polymorphisms (SNP) of five selenoenzyme genes [i.e., glutathione peroxidase 1-4 (GPX1-4) and selenoprotein P (SEPP1)] was associated with activity of GPX1 in white blood cells and GPX3 in plasma, and concentrations of SEPP1 and markers of oxidative stress [malondialdehyde (MDA) and protein carbonyl content] in plasma. At the gene level, associations were observed between overall variation in GPX1 and GPX1 activity (P = 0.02) as well as between overall variation in GPX2 and SEPP1 concentrations (P = 0.03). By individual SNP, two variants in GPX1 (rs8179164 and rs1987628) showed a suggestive association with GPX1 activity (P = 0.10 and 0.08, respectively) and two GPX2 variants (rs4902346 and rs2071566) were associated with SEPP1 concentration (P = 0.004 and 0.002, respectively). Furthermore, two SNP in the SEPP1 gene (rs230813 and rs230819) were associated with MDA concentrations (P = 0.03 and 0.02, respectively). Overall, our study supports the hypothesis that common genetic variants in selenoenzymes affect their activity.


Assuntos
Glutationa Peroxidase/sangue , Glutationa Peroxidase/genética , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Polimorfismo de Nucleotídeo Único , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Carbonilação Proteica/genética , Fatores de Risco , Selênio/metabolismo , Selenoproteína P/sangue , Selenoproteína P/genética , Glutationa Peroxidase GPX1
12.
Artigo em Inglês | MEDLINE | ID: mdl-21493731

RESUMO

Glutathione peroxidase-3 (Gpx3), the extracellular glutathione peroxidase synthesized largely in the kidney, binds to basement membranes of renal cortical epithelial cells. The present study assessed extrarenal expression of Gpx3 using RT-PCR and presence of Gpx3 protein using immunocytochemistry. Gpx3 expression was higher in kidney and epididymis than in other tissues. Gpx3 bound to basement membranes of epithelial cells in the gastrointestinal tract, the efferent ducts connecting the seminiferous tubules with the epididymis, the bronchi, and type II pneumocytes. It was not detected on the basement membrane of type I pneumocytes. Gpx3 was also present in the lumen of the epididymis. Transplantation of Gpx3(+/+) kidneys into Gpx3(-/-) mice led to Gpx3 binding to the same basement membranes to which it bound in Gpx3(+/+) mice but not to its presence in the epididymal lumen. These results show that Gpx3 from the blood binds to basement membranes of specific epithelial cells and indicate that the cells modify their basement membranes to cause the binding. They further indicate that at least two Gpx3 compartments exist in the organism. In one compartment, kidney supplies Gpx3 through the blood to specific basement membranes in a number of tissues. In the other compartment, the epididymis provides Gpx3 to its own lumen. Tissues other than kidney and epididymis express Gpx3 at lower levels and may supply Gpx3 to other compartments.


Assuntos
Membrana Basal/enzimologia , Trato Gastrointestinal/enzimologia , Glutationa Peroxidase/metabolismo , Rim/enzimologia , Células Epiteliais Alveolares/enzimologia , Animais , Brônquios/enzimologia , Epididimo/enzimologia , Epididimo/metabolismo , Células Epiteliais/enzimologia , Glutationa Peroxidase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Túbulos Seminíferos/enzimologia
13.
Biochim Biophys Acta ; 1790(11): 1441-7, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19345254

RESUMO

Selenoprotein P (Sepp1) is a secreted protein that is made up of 2 domains. The larger N-terminal domain contains 1 selenocysteine residue in a redox motif and the smaller C-terminal domain contains the other 9 selenocysteines. Sepp1 isoforms of varying lengths occur but quantitation of them has not been achieved. Hepatic synthesis of Sepp1 affects whole-body selenium content and the liver is the source of most plasma Sepp1. ApoER2, a member of the lipoprotein receptor family, binds Sepp1 and facilitates its uptake into the testis and retention of its selenium by the brain. Megalin, another lipoprotein receptor, facilitates uptake of filtered Sepp1 into proximal tubule cells of the kidney. Thus, Sepp1 serves in homeostasis and distribution of selenium. Mice with deletion of Sepp1 suffer greater morbidity and mortality from infection with Trypanosoma congolense than do wild-type mice. Mice that express only the N-terminal domain of Sepp1 have the same severity of illness as wild-type mice, indicating that the protective function of Sepp1 against the infection resides in the N-terminal (redox) domain. Thus, Sepp1 has several functions. In addition, plasma Sepp1 concentration falls in selenium deficiency and, therefore, it can be used as an index of selenium nutritional status.


Assuntos
Mamíferos/genética , Selenoproteína P/genética , Selenoproteína P/fisiologia , Animais , Transporte Biológico/genética , Transporte Biológico/fisiologia , Lesões Encefálicas/genética , Lesões Encefálicas/metabolismo , Homeostase/genética , Humanos , Masculino , Mamíferos/metabolismo , Mamíferos/fisiologia , Camundongos , Modelos Biológicos , Doenças Parasitárias/genética , Doenças Parasitárias/metabolismo , Selênio/metabolismo , Selenoproteína P/metabolismo , Espermatogênese/genética
14.
Am J Physiol Renal Physiol ; 298(5): F1244-53, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20015939

RESUMO

Glutathione peroxidase-3 (Gpx3), also known as plasma or extracellular glutathione peroxidase, is a selenoprotein secreted primarily by kidney proximal convoluted tubule cells. In this study Gpx3(-/-) mice have been produced and immunocytochemical techniques have been developed to investigate Gpx3 metabolism. Gpx3(-/-) mice maintained the same whole-body content and urinary excretion of selenium as did Gpx3(+/+) mice. They tolerated selenium deficiency without observable ill effects. The simultaneous knockout of Gpx3 and selenoprotein P revealed that these two selenoproteins account for >97% of plasma selenium. Immunocytochemistry experiments demonstrated that Gpx3 binds selectively, both in vivo and in vitro, to basement membranes of renal cortical proximal and distal convoluted tubules. Based on calculations using selenium content, the kidney pool of Gpx3 is over twice as large as the plasma pool. These data indicate that Gpx3 does not serve in the regulation of selenium metabolism. The specific binding of a large pool of Gpx3 to basement membranes in the kidney cortex strongly suggests a need for glutathione peroxidase activity in the cortical peritubular space.


Assuntos
Membrana Basal/metabolismo , Glutationa Peroxidase/metabolismo , Córtex Renal/citologia , Córtex Renal/metabolismo , Animais , Feminino , Glutationa Peroxidase/deficiência , Glutationa Peroxidase/genética , Túbulos Renais Distais/citologia , Túbulos Renais Distais/metabolismo , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Selênio/metabolismo , Selenoproteína P/deficiência , Selenoproteína P/genética , Selenoproteína P/metabolismo
15.
FASEB J ; 23(8): 2394-402, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19351701

RESUMO

Selenium is an essential micronutrient for humans and animals, and its deficiency can predispose to the development of pathological conditions. This study evaluates the effect of selenium deficiency on the thioredoxin system, consisting of NADPH, selenoprotein thioredoxin reductase (TrxR), and thioredoxin (Trx); and the glutathione system, including NADPH, glutathione reductase, glutathione, and glutaredoxin coupled with selenoprotein glutathione peroxidase (GPx). We particularly investigate whether inactive truncated TrxR is present under selenium-starvation conditions due to reading of the UGA codon as stop. Feeding rats a selenium-deficient diet resulted in a large decrease in activity of TrxR and GPx in rat liver but not in the levels of Trx1 and Grx1. However, selenium deficiency induced mitochondrial Grx2 10-fold and markedly changed the expression of some flavoproteins that are involved in the cellular folate, glucose, and lipid metabolism. Liver TrxR mRNA was nearly unchanged, but no truncated enzyme was found. Instead, a low-activity form of TrxR with a cysteine substituted for the penultimate selenocysteine in the C-terminal active site was identified in selenium-deficient rat liver. These results show a novel mechanism for decoding the UGA stop codon, inserting cysteine to make a full-length enzyme that may be required for selenium assimilation.


Assuntos
Fígado/enzimologia , Selênio/deficiência , Selenocisteína/química , Tiorredoxina Redutase 1/química , Sequência de Aminoácidos , Animais , Códon de Terminação/genética , Cisteína/química , Retroalimentação Fisiológica , Glutarredoxinas/genética , Glutarredoxinas/metabolismo , Masculino , Modelos Biológicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Tiorredoxina Redutase 1/genética , Tiorredoxina Redutase 1/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
16.
J Neurosci ; 27(23): 6207-11, 2007 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-17553992

RESUMO

Selenoprotein P (Sepp1) is a plasma and extracellular protein that is rich in selenium. Deletion of Sepp1 results in sharp decreases of selenium levels in the brain and testis with dysfunction of those organs. Deletion of Sepp1 also causes increased urinary selenium excretion, leading to moderate depletion of whole-body selenium. The lipoprotein receptor apolipoprotein E receptor-2 (apoER2) binds Sepp1 and facilitates its uptake by Sertoli cells, thus providing selenium for spermatogenesis. Experiments were performed to assess the effect of apoER2 on the concentration and function of selenium in the brain and on whole-body selenium. ApoER2-/- and apoER2+/+ male mice were fed a semipurified diet with selenite added as the source of selenium. ApoER2-/- mice had depressed brain and testis selenium, but normal levels in liver, kidney, muscle, and the whole body. Feeding a selenium-deficient diet to apoER2-/- mice led to neurological dysfunction and death, with some of the characteristics exhibited by Sepp1-/- mice fed the same diet. Thus, although it does not affect whole-body selenium, apoER2 is necessary for maintenance of brain selenium and for prevention of neurological dysfunction and death under conditions of selenium deficiency, suggesting an interaction of apoER2 with Sepp1 in the brain.


Assuntos
Encéfalo/metabolismo , Dieta/efeitos adversos , Deleção de Genes , Desnutrição/genética , Doenças do Sistema Nervoso/mortalidade , Receptores de Lipoproteínas/deficiência , Receptores de Lipoproteínas/genética , Selênio/deficiência , Animais , Morte , Dieta/métodos , Proteínas Relacionadas a Receptor de LDL , Masculino , Desnutrição/metabolismo , Desnutrição/mortalidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Doenças do Sistema Nervoso/metabolismo , Selênio/metabolismo
17.
J Neuropathol Exp Neurol ; 67(1): 68-77, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18172410

RESUMO

Selenoprotein P (Sepp1) is involved in selenium homeostasis. Mice with a deletion of Sepp1, replacement of it by the shortened form Sepp1(Delta240-361), or deletion of its receptor apolipoprotein E receptor 2 develop severe neurologic dysfunction when fed low-selenium diet. Because the brainstems of Sepp1(-/-) mice had been observed to contain degenerated axons, a study of these 3 strains was made under selenium-deficient and high-selenium (control) conditions. Selenium-deficient wild-type mice were additional controls. Serial sections of the brain were evaluated with amino cupric silver degeneration and anti-glial fibrillary acidic protein stains. All 3 strains with altered Sepp1 metabolism developed severe axonal injury when fed selenium deficient diet. This injury was mitigated by high-selenium diet and was absent from selenium-deficient wild-type mice. Injury was most severe in Sepp1(-/-) mice, with staining in at least 6 brain regions. Injury in Sepp1(Delta240-361) and apolipoprotein E receptor 2 mice was less severe and occurred only in areas injured in Sepp1(-/-) mice, suggesting a common selenium-related etiology. Affected brain regions were primarily associated with auditory and motor functions, consistent with the clinical signs. Those areas have high metabolic rates. We conclude that interference with Sepp1 function damages auditory and motor areas, at least in part by restricting selenium supply to the brain regions.


Assuntos
Degeneração Neural/genética , Degeneração Neural/patologia , Receptores de Lipoproteínas/deficiência , Selenoproteína P/deficiência , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/ultraestrutura , Deleção de Genes , Proteína Glial Fibrilar Ácida/metabolismo , Imageamento Tridimensional/métodos , Proteínas Relacionadas a Receptor de LDL , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Degeneração Neural/fisiopatologia , Selenoproteína P/genética , Coloração pela Prata/métodos
18.
Free Radic Biol Med ; 44(8): 1617-23, 2008 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-18279678

RESUMO

Selenium (Se) and vitamin E are antioxidant micronutrients. Se functions through selenoproteins and vitamin E reacts with oxidizing molecules in membranes. The relationship of these micronutrients with the Nrf2-antioxidant response element (ARE) pathway was investigated using ARE-reporter mice and Nrf2-/- mice. Weanling males were fed Se-deficient (0 Se), vitamin E-deficient (0 E), or control diet for 16 or 22 weeks. The ARE reporter was elevated 450-fold in 0 Se liver but was not elevated in 0 E liver. Antioxidant enzymes induced by Nrf2-ARE (glutathione S-transferase (GST), NAD(P)H quinone oxidoreductase (NQOR), and heme oxygenase-1 (HO-1)) were elevated in 0 Se livers but not in 0 E livers. Deletion of Nrf2 had varying effects on the inductions, with GST induction being abolished by it but induction of NQOR and HO-1 still occurring. Thus, Se deficiency, but not vitamin E deficiency, induces a number of enzymes that protect against oxidative stress and modify xenobiotic metabolism through Nrf2-ARE and other stress-response pathways. We conclude that Se deficiency causes cytosolic oxidative stress but that vitamin E deficiency does not. This suggests that the oxidant defense mechanisms in which these antioxidant nutrients function are independent of one another.


Assuntos
Antioxidantes/metabolismo , Fígado/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Selênio/deficiência , Deficiência de Vitamina E/metabolismo , Animais , Deleção de Genes , Glutationa Transferase/metabolismo , Heme Oxigenase-1/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , Quinona Redutases/metabolismo
20.
Arch Med Res ; 39(4): 443-51, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18375257

RESUMO

BACKGROUND: An inverse association between selenium status and incidence of different neoplasias including gastric cancer has been reported. This pilot study aimed to determine and compare selenium status in two Colombian populations with different gastric cancer risks: a high-risk area in the volcanic region of the Andes Mountains and a low-risk area on the Pacific coast. METHODS: Eighty nine adult males were recruited in the outpatient clinics of two public hospitals (44 and 45 from high- and low-risk areas, respectively) and provided a blood sample. Seventy one (79.8%) participants underwent upper gastrointestinal endoscopy. Plasma selenium was assayed using a fluorometric method, selenoprotein-P by ELISA, and glutathione peroxidase activity by a spectrophometric method. Histological diagnosis and Helicobacter pylori infection were evaluated in gastric biopsy samples. Unpaired samples t-test and linear regression analyses were used for statistical analyses. RESULTS: Although none of the subjects in either of the two geographic areas was selenium deficient, the level of plasma selenium was significantly lower in men from the high-risk area compared with those from the low-risk area. Levels of selenoprotein-P and glutathione peroxidase activity were similar between groups after adjustment for confounders. Selenium measurements were not associated with histopathological diagnosis. CONCLUSIONS: The high incidence of gastric cancer in the Andean region of Colombia is unlikely to be explained by selenium deficiency. We cannot exclude, however, that suboptimal selenium levels may exist in the gastric mucosa of subjects in the high-risk area. Therefore, the benefit of selenium supplementation in gastric cancer prevention cannot be dismissed.


Assuntos
Selênio/sangue , Selenoproteína P/sangue , Neoplasias Gástricas/epidemiologia , Adulto , Colômbia/epidemiologia , Dieta , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Fatores de Risco , Neoplasias Gástricas/sangue
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