Selenoprotein P Levels Research Articles

Circulating selenoprotein P levels in relation to MRI-derived body fat volumes, liver fat content, and metabolic disorders.

Association studies of selenoprotein P (SELENOP) with cardiometabolic traits in humans are relatively scarce and, in part, conflicting. A general population sample from Northern Germany was evaluated for cross-sectional associations of circulating SELENOP concentrations with metabolic syndrome (MetS), total volumes of MRI-determined visceral (VAT) and subcutaneous (SAT) abdominal adipose tissue, liver signal intensity, and fatty liver disease (FLD). Nine hundred and five participants received comprehensive clinical and molecular phenotyping along with measurement of serum SELENOP; 584 individuals received MRI. Multivariable-adjusted restricted cubic regression splines displayed statistically significant inverse relations of SELENOP levels with MetS, VAT, and SAT (P < 0.0001 for all). Compared with the second quartile of SELENOP distribution, the MetS odds ratios for the first, third, and fourth quartiles were 1.62 (95% confidence interval [CI]: 1.08-2.43), 0.85 (95% CI: 0.57-1.26), and 0.41 (95% CI: 0.27-0.62), respectively. Furthermore, participants in the second, third, and fourth SELENOP quartiles had significantly lower VAT and SAT volumes as compared to those in the first biomarker quartile. A J-shaped relation was observed for SELENOP levels and liver signal intensity/FLD (P = 0.01). The findings suggest inverse associations of circulating SELENOP concentrations with several metabolic traits, to be further investigated in longitudinal studies.

Association of expression of selenoprotein P in mRNA and protein levels with metabolic syndrome in subjects with cardiovascular disease: Results of the Selenegene study.

Selenoprotein P (SeP) is involved in transporting selenium from the liver to target tissues. Because SeP confers protection against disease by reducing chronic oxidative stress, the present study aimed to assess the level of SeP in the serum of patients with metabolic syndrome (MetS) with a history of cardiovascular disease (CVD). A cross-sectional study was conducted in 63 and 71 subjects with and without MetS in the presence of documented CVD. All demographic, anthropometric and cardiometabolic variables (lipids, blood glucose, blood pressure) were assessed. Lifestyle-related factors and personal history and familial CVD risk factors were recorded. The expression of SELP in mRNA and protein levels in the serum was measured, and MetS was determined using ATPIII criteria. Binary logistic regression analysis demonstrated MetS and SeP to be dependent and independent variables, respectively. Mean of systolic and diastolic blood pressure, triglyceride, high-density lipoprotein-cholesterol, fasting blood sugar, body mass index and waist circumference were higher among subjects with MetS (p=0.05). The mean of selenium was higher among subjects with MetS, whereas the mean of SeP was lower among subjects with MetS (p<0.001). In the unadjusted model, the SeP had decreased odds for MetS [odds ratio (OR)=0.995; 95% confidence interval (CI)=0.989-1.00] (p<0.04). Furthermore, the association between MetS and SeP levels remained marginally significant even after adjusting for potential confounders such as age, gender, family history, smoking status and nutrition. SeP and waist circumference show a significant relationship (OR =0.995; 95% CI=0.990-1.00) (p<0.033). We have demonstrated a significant decrease in circulating SeP levels according to MetS status in patients with documented cardiovascular disease.

Abstract 62: Selenoprotein P Promotes Vascular Smooth Muscle Cell Proliferation and Pulmonary Hypertension -A Possible Novel Therapeutic Target-

Background: Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) is the main characteristics in pulmonary arterial hypertension (PAH); however, its mechanism still remains unclear. Methods &amp; Results: To explore a novel therapeutic target in PAH, we performed a gene expression microarray screening using PASMCs from patients with PAH (PAH-PASMCs) and those from controls and found up-regulation of selenoprotein P (SeP) in PAH-PASMCs (&gt;5-fold, P&lt;0.01). SeP is a widely expressed extracellular protein, which transports selenium to whole body. Immunostaining showed strong expression of SeP in thickened pulmonary arteries (PA) in PAH. Chronic exposure of mice to hypoxia (O 2 10%) increased SeP expression in the lung. In PAH-PASMCs, hypoxia (O 2 2%, 24 hours) increased SeP expression compared with normoxic controls (O 2 21%) (1.6-fold, P&lt;0.05). Treatment with human recombinant SeP (10μg/mL) up-regulated pro-proliferative genes, activated signals associated with cell-cycle, and increased PAH-PASMCs proliferation (P&lt;0.05, n=8 each). SeP siRNA suppressed pro-proliferative signals with a resultant reduction in PASMCs proliferation. Next, SeP-deficient mice ( SeP -/- ) were exposed to hypoxia (O 2 10%) for 4 weeks, which resulted in suppression of right ventricular systolic pressure (RVSP), RV hypertrophy and PA remodeling compared with controls (all P&lt;0.05, n=11 each). PASMCs proliferation was reduced in SeP -/- PASMCs compared with SeP +/+ PASMCs (P&lt;0.05). SeP -/- PASMCs showed ERK1/2 inactivation, AMPK activation, and reduced secretion of pro-inflammatory cytokines. SMC-targeted deletion of SeP suppressed the development of hypoxia-induced PH compared with controls (all P&lt;0.05, n=10). In contrast, liver-specific deletion of SeP did not affect the development of hypoxia-induced PH (all P&gt;0.05, n=8-9). In the clinical study, serum SeP levels were significantly elevated in PAH patients (n=203) compared with controls (n=20) (P&lt;0.001). Event-free curve revealed that high plasma SeP (≥27μg/ml) predicted poor outcome in PH patients (death or lung transplantation, P&lt;0.01). Conclusions: These results indicate that SeP, especially in PASMCs, promotes PA remodeling, suggesting that it is a novel therapeutic target for PAH.

Selenium and its relationship with selenoprotein P and glutathione peroxidase in children and adolescents with Hashimoto’s thyroiditis and hypothyroidism

The essential trace element selenium (Se) is required for thyroid hormone synthesis and metabolism. Selenoproteins contain selenocysteine and are responsible for biological functions of selenium. Glutathione peroxidase (GPx) is one of the major selenoproteins which protects the thyroid cells from oxidative damage. Selenoprotein P (SePP) is considered as the plasma selenium transporter to tissues. The aim of this study was to evaluate serum Se and SePP levels, and GPx activity in erythrocytes of children and adolescents with treated Hashimoto’s thyroiditis, hypothyroidism, and normal subjects.Blood samples were collected from 32 patients with Hashimoto’s thyroiditis, 20 with hypothyroidism, and 25 matched normal subjects. All the patients were under treatment with levothyroxine and at the time of analysis all of the thyroid function tests were normal. GPx enzyme activity was measured by spectrophotometry at 340nm. Serum selenium levels were measured by high-resolution continuum source graphite furnace atomic absorption. SePP, TPOAb (anti-thyroid peroxidase antibody), and TgAb (anti-thyroglobulin antibody) were determined by ELISA kits. T4, T3, T3 uptake and TSH were also measured.Neither GPx activity nor SePP levels were significantly different in patients with Hashimoto’s thyroiditis or hypothyroidism compared to normal subjects. Although GPx and SePP were both lower in patients with hypothyroidism compared to those with Hashimoto’s thyroiditis and normal subjects but the difference was not significant. Serum Se levels also did not differ significantly in patients and normal subjects. We did not find any correlation between GPx or SePP with TPOAb or TgAb but SePP was significantly correlated with Se.Results show that in patients with Hashimoto’s thyroiditis or hypothyroidism who have been under treatment with levothyroxine and have normal thyroid function tests, the GPx, SePP and Se levels are not significantly different.

Development of a Sol Particle Homogeneous Immunoassay for Measuring Full‐Length Selenoprotein P in Human Serum

Selenoprotein P (SeP), a selenium-rich extracellular glycoprotein, is the primary selenoprotein in the plasma. SeP plays an important role in the maintenance of selenium levels in the peripheral tissues. We developed a new sol particle homogeneous immunoassay (SPIA) for measuring full-length SeP (FL-SeP) levels in the human serum. We used colloidal gold particles coated with two types of anti-SeP monoclonal antibodies, one recognizing the N-terminal side domain of SeP and the other recognizing the C-terminal side domain. The assay range was 0.2-9 mg/l, and the linearity was excellent. The within-day and between-day coefficients of variation ranged from 0.73% to 2.24% and 0.45% to 1.11%, respectively. Serum samples (n = 200) were examined using the newly developed assay system (employing a Model 7070 Hitachi automatic clinical analyzer) and the conventional enzyme-linked immunosorbent assay. These two methods were compared using the Passing-Bablok regression analysis; the resulting regression equation and correlation coefficient were y = 0.940x + 0.165 and r = 0.954, respectively. Our new SPIA assay is a fully automated homogeneous immunoassay that can be used in conjunction with various commercial analyzers. The assay was sensitive, precise, and suitable for clinical measurement of the FL-SeP in the human serum.

Levels of circulating selenoprotein P, fibroblast growth factor (FGF) 21 and FGF23 in relation to the metabolic syndrome in young children

Circulating selenoprotein P (SeP), fibroblast growth factor (FGF) 21 and FGF23 have been associated with metabolic syndrome (MetS) in adults but not in children. We sought to evaluate the association among SeP, FGF21, FGF23 and MetS in young children. A cross-sectional study conducted during a school health examination on 210 children aged 9 years. We measured serum SeP, FGF21 and FGF23 levels, and assessed anthropometric and cardiometabolic variables. MetS was defined as the presence of ⩾3 of the following five criteria: high blood pressure, low high-density lipoprotein cholesterol (HDL-C), high triglyceride, high fasting glucose and abdominal obesity. SeP was correlated positively with HDL-C and negatively with body mass index, waist circumference (WC), blood pressure, transaminases, triglyceride and homeostasis model assessment of insulin resistance (HOMA-IR). FGF21 was directly correlated with WC, triglyceride and HOMA-IR, and FGF23 was inversely correlated with fasting glucose and alanine aminotransferase. Children with MetS had lower SeP and FGF23 levels and higher HOMA-IR than children without MetS. The highest tertile of SeP had decreased odds for MetS (odds ratio 0.05, 95% confidence interval (CI) 0.00-0.96, P for trend=0.042), whereas FGF21 and FGF23 did not relate to the risk for MetS after controlling for confounders. Elevated SeP concentrations are independently associated with a reduced risk of MetS in children. The associations between FGF21, FGF23 and metabolic parameters are not of comparable significance.

Selenoprotein P in seminal fluid is a novel biomarker of sperm quality

Hepatically-derived selenoprotein P (SePP) transports selenium (Se) via blood to other tissues including the testes. Male Sepp-knockout mice are infertile. SePP-mediated Se transport to Sertoli cells is needed for supporting biosynthesis of the selenoenzyme glutathione peroxidase-4 (GPX4) in spermatozoa. GPX4 becomes a structural component of sperm midpiece during sperm maturation, and its expression correlates to semen quality. We tested whether SePP is also present in seminal plasma, potentially correlating to fertility parameters. Semen quality was assessed by sperm density, morphology and motility. SePP was measured by an immunoluminometric assay, and trace elements were determined by X-ray fluorescence spectroscopy. SePP levels were considerably lower in seminal plasma as compared to serum (0.4±0.1mg/l vs. 3.5±1.0mg/l); Se concentrations showed a similar but less pronounced difference (48.9±20.7μg/l vs. 106.7±17.3μg/l). Se and Zn correlated positively in seminal fluid but not in serum. Seminal plasma SePP concentrations were independent of serum SePP concentrations, but correlated positively to sperm density and fraction of vital sperm. SePP concentrations in seminal plasma of vasectomized men were similar to controls indicating that accessory sex glands are a testes-independent source of SePP. This notion was corroborated by histochemical analyses localizing SePP in epithelial cells of seminal vesicles. We conclude that SePP is not only involved in Se transport to testes supporting GPX4 biosynthesis but it also becomes secreted into seminal plasma, likely important to protect sperm during storage, genital tract passage and final journey.

Increased Selenoprotein P Levels in Subjects with Visceral Obesity and Nonalcoholic Fatty Liver Disease

BackgroundSelenoprotein P (SeP) has recently been reported as a novel hepatokine that regulates insulin resistance and systemic energy metabolism in rodents and humans. We explored the associations among SeP, visceral obesity, and nonalcoholic fatty liver disease (NAFLD).MethodsWe examined serum SeP concentrations in subjects with increased visceral fat area (VFA) or liver fat accumulation measured with computed tomography. Our study subjects included 120 nondiabetic individuals selected from participants of the Korean Sarcopenic Obesity Study. In addition, we evaluated the relationship between SeP and cardiometabolic risk factors, including homeostasis model of insulin resistance (HOMA-IR), high sensitivity C-reactive protein (hsCRP), adiponectin values, and brachial-ankle pulse wave velocity (baPWV).ResultsSubjects with NAFLD showed increased levels of HOMA-IR, hsCRP, VFA, and several components of metabolic syndrome and decreased levels of adiponectin and high density lipoprotein cholesterol than those of controls. Serum SeP levels were positively correlated with VFA, hsCRP, and baPWV and negatively correlated with the liver attenuation index. Not only subjects with visceral obesity but also those with NAFLD exhibited significantly increased SeP levels (P<0.001). In multiple logistic regression analysis, the subjects in the highest SeP tertile showed a higher risk for NAFLD than those in the lowest SeP tertile, even after adjusting for potential confounding factors (odds ratio, 7.48; 95% confidence interval, 1.72 to 32.60; P=0.007).ConclusionCirculating SeP levels were increased in subjects with NAFLD as well as in those with visceral obesity and may be a novel biomarker for NAFLD.

SeP, ApoER2 and megalin as necessary factors to maintain Se homeostasis in mammals

Selenoprotein P (SeP) is an extracellular protein containing ten selenium atoms in the form of selenocysteine, secreted mainly from the liver. About 60% of the whole plasma selenium level is present in SeP, which makes it a useful biomarker of selenium nutritional status. The main functions of SeP are transport and storage of selenium in plasma. It is especially an important protein for the brain, testes and kidneys where the supplementation of the proper amount of Se ensures the synthesis of selenoenzymes with antioxidant properties.Recently, it has been found that SeP uptake in kidneys, testes and brain depends on the apolipoprotein receptor 2 (ApoER2) and lipoprotein megalin receptor (Lrp2). Megalin receptor represents a physiological SeP receptor in kidneys, mediating the re-uptake of secreted SeP from the primary urine. The absence of a functional megalin receptor causes a significant reduction of plasma selenium and the SeP levels as a result of Se excretion. ApoER2 is a SeP receptor in the brain and testes which uptakes Se from the extracellular fluid. Deletion of ApoER2 in mice leads to a lowered selenium level in the brain and testes, neurological dysfunction, production of abnormal spermatozoa, infertility and even death when the subjects are fed a low-selenium diet.

Inverse Correlation between Serum Levels of Selenoprotein P and Adiponectin in Patients with Type 2 Diabetes

BackgroundWe recently identified selenoprotein P (SeP) as a liver-derived secretory protein that causes insulin resistance in the liver and skeletal muscle; however, it is unknown whether and, if so, how SeP acts on adipose tissue. The present study tested the hypothesis that SeP is related to hypoadiponectinemia in patients with type 2 diabetes.Methodology/Principal FindingsWe compared serum levels of SeP with those of adiponectin and other clinical parameters in 36 patients with type 2 diabetes. We also measured levels of blood adiponectin in SeP knockout mice. Circulating SeP levels were positively correlated with fasting plasma glucose (r = 0.35, P = 0.037) and negatively associated with both total and high-molecular adiponectin in patients with type 2 diabetes (r = −0.355, P = 0.034; r = −0.367, P = 0.028). SeP was a predictor of both total and high-molecular adiponectin, independently of age, body weight, and quantitative insulin sensitivity index (β = −0.343, P = 0.022; β = −0.357, P = 0.017). SeP knockout mice exhibited an increase in blood adiponectin levels when fed regular chow or a high sucrose, high fat diet.Conclusions/SignificanceThese results suggest that overproduction of liver-derived secretory protein SeP is connected with hypoadiponectinemia in patients with type 2 diabetes.

Serum Selenoprotein P Levels in Patients with Type 2 Diabetes and Prediabetes: Implications for Insulin Resistance, Inflammation, and Atherosclerosis

The dysregulation of hepatokines may be associated with the pathogenesis of insulin resistance and type 2 diabetes. A recent study has suggested that selenoprotein P (SeP), a novel hepatokine, may play a role in the regulation of glucose metabolism and insulin sensitivity. We examined the relationship between circulating SeP levels and clinical parameters associated with insulin resistance in humans. We compared serum SeP concentrations in 100 subjects with diverse glucose tolerance statuses. Furthermore, we evaluated the relationship between SeP and cardiometabolic risk factors including insulin resistance, high-sensitivity C-reactive protein, and carotid intima-media thickness. Serum SeP concentrations were significantly higher in patients with type 2 diabetes or prediabetes than those with normal glucose tolerance (all P < 0.01) and decreased in a stepwise manner [1032.4 (495.9-2149.4) vs. 867.3 (516.3-1582.7) vs. 362.0 (252.5-694.5), P = 0.004]. In addition, overweight and obese subjects had significantly increased SeP levels compared with lean subjects (P = 0.002). Spearman's partial correlation analysis adjusted for age and gender showed a significant relationship between SeP and cardiometabolic factors including body mass index, waist circumference, systolic blood pressure, triglycerides, glucose, hemoglobin A1c, aspartate aminotransferase, and insulin resistance. Furthermore, in multiple regression analyses, SeP showed an independent association with carotid intima-media thickness as well as high-sensitivity C-reactive protein, even after adjustment for other confounding factors. Circulating SeP concentrations were elevated in patients with glucose metabolism dysregulation and were related to various cardiometabolic parameters including insulin resistance, inflammation, and atherosclerosis.

Mutation of megalin leads to urinary loss of selenoprotein P and selenium deficiency in serum, liver, kidneys and brain

Distribution of selenium (Se) within the mammalian body is mediated by SePP (selenoprotein P), an Se-rich glycoprotein secreted by hepatocytes. Genetic and biochemical evidence indicate that the endocytic receptors ApoER2 (apolipoprotein E receptor 2) and megalin mediate tissue-specific SePP uptake. In the present study megalin-mutant mice were fed on diets containing adequate (0.15 p.p.m.) or low (0.08 p.p.m.) Se content and were analysed for tissue and plasma Se levels, cellular GPx (glutathione peroxidase) activities and protein expression patterns. Megalin-mutant mice displayed increased urinary Se loss, which correlated with SePP excretion in their urine. Accordingly, serum Se and SePP levels were significantly reduced in megalin-mutant mice, reaching marginal levels on the low-Se diet. Moreover, kidney Se content and expression of renal selenoproteins were accordingly reduced, as was SePP internalization along the proximal tubule epithelium. Although GPx4 expression was not altered in testis, Se and GPx activity in liver and brain were significantly reduced. When fed on a low-Se diet, megalin-mutant mice developed impaired movement co-ordination, but no astrogliosis. These findings suggest that megalin prevents urinary SePP loss and participates in brain Se/SePP uptake.

Serum selenoprotein-P levels in patients with inflammatory bowel disease

Objective Selenoprotein-P is a selenium-rich serum protein that carries more than 50% of serum selenium. We evaluated changes in serum selenoprotein-P levels in patients with inflammatory bowel disease. Methods Serum selenoprotein-P levels were measured by enzyme-linked immunosorbent assay. Twenty healthy individuals (controls), 34 patients with ulcerative colitis, and 37 patients with Crohn’s disease (CD) were studied. Results A highly significant correlation was found between the serum selenium and selenoprotein-P levels. There was no significant difference in serum selenoprotein-P levels between healthy controls (average 3.4 ± 0.8 μg/mL, n = 20) and patients with ulcerative colitis (3.0 ± 1.0 μg/mL, n = 34). Serum selenoprotein-P levels were significantly lower in patients with CD (average 1.8 ± 0.5 μg/mL, n = 37). Serum selenoprotein-P levels were significantly lower in the elemental diet group of patients who had CD (average 1.4 ± 0.4 μg/mL, n = 17) than in the non-elemental diet group of patients who had CD (average 2.1 ± 0.3 μg/mL, n = 20). Conclusion We found that the serum selenoprotein-P level is decreased in patients with CD. It may be a useful marker to monitor the systemic selenium status in various disorders.

Transforming growth factor-β 1 inhibits expression of selenoprotein P in cultured human liver cells

The effect of cytokines on the expression of selenoprotein P (SeP) in the human liver cell line HepG2 was investigated. Treatment with interleukin-1β, interferon-γ, and tumor necrosis factor-α had no effect on SeP levels in culture media or on SeP mRNA expression. Conversely, Western analysis revealed a dose-dependent reduction of SeP content in culture medium after treatment with transforming growth factor (TGF)-β 1 with an IC 50 of 31 pM. Treatment with 100 pM TGF-β 1 for 48 h led to a decrease to 21±9% of controls. RT-PCR analysis of SeP mRNA expression demonstrated an inhibition of SeP transcription to 40±2% of control levels after 24 h. The expression of a luciferase reporter construct under control of the human SeP promoter was downregulated by TGF-β 1 treatment in a dose-dependent fashion indicating a transcriptional regulation of the SeP gene by TGF-β 1.