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Roles for selenium and selenoprotein P in the development, progression, and prevention of intestinal disease.
Short SP, Pilat JM, Williams CS
(2018) Free Radic Biol Med 127: 26-35
MeSH Terms: Animals, Disease Progression, Humans, Intestinal Diseases, Selenium, Selenoprotein P
Show Abstract · Added April 15, 2019
Selenium (Se) is a micronutrient essential to human health, the function of which is mediated in part by incorporation into a class of proteins known as selenoproteins (SePs). As many SePs serve antioxidant functions, Se has long been postulated to protect against inflammation and cancer development in the gut by attenuating oxidative stress. Indeed, numerous studies over the years have correlated Se levels with incidence and severity of intestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). Similar results have been obtained with the Se transport protein, selenoprotein P (SELENOP), which is decreased in the plasma of both IBD and CRC patients. While animal models further suggest that decreases in Se or SELENOP augment colitis and intestinal tumorigenesis, large-scale clinical trials have yet to show a protective effect in patient populations. In this review, we discuss the function of Se and SELENOP in intestinal diseases and how research into these mechanisms may impact patient treatment.
Copyright © 2018 Elsevier Inc. All rights reserved.
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6 MeSH Terms
Competition between the Brain and Testes under Selenium-Compromised Conditions: Insight into Sex Differences in Selenium Metabolism and Risk of Neurodevelopmental Disease.
Pitts MW, Kremer PM, Hashimoto AC, Torres DJ, Byrns CN, Williams CS, Berry MJ
(2015) J Neurosci 35: 15326-38
MeSH Terms: Age Factors, Animals, Brain, Castration, Dizocilpine Maleate, Epilepsy, Reflex, Exploratory Behavior, Female, Gene Expression Regulation, Glutamate Decarboxylase, Lyases, Male, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Nerve Tissue Proteins, Neurodevelopmental Disorders, Selenium, Selenoprotein P, Sex Factors, Transcription Factors
Show Abstract · Added March 29, 2016
UNLABELLED - Selenium (Se) is essential for both brain development and male fertility. Male mice lacking two key genes involved in Se metabolism (Scly(-/-)Sepp1(-/-) mice), selenoprotein P (Sepp1) and Sec lyase (Scly), develop severe neurological dysfunction, neurodegeneration, and audiogenic seizures that manifest beginning in early adulthood. We demonstrate that prepubescent castration of Scly(-/-)Sepp1(-/-) mice prevents behavioral deficits, attenuates neurodegeneration, rescues maturation of GABAergic inhibition, and increases brain selenoprotein levels. Moreover, castration also yields similar neuroprotective benefits to Sepp1(-/-) and wild-type mice challenged with Se-deficient diets. Our data show that, under Se-compromised conditions, the brain and testes compete for Se utilization, with concomitant effects on neurodevelopment and neurodegeneration.
SIGNIFICANCE STATEMENT - Selenium is an essential trace element that promotes male fertility and brain function. Herein, we report that prepubescent castration provides neuroprotection by increasing selenium-dependent antioxidant activity in the brain, revealing a competition between the brain and testes for selenium utilization. These findings provide novel insight into the interaction of sex and oxidative stress upon the developing brain and have potentially significant implications for the prevention of neurodevelopmental disorders characterized by aberrant excitatory/inhibitory balance, such as schizophrenia and epilepsy.
Copyright © 2015 the authors 0270-6474/15/3515326-13$15.00/0.
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23 MeSH Terms
Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage.
Barrett CW, Reddy VK, Short SP, Motley AK, Lintel MK, Bradley AM, Freeman T, Vallance J, Ning W, Parang B, Poindexter SV, Fingleton B, Chen X, Washington MK, Wilson KT, Shroyer NF, Hill KE, Burk RF, Williams CS
(2015) J Clin Invest 125: 2646-60
MeSH Terms: Animals, Antioxidants, Apoptosis, Colitis, Colonic Neoplasms, DNA Damage, Genomic Instability, Haploinsufficiency, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutagenesis, Site-Directed, Neoplastic Stem Cells, Oxidative Stress, Protein Structure, Tertiary, Selenium, Selenoprotein P, Tumor Microenvironment, Tumor Suppressor Proteins
Show Abstract · Added July 10, 2015
Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice with Sepp1 haploinsufficiency or mutations that disrupt either the selenium transport or the enzymatic domain of SEPP1 exhibit increased colitis-associated carcinogenesis as the result of increased genomic instability and promotion of a protumorigenic microenvironment. Reduced SEPP1 function markedly increased M2-polarized macrophages, indicating a role for SEPP1 in macrophage polarization and immune function. Furthermore, compared with partial loss, complete loss of SEPP1 substantially reduced tumor burden, in part due to increased apoptosis. Using intestinal organoid cultures, we found that, compared with those from WT animals, Sepp1-null cultures display increased stem cell characteristics that are coupled with increased ROS production, DNA damage, proliferation, decreased cell survival, and modulation of WNT signaling in response to H2O2-mediated oxidative stress. Together, these data demonstrate that SEPP1 influences inflammatory tumorigenesis by affecting genomic stability, the inflammatory microenvironment, and epithelial stem cell functions.
0 Communities
6 Members
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20 MeSH Terms
Regulation of Selenium Metabolism and Transport.
Burk RF, Hill KE
(2015) Annu Rev Nutr 35: 109-34
MeSH Terms: Animals, Biological Availability, Biological Transport, Biomarkers, Diet, Dietary Supplements, Health Status, Homeostasis, Humans, Kidney Tubules, Proximal, LDL-Receptor Related Proteins, Liver, Low Density Lipoprotein Receptor-Related Protein-2, Nutritional Requirements, Organ Specificity, Selenium, Selenocysteine, Selenomethionine, Selenoprotein P, Selenoproteins
Show Abstract · Added September 28, 2015
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.
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20 MeSH Terms
Selenoprotein P is the major selenium transport protein in mouse milk.
Hill KE, Motley AK, Winfrey VP, Burk RF
(2014) PLoS One 9: e103486
MeSH Terms: Animals, Animals, Newborn, Biological Transport, Electrophoresis, Polyacrylamide Gel, Female, Glutathione Peroxidase, In Situ Hybridization, Male, Mammary Glands, Animal, Mice, Inbred C57BL, Mice, Knockout, Milk, Selenium, Selenoprotein P, Weaning, Weight Gain
Show Abstract · Added September 28, 2015
Selenium is transferred from the mouse dam to its neonate via milk. Milk contains selenium in selenoprotein form as selenoprotein P (Sepp1) and glutathione peroxidase-3 (Gpx3) as well as in non-specific protein form as selenomethionine. Selenium is also present in milk in uncharacterized small-molecule form. We eliminated selenomethionine from the mice in these experiments by feeding a diet that contained sodium selenite as the source of selenium. Selenium-replete dams with deletion of Sepp1 or Gpx3 were studied to assess the effects of these genes on selenium transfer to the neonate. Sepp1 knockout caused a drop in milk selenium to 27% of the value in wild-type milk and a drop in selenium acquisition by the neonates to 35%. In addition to decreasing milk selenium by eliminating Sepp1, deletion of Sepp1 causes a decline in whole-body selenium, which likely also contributes to the decreased transfer of selenium to the neonate. Deletion of Gpx3 did not decrease milk selenium content or neonate selenium acquisition by measurable amounts. Thus, when the dam is fed selenium-adequate diet (0.25 mg selenium/kg diet), milk Sepp1 transfers a large amount of selenium to neonates but the transfer of selenium by Gpx3 is below detection by our methods.
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16 MeSH Terms
A prospective study of plasma Selenoprotein P and lung cancer risk among low-income adults.
Epplein M, Burk RF, Cai Q, Hargreaves MK, Blot WJ
(2014) Cancer Epidemiol Biomarkers Prev 23: 1238-44
MeSH Terms: Adult, Aged, Enzyme-Linked Immunosorbent Assay, Female, Humans, Lung Neoplasms, Male, Middle Aged, Prospective Studies, Selenoprotein P, Southeastern United States
Show Abstract · Added September 28, 2015
BACKGROUND - Epidemiologic studies have shown increased risks of lung cancer among adults with low blood levels of selenium, although evidence is inconsistent. In the United States, the incidence of lung cancer is higher and mean serum selenium levels lower among Blacks than Whites, but prior studies have not assessed the selenium-lung cancer association among Blacks.
METHODS - From the prospective Southern Community Cohort Study, we identified 372 participants who provided blood samples and subsequently developed lung cancer. Selenoprotein P (SEPP1), the most abundant selenoprotein in plasma and a biomarker of selenium nutriture, was measured in the plasma from these individuals and from 716 matched controls.
RESULTS - Mean SEPP1 levels were significantly (P < 0.0001) lower among Blacks than Whites. Conditional logistic regression models accounting for smoking revealed a significant trend of increasing OR of lung cancer with decreasing SEPP1 tertiles among Blacks (P = 0.0006) but not Whites (P = 0.69; Pinteraction = 0.10). The ORs and corresponding 95% confidence intervals of lung cancer risk among those with lowest versus highest tertile levels of SEPP1 were 2.4 (1.5-3.0) among Blacks and 1.1 (0.6-2.1) among Whites.
CONCLUSIONS - Among a mostly low-income population in the southeastern United States, lower levels of SEPP1 were associated with an increasing risk of lung cancer among Blacks but not Whites.
IMPACT - The combined findings of higher prevalence of low selenium status and higher lung cancer risk associated with low status raise the possibility that selenium deficiency may contribute to observed racial disparities in lung cancer incidence.
©2014 American Association for Cancer Research.
0 Communities
3 Members
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11 MeSH Terms
Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration.
Burk RF, Hill KE, Motley AK, Winfrey VP, Kurokawa S, Mitchell SL, Zhang W
(2014) FASEB J 28: 3579-88
MeSH Terms: Animals, Animals, Congenic, Biological Transport, Blood-Brain Barrier, Brain, Capillaries, Choroid Plexus, Endocytosis, Endothelial Cells, Female, LDL-Receptor Related Proteins, Low Density Lipoprotein Receptor-Related Protein-2, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nerve Degeneration, Neurons, Pregnancy, Selenium, Selenoprotein P
Show Abstract · Added September 28, 2015
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.
© FASEB.
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21 MeSH Terms
Isoform-specific binding of selenoprotein P to the β-propeller domain of apolipoprotein E receptor 2 mediates selenium supply.
Kurokawa S, Bellinger FP, Hill KE, Burk RF, Berry MJ
(2014) J Biol Chem 289: 9195-207
MeSH Terms: Amino Acid Sequence, Animals, Endocytosis, Female, HEK293 Cells, Humans, Ligands, Low Density Lipoprotein Receptor-Related Protein-1, Male, Mice, Molecular Sequence Data, Protein Isoforms, Protein Structure, Tertiary, Selenium, Selenocysteine, Selenoprotein P, Sequence Alignment, Substrate Specificity
Show Abstract · Added March 10, 2014
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 β-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.
0 Communities
1 Members
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18 MeSH Terms
Genetic variants in selenoprotein P plasma 1 gene (SEPP1) are associated with fasting insulin and first phase insulin response in Hispanics.
Hellwege JN, Palmer ND, Ziegler JT, Langefeld CD, Lorenzo C, Norris JM, Takamura T, Bowden DW
(2014) Gene 534: 33-9
MeSH Terms: Adult, Cohort Studies, Fasting, Female, Genetic Association Studies, Genetic Variation, Genotype, Hispanic Americans, Humans, Insulin, Insulin Resistance, Male, Middle Aged, Polymorphism, Single Nucleotide, Selenoprotein P
Show Abstract · Added September 15, 2015
CONTEXT - Insulin resistance is not fully explained on a molecular level, though several genes and proteins have been tied to this defect. Knockdowns of the SEPP1 gene, which encodes the selenoprotein P (SeP) protein, have been shown to increase insulin sensitivity in mice. SeP is a liver-derived plasma protein and a major supplier of selenium, which is a proposed insulin mimetic and antidiabetic agent.
OBJECTIVE - SEPP1 single nucleotide polymorphisms (SNPs) were selected for analysis with glucometabolic measures.
PARTICIPANTS AND MEASURES - The study included1424 Hispanics from families in the Insulin Resistance Atherosclerosis Family Study (IRASFS). Additionally, the multi-ethnic Insulin Resistance Atherosclerosis Study was used. A frequently sampled intravenous glucose tolerance test was used to obtain precise measures of acute insulin response (AIR) and the insulin sensitivity index (SI).
DESIGN - 21 SEPP1 SNPs (tagging SNPs (n=12) from HapMap, 4 coding variants and 6 SNPs in the promoter region) were genotyped and analyzed for association.
RESULTS - Two highly correlated (r(2)=1) SNPs showed association with AIR (rs28919926; Cys368Arg; p=0.0028 and rs146125471; Ile293Met; p=0.0026) while rs16872779 (intronic) was associated with fasting insulin levels (p=0.0097). In the smaller IRAS Hispanic cohort, few of the associations seen in the IRASFS were replicated, but meta-analysis of IRASFS and all 3 IRAS cohorts (N=2446) supported association of rs28919926 and rs146125471 with AIR (p=0.013 and 0.0047, respectively) as well as rs7579 with SI (p=0.047).
CONCLUSIONS - Overall, these results in a human sample are consistent with the literature suggesting a role for SEPP1 in insulin resistance.
© 2013.
0 Communities
1 Members
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15 MeSH Terms
Maternal-fetal transfer of selenium in the mouse.
Burk RF, Olson GE, Hill KE, Winfrey VP, Motley AK, Kurokawa S
(2013) FASEB J 27: 3249-56
MeSH Terms: Animals, Biological Transport, Female, Glutathione Peroxidase, Immunohistochemistry, LDL-Receptor Related Proteins, Low Density Lipoprotein Receptor-Related Protein-2, Male, Maternal-Fetal Exchange, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Fluorescence, Placenta, Pregnancy, Selenium, Selenoprotein P, Time Factors, Yolk Sac
Show Abstract · Added March 7, 2014
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.
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19 MeSH Terms