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Raymond F. Burk - One of the best experts on this subject based on the ideXlab platform.
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regulation of Selenium metabolism and transport
Annual Review of Nutrition, 2015Co-Authors: Raymond F. Burk, Kristina E HillAbstract: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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selenoprotein p is the major Selenium transport protein in mouse milk
PLOS ONE, 2014Co-Authors: Kristina E Hill, Amy K Motley, Virginia P. Winfrey, Raymond F. BurkAbstract: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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production of selenoprotein p sepp1 by hepatocytes is central to Selenium homeostasis
Journal of Biological Chemistry, 2012Co-Authors: Kristina E Hill, Amy K Motley, Sen Wu, Teri D Stevenson, John F. Atkins, Virginia P. Winfrey, Mario R Capecchi, Raymond F. BurkAbstract:Abstract 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 (Sepp1c/c/alb-cre+/− mice). Deletion of Sepp1 in hepatocytes lowered plasma Sepp1 concentration to 10% of that in Sepp1c/c mice (controls) and increased urinary Selenium excretion, decreasing whole-body and tissue Selenium concentrations. Under Selenium-deficient conditions, Sepp1c/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.
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the Selenium rich c terminal domain of mouse selenoprotein p is necessary for the supply of Selenium to brain and testis but not for the maintenance of whole body Selenium
Journal of Biological Chemistry, 2007Co-Authors: Kristina E Hill, Amy K Motley, Lori M Austin, John F. Atkins, Gary E. Olson, Jiadong Zhou, Raymond F Gesteland, Raymond F. BurkAbstract:Abstract Selenoprotein P (Sepp1) has two domains with respect to Selenium content: the N-terminal, Selenium-poor domain and the C-terminal, Selenium-rich domain. To assess domain function, mice with deletion of the C-terminal domain have been produced and compared with Sepp1–/– and Sepp1+/+ mice. All mice studied were males fed a semipurified diet with defined Selenium content. The Sepp1 protein in the plasma of mice with the C-terminal domain deleted was determined by mass spectrometry to terminate after serine 239 and thus was designated Sepp1Δ240–361. Plasma Sepp1 and Selenium concentrations as well as glutathione peroxidase activity were determined in the three types of mice. Glutathione peroxidase and Sepp1Δ240–361 accounted for over 90% of the Selenium in the plasma of Sepp1Δ240–361 mice. Calculations using results from Sepp1+/+ mice revealed that Sepp1, with a potential for containing 10 selenocysteine residues, contained an average of 5 Selenium atoms per molecule, indicating that shortened and/or Selenium-depleted forms of the protein were present in these wild-type mice. Sepp1Δ240–361 mice had low brain and testis Selenium concentrations that were similar to those in Sepp1–/– mice but they better maintained their whole body Selenium. Sepp1Δ240–361 mice had depressed fertility, even when they were fed a high Selenium diet, and their spermatozoa were defective and morphologically indistinguishable from those of Selenium-deficient mice. Neurological dysfunction and death occurred when Sepp1Δ240–361 mice were fed Selenium-deficient diet. These phenotypes were similar to those of Sepp1–/– mice but had later onset or were less severe. The results of this study demonstrate that the C terminus of Sepp1 is critical for the maintenance of Selenium in brain and testis but not for the maintenance of whole body Selenium.
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all regions of mouse brain are dependent on selenoprotein p for maintenance of Selenium
Journal of Nutrition, 2007Co-Authors: Akihiro Nakayama, Amy K Motley, Kristina E Hill, Lori M Austin, Raymond F. BurkAbstract:The brain and testis retain Selenium better than other tissues during Selenium deficiency. Studies of mice with selenoprotein P (Sepp1) deleted (Sepp1(-/-) mice) showed that brain and testis Selenium levels are largely dependent on Sepp1. Therefore, we examined tissue Selenium in mice fed varying amounts of Selenium and in Sepp1(-/-) mice to characterize better the role(s) of Sepp1. Mice were fed a Selenium-deficient diet for 8 wk supplemented with Selenium as selenite from none to 0.25 mg/kg diet and tissue Selenium was measured. Brain and testis maintained their Selenium better than did liver, kidney, and muscle when dietary Selenium was limiting but testis Selenium fell sharply in the group fed the deficient diet. Brain retained its Selenium well, even in the group fed the deficient diet. After intravenous injection of (75)Se-Sepp1 into Sepp1(-/-) and Sepp1(+/+) mice, qualitative differences between brain and testis (75)Se uptake were noted, further suggesting differences in their uptake of Selenium from Sepp1. Finally, Selenium was measured in brain regions of Sepp1(-/-) and Sepp1(+/+) mice fed the diet supplemented with 1 mg Selenium/kg and Sepp1(+/+) mice fed the deficient diet. Deletion of Sepp1 and Selenium deficiency each lowered Selenium a similar amount in cortex, midbrain, brainstem, and cerebellum. Selenium in the hippocampus was lowered by deletion of Sepp1 but not by Selenium deficiency. These results suggest that Sepp1 is more important for maintaining Selenium in the hippocampus than in other brain regions. They also confirm the position of the brain at the apex of the organ Selenium hierarchy.
James S. M. Cuffe - One of the best experts on this subject based on the ideXlab platform.
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Maternal Selenium Deficiency in Mice Alters Offspring Glucose Metabolism and Thyroid Status in a Sexually Dimorphic Manner
Nutrients, 2020Co-Authors: Pierre Hofstee, Daniel R. Mckeating, Lucy A. Bartho, Stephen T. Anderson, Anthony V. Perkins, James S. M. CuffeAbstract:Selenium is an essential micronutrient commonly deficient in human populations. Selenium deficiency increases the risks of pregnancy complications; however, the long-term impact of Selenium deficiency on offspring disease remains unclear. This study investigates the effects of Selenium deficiency during pregnancy on offspring metabolic function. Female C57BL/6 mice were allocated to control (>190 μg Selenium/kg, n = 8) or low Selenium (
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maternal Selenium deficiency in mice alters offspring glucose metabolism and thyroid status in a sexually dimorphic manner
Nutrients, 2020Co-Authors: Pierre Hofstee, Daniel R. Mckeating, Lucy A. Bartho, Stephen T. Anderson, Anthony V. Perkins, James S. M. CuffeAbstract:Selenium is an essential micronutrient commonly deficient in human populations. Selenium deficiency increases the risks of pregnancy complications; however, the long-term impact of Selenium deficiency on offspring disease remains unclear. This study investigates the effects of Selenium deficiency during pregnancy on offspring metabolic function. Female C57BL/6 mice were allocated to control (>190 μg Selenium/kg, n = 8) or low Selenium (<50 μg Selenium/kg, n = 8) diets prior to mating and throughout gestation. At postnatal day (PN) 170, mice underwent an intraperitoneal glucose tolerance test and were culled at PN180 for biochemical analysis. Mice exposed to Selenium deficiency in utero had reduced fasting blood glucose but increased postprandial blood glucose concentrations. Male offspring from Selenium-deficient litters had increased plasma insulin levels in conjunction with reduced plasma thyroxine (tetraiodothyronine or T4) concentrations. Conversely, females exposed to Selenium deficiency in utero exhibited increased plasma thyroxine levels with no change in plasma insulin. This study demonstrates the importance of adequate Selenium intake around pregnancy for offspring metabolic health. Given the increasing prevalence of metabolic disease, this study highlights the need for appropriate micronutrient intake during pregnancy to ensure a healthy start to life.
Kristina E Hill - One of the best experts on this subject based on the ideXlab platform.
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regulation of Selenium metabolism and transport
Annual Review of Nutrition, 2015Co-Authors: Raymond F. Burk, Kristina E HillAbstract: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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selenoprotein p is the major Selenium transport protein in mouse milk
PLOS ONE, 2014Co-Authors: Kristina E Hill, Amy K Motley, Virginia P. Winfrey, Raymond F. BurkAbstract: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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production of selenoprotein p sepp1 by hepatocytes is central to Selenium homeostasis
Journal of Biological Chemistry, 2012Co-Authors: Kristina E Hill, Amy K Motley, Sen Wu, Teri D Stevenson, John F. Atkins, Virginia P. Winfrey, Mario R Capecchi, Raymond F. BurkAbstract:Abstract 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 (Sepp1c/c/alb-cre+/− mice). Deletion of Sepp1 in hepatocytes lowered plasma Sepp1 concentration to 10% of that in Sepp1c/c mice (controls) and increased urinary Selenium excretion, decreasing whole-body and tissue Selenium concentrations. Under Selenium-deficient conditions, Sepp1c/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.
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the Selenium rich c terminal domain of mouse selenoprotein p is necessary for the supply of Selenium to brain and testis but not for the maintenance of whole body Selenium
Journal of Biological Chemistry, 2007Co-Authors: Kristina E Hill, Amy K Motley, Lori M Austin, John F. Atkins, Gary E. Olson, Jiadong Zhou, Raymond F Gesteland, Raymond F. BurkAbstract:Abstract Selenoprotein P (Sepp1) has two domains with respect to Selenium content: the N-terminal, Selenium-poor domain and the C-terminal, Selenium-rich domain. To assess domain function, mice with deletion of the C-terminal domain have been produced and compared with Sepp1–/– and Sepp1+/+ mice. All mice studied were males fed a semipurified diet with defined Selenium content. The Sepp1 protein in the plasma of mice with the C-terminal domain deleted was determined by mass spectrometry to terminate after serine 239 and thus was designated Sepp1Δ240–361. Plasma Sepp1 and Selenium concentrations as well as glutathione peroxidase activity were determined in the three types of mice. Glutathione peroxidase and Sepp1Δ240–361 accounted for over 90% of the Selenium in the plasma of Sepp1Δ240–361 mice. Calculations using results from Sepp1+/+ mice revealed that Sepp1, with a potential for containing 10 selenocysteine residues, contained an average of 5 Selenium atoms per molecule, indicating that shortened and/or Selenium-depleted forms of the protein were present in these wild-type mice. Sepp1Δ240–361 mice had low brain and testis Selenium concentrations that were similar to those in Sepp1–/– mice but they better maintained their whole body Selenium. Sepp1Δ240–361 mice had depressed fertility, even when they were fed a high Selenium diet, and their spermatozoa were defective and morphologically indistinguishable from those of Selenium-deficient mice. Neurological dysfunction and death occurred when Sepp1Δ240–361 mice were fed Selenium-deficient diet. These phenotypes were similar to those of Sepp1–/– mice but had later onset or were less severe. The results of this study demonstrate that the C terminus of Sepp1 is critical for the maintenance of Selenium in brain and testis but not for the maintenance of whole body Selenium.
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all regions of mouse brain are dependent on selenoprotein p for maintenance of Selenium
Journal of Nutrition, 2007Co-Authors: Akihiro Nakayama, Amy K Motley, Kristina E Hill, Lori M Austin, Raymond F. BurkAbstract:The brain and testis retain Selenium better than other tissues during Selenium deficiency. Studies of mice with selenoprotein P (Sepp1) deleted (Sepp1(-/-) mice) showed that brain and testis Selenium levels are largely dependent on Sepp1. Therefore, we examined tissue Selenium in mice fed varying amounts of Selenium and in Sepp1(-/-) mice to characterize better the role(s) of Sepp1. Mice were fed a Selenium-deficient diet for 8 wk supplemented with Selenium as selenite from none to 0.25 mg/kg diet and tissue Selenium was measured. Brain and testis maintained their Selenium better than did liver, kidney, and muscle when dietary Selenium was limiting but testis Selenium fell sharply in the group fed the deficient diet. Brain retained its Selenium well, even in the group fed the deficient diet. After intravenous injection of (75)Se-Sepp1 into Sepp1(-/-) and Sepp1(+/+) mice, qualitative differences between brain and testis (75)Se uptake were noted, further suggesting differences in their uptake of Selenium from Sepp1. Finally, Selenium was measured in brain regions of Sepp1(-/-) and Sepp1(+/+) mice fed the diet supplemented with 1 mg Selenium/kg and Sepp1(+/+) mice fed the deficient diet. Deletion of Sepp1 and Selenium deficiency each lowered Selenium a similar amount in cortex, midbrain, brainstem, and cerebellum. Selenium in the hippocampus was lowered by deletion of Sepp1 but not by Selenium deficiency. These results suggest that Sepp1 is more important for maintaining Selenium in the hippocampus than in other brain regions. They also confirm the position of the brain at the apex of the organ Selenium hierarchy.
Pierre Hofstee - One of the best experts on this subject based on the ideXlab platform.
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Maternal Selenium Deficiency in Mice Alters Offspring Glucose Metabolism and Thyroid Status in a Sexually Dimorphic Manner
Nutrients, 2020Co-Authors: Pierre Hofstee, Daniel R. Mckeating, Lucy A. Bartho, Stephen T. Anderson, Anthony V. Perkins, James S. M. CuffeAbstract:Selenium is an essential micronutrient commonly deficient in human populations. Selenium deficiency increases the risks of pregnancy complications; however, the long-term impact of Selenium deficiency on offspring disease remains unclear. This study investigates the effects of Selenium deficiency during pregnancy on offspring metabolic function. Female C57BL/6 mice were allocated to control (>190 μg Selenium/kg, n = 8) or low Selenium (
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maternal Selenium deficiency in mice alters offspring glucose metabolism and thyroid status in a sexually dimorphic manner
Nutrients, 2020Co-Authors: Pierre Hofstee, Daniel R. Mckeating, Lucy A. Bartho, Stephen T. Anderson, Anthony V. Perkins, James S. M. CuffeAbstract:Selenium is an essential micronutrient commonly deficient in human populations. Selenium deficiency increases the risks of pregnancy complications; however, the long-term impact of Selenium deficiency on offspring disease remains unclear. This study investigates the effects of Selenium deficiency during pregnancy on offspring metabolic function. Female C57BL/6 mice were allocated to control (>190 μg Selenium/kg, n = 8) or low Selenium (<50 μg Selenium/kg, n = 8) diets prior to mating and throughout gestation. At postnatal day (PN) 170, mice underwent an intraperitoneal glucose tolerance test and were culled at PN180 for biochemical analysis. Mice exposed to Selenium deficiency in utero had reduced fasting blood glucose but increased postprandial blood glucose concentrations. Male offspring from Selenium-deficient litters had increased plasma insulin levels in conjunction with reduced plasma thyroxine (tetraiodothyronine or T4) concentrations. Conversely, females exposed to Selenium deficiency in utero exhibited increased plasma thyroxine levels with no change in plasma insulin. This study demonstrates the importance of adequate Selenium intake around pregnancy for offspring metabolic health. Given the increasing prevalence of metabolic disease, this study highlights the need for appropriate micronutrient intake during pregnancy to ensure a healthy start to life.
Amy K Motley - One of the best experts on this subject based on the ideXlab platform.
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selenoprotein p is the major Selenium transport protein in mouse milk
PLOS ONE, 2014Co-Authors: Kristina E Hill, Amy K Motley, Virginia P. Winfrey, Raymond F. BurkAbstract: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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production of selenoprotein p sepp1 by hepatocytes is central to Selenium homeostasis
Journal of Biological Chemistry, 2012Co-Authors: Kristina E Hill, Amy K Motley, Sen Wu, Teri D Stevenson, John F. Atkins, Virginia P. Winfrey, Mario R Capecchi, Raymond F. BurkAbstract:Abstract 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 (Sepp1c/c/alb-cre+/− mice). Deletion of Sepp1 in hepatocytes lowered plasma Sepp1 concentration to 10% of that in Sepp1c/c mice (controls) and increased urinary Selenium excretion, decreasing whole-body and tissue Selenium concentrations. Under Selenium-deficient conditions, Sepp1c/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.
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the Selenium rich c terminal domain of mouse selenoprotein p is necessary for the supply of Selenium to brain and testis but not for the maintenance of whole body Selenium
Journal of Biological Chemistry, 2007Co-Authors: Kristina E Hill, Amy K Motley, Lori M Austin, John F. Atkins, Gary E. Olson, Jiadong Zhou, Raymond F Gesteland, Raymond F. BurkAbstract:Abstract Selenoprotein P (Sepp1) has two domains with respect to Selenium content: the N-terminal, Selenium-poor domain and the C-terminal, Selenium-rich domain. To assess domain function, mice with deletion of the C-terminal domain have been produced and compared with Sepp1–/– and Sepp1+/+ mice. All mice studied were males fed a semipurified diet with defined Selenium content. The Sepp1 protein in the plasma of mice with the C-terminal domain deleted was determined by mass spectrometry to terminate after serine 239 and thus was designated Sepp1Δ240–361. Plasma Sepp1 and Selenium concentrations as well as glutathione peroxidase activity were determined in the three types of mice. Glutathione peroxidase and Sepp1Δ240–361 accounted for over 90% of the Selenium in the plasma of Sepp1Δ240–361 mice. Calculations using results from Sepp1+/+ mice revealed that Sepp1, with a potential for containing 10 selenocysteine residues, contained an average of 5 Selenium atoms per molecule, indicating that shortened and/or Selenium-depleted forms of the protein were present in these wild-type mice. Sepp1Δ240–361 mice had low brain and testis Selenium concentrations that were similar to those in Sepp1–/– mice but they better maintained their whole body Selenium. Sepp1Δ240–361 mice had depressed fertility, even when they were fed a high Selenium diet, and their spermatozoa were defective and morphologically indistinguishable from those of Selenium-deficient mice. Neurological dysfunction and death occurred when Sepp1Δ240–361 mice were fed Selenium-deficient diet. These phenotypes were similar to those of Sepp1–/– mice but had later onset or were less severe. The results of this study demonstrate that the C terminus of Sepp1 is critical for the maintenance of Selenium in brain and testis but not for the maintenance of whole body Selenium.
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all regions of mouse brain are dependent on selenoprotein p for maintenance of Selenium
Journal of Nutrition, 2007Co-Authors: Akihiro Nakayama, Amy K Motley, Kristina E Hill, Lori M Austin, Raymond F. BurkAbstract:The brain and testis retain Selenium better than other tissues during Selenium deficiency. Studies of mice with selenoprotein P (Sepp1) deleted (Sepp1(-/-) mice) showed that brain and testis Selenium levels are largely dependent on Sepp1. Therefore, we examined tissue Selenium in mice fed varying amounts of Selenium and in Sepp1(-/-) mice to characterize better the role(s) of Sepp1. Mice were fed a Selenium-deficient diet for 8 wk supplemented with Selenium as selenite from none to 0.25 mg/kg diet and tissue Selenium was measured. Brain and testis maintained their Selenium better than did liver, kidney, and muscle when dietary Selenium was limiting but testis Selenium fell sharply in the group fed the deficient diet. Brain retained its Selenium well, even in the group fed the deficient diet. After intravenous injection of (75)Se-Sepp1 into Sepp1(-/-) and Sepp1(+/+) mice, qualitative differences between brain and testis (75)Se uptake were noted, further suggesting differences in their uptake of Selenium from Sepp1. Finally, Selenium was measured in brain regions of Sepp1(-/-) and Sepp1(+/+) mice fed the diet supplemented with 1 mg Selenium/kg and Sepp1(+/+) mice fed the deficient diet. Deletion of Sepp1 and Selenium deficiency each lowered Selenium a similar amount in cortex, midbrain, brainstem, and cerebellum. Selenium in the hippocampus was lowered by deletion of Sepp1 but not by Selenium deficiency. These results suggest that Sepp1 is more important for maintaining Selenium in the hippocampus than in other brain regions. They also confirm the position of the brain at the apex of the organ Selenium hierarchy.
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deletion of selenoprotein p upregulates urinary Selenium excretion and depresses whole body Selenium content
Biochimica et Biophysica Acta, 2006Co-Authors: Raymond F. Burk, Kristina E Hill, Amy K Motley, Lori M Austin, Brooke K NorsworthyAbstract:Deletion of the mouse selenoprotein P gene (Sepp1) lowers Selenium concentrations in many tissues. We examined Selenium homeostasis in Sepp1(-/-) and Sepp1(+/+) mice to assess the mechanism of this. The liver produces and exports selenoprotein P, which transports Selenium to peripheral tissues, and urinary Selenium metabolites, which regulate whole-body Selenium. At intakes of Selenium near the nutritional requirement, Sepp1(-/-) mice had whole-body Selenium concentrations 72 to 75% of Sepp1(+/+) mice. Genotype did not affect dietary intake of Selenium. Sepp1(-/-) mice excreted in their urine approximately 1.5 times more Selenium in relation to their whole-body Selenium than did Sepp1(+/+) mice. In addition, Sepp1(-/-) mice gavaged with (75)SeO(2-)(3) excreted 1.7 to 2.4 times as much of the (75)Se in the urine as did Sepp1(+/+) mice. These findings demonstrate that deletion of selenoprotein P raises urinary excretion of Selenium. When urinary small-molecule (75)Se was injected intravenously into mice, over 90% of the (75)Se appeared in the urine within 24 h, regardless of Selenium status. This shows that urinary Selenium is dedicated to excretion and not to utilization by tissues. Our results indicate that deletion of selenoprotein P leads to increased urinary Selenium excretion. We propose that the absence of selenoprotein P synthesis in the liver makes more Selenium available for urinary metabolite synthesis, increasing loss of Selenium from the organism and causing the decrease in whole-body Selenium and some of the decreases observed in tissues of Sepp1(-/-) mice.
