BACKGROUND: Selenoprotein 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). METHODS: We 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). RESULTS: Subjects 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). CONCLUSION: Circulating SeP levels were increased in subjects with NAFLD as well as in those with visceral obesity and may be a novel biomarker for NAFLD.
Adiponectin ; C-Reactive Protein ; Cholesterol ; Cholesterol, HDL ; Energy Metabolism ; Fatty Liver ; Homeostasis ; Humans ; Insulin Resistance ; Intra-Abdominal Fat ; Lipoproteins ; Liver ; Logistic Models ; Obesity ; Obesity, Abdominal ; Pulse Wave Analysis ; Risk Factors ; Rodentia ; Selenoprotein P ; Selenoproteins

<p>OBJECTIVEHuman selenoprotein P (HSelP) is unique protein that contains 10 selenocysteines encoded by 10 inframe UGA, which typically function as stop codon. The function of HSelP remains unclear, in part due to the inability to express it by gene recombinant technique. This study is to investigate expression and purification of recombinant HSelP in prokaryotic expression system, and its activity to induce apoptosis in vitro.p><p>METHODSThe shorter HSelP isoform was cloned. After the selenocysteine (SeCys) at 40th position from N terminus of the HSelP shorter isoform was mutated into cysteine by PCR, it was expressed in E. coli. The expressed product was purified with DEAE column and identified by Western blot. Subsequently, its function on induction of mitochondrial apoptotic activity was studied.p><p>RESULTSThe mutant HSelP shorter isoform expressed in prokaryotic system was purified by DEAE column to 90% homogeneity. The purified product, HSelP280m, induced the opening of mitochondrial permeability transition pore (PTP) and decreased the transmembrane potential in a dose-dependent manner. These events could be abolished by PTP specific inhibitors.p><p>CONCLUSIONHSelP280m can induce the opening of mitochondrial PTP, which provides a basis for investigating the structure and function of recombinant HSelP.p>
Animals ; Apoptosis ; drug effects ; Cloning, Molecular ; Cysteine ; genetics ; Escherichia coli ; metabolism ; Humans ; Ion Channels ; drug effects ; Male ; Membrane Potentials ; drug effects ; Mice ; Mice, Inbred BALB C ; Mitochondria, Liver ; physiology ; Mitochondrial Membrane Transport Proteins ; Mutation ; Protein Isoforms ; Proteins ; genetics ; metabolism ; pharmacology ; Selenium ; Selenocysteine ; genetics ; Selenoprotein P ; Selenoproteins

Objective To study the expression of selenoprotein genes in human immunodeficiency virus(HIV)infection and its mother-to-child transmission,so as to provide a theoretical basis for the prevention,diagnosis,and treatment of acquired immunodeficiency syndrome.Methods The dataset GSE4124 was downloaded from the Gene Expression Omnibus(GEO).Two groups of HIV-positive mothers(n=25)and HIV-negative mothers(n=20)were designed.HIV-positive mothers included a subset of transmitter(TR)mothers(n=11)and non-transmitter(NTR)mothers(n=14).Then,t-test was carried out to compare the expression levels of selenoprotein genes between the four groups(HIV-positive vs. HIV-negative,NTR vs. HIV-negative,TR vs. HIV-negative,TR vs. NTR).Univariate and multivariate Logistic regression were adopted to analyze the effects of differentially expressed genes on HIV infection and mother-to-child transmission.R software was used to establish a nomogram prediction model and evaluate the model performance.Results Compared with the HIV-negative group,HIV-positive,NTR,and TR groups had 8,5 and 8 down-regulated selenoprotein genes,respectively.Compared with the NTR group,the TR group had 4 down-regulated selenoprotein genes.Univariate Logistic regression analysis showed that abnormally high expression of GPX1,GPX3,GPX4,TXNRD1,TXNRD3,and SEPHS2 affected HIV infection and had no effect on mother-to-child transmission.The multivariate Logistic regression analysis showed that the abnormally high expression of TXNRD3(OR=0.032,95%CI=0.002-0.607,P=0.022)was positively correlated with HIV infection.As for the nomogram prediction model,the area under the receiver-operating characteristic curve for 1-year survival of HIV-infected patients was 0.840(95%CI=0.690-1.000),and that for 3-year survival of HIV-infected patients was 0.870(95%CI=0.730-1.000).Conclusions Multiple selenoprotein genes with down-regulated expression levels were involved in the regulation of HIV infection and mother-to-child transmission.The abnormal high expression of TXNRD3 was positively correlated with HIV infection.The findings provide new ideas for the prevention,diagnosis,and treatment of acquired immunodeficiency syndrome.
Humans ; Female ; HIV Infections ; Acquired Immunodeficiency Syndrome ; Infectious Disease Transmission, Vertical ; Nomograms ; Selenoproteins/genetics*

Selenoprotein S (SelS) is widely expressed in diverse tissues where it localizes in the plasma membrane and endoplasmic reticulum. We studied the potential function of SelS in erythrocyte differentiation using K562 cells stably overexpressing SelS wild-type (WT) or one of two SelS point mutants, U188S or U188C. We found that in the K562 cells treated with 1 microM Ara-C, SelS gradually declined over five days of treatment. On day 4, intracellular ROS levels were higher in cells expressing SelS-WT than in those expressing a SelS mutant. Moreover, the cell cycle patterns in cells expressing SelS-WT or U188C were similar to the controls. The expression and activation of SIRT1 were also reduced during K562 differentiation. Cells expressing SelS-WT showed elevated SIRT1 expression and activation (phosphorylation), as well as higher levels of FoxO3a expression. SIRT1 activation was diminished slightly in cells expressing SelS-WT after treatment with the ROS scavenger NAC (12mM), but not in those expressing a SelS mutant. After four days of Ara-C treatment, SelS-WT-expressing cells showed elevated transcription of beta-globin, gamma-globin, epsilon-globin, GATA-1 and zfpm-1, whereas cells expressing a SelS mutant did not. These results suggest that the suppression of SelS acts as a trigger for proerythrocyte differentiation via the ROS-mediated downregulation of SIRT1.
beta-Globins ; Cell Cycle ; Cell Membrane ; Cytarabine ; Down-Regulation ; Endoplasmic Reticulum ; epsilon-Globins ; Erythrocytes ; gamma-Globins ; K562 Cells ; Selenoproteins

The aim of this study was to investigate the role of selenoprotein M (SelM) in endoplasmic reticulum stress and apoptosis in nickel-exposed mouse hearts and to explore the detoxifying effects of melatonin. At 21 d after intraperitoneal injection of nickel chloride (NiCl₂) and/or melatonin into male wild-type (WT) and SelM knockout (KO) C57BL/6J mice, NiCl₂ was found to induce changes in the microstructure and ultrastructure of the hearts of both WT and SelM KO mice, which were caused by oxidative stress, endoplasmic reticulum stress, and apoptosis, as evidenced by decreases in malondialdehyde (MDA) content and total antioxidant capacity (T-AOC) activity. Changes in the messenger RNA (mRNA) and protein expression of genes related to endoplasmic reticulum stress (activating transcription factor 4 (ATF4), inositol-requiring protein 1 (IRE1), c-Jun N-terminal kinase (JNK), and C/EBP homologous protein (CHOP)) and apoptosis (B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, Caspase-9, and Caspase-12) were also observed. Notably, the observed damage was worse in SelM KO mice. Furthermore, melatonin alleviated the heart injury caused by NiCl₂ in WT mice but could not exert a good protective effect in the heart of SelM KO mice. Overall, the findings suggested that the antioxidant capacity of SelM, as well as its modulation of endoplasmic reticulum stress and apoptosis, plays important roles in nickel-induced heart injury.
Animals ; Male ; Mice ; Antioxidants/pharmacology* ; Apoptosis ; Endoplasmic Reticulum Stress ; Melatonin/pharmacology* ; Mice, Inbred C57BL ; Nickel/adverse effects* ; Selenoproteins/genetics* ; Heart/drug effects*

<p>BACKGROUNDTanis was reported as a putative receptor for serum amyloid A (SAA) involving glucose regulated protein in insulin regulated resistance. It was found to be dysregulated in diabetic rats (Psammomys obesus, Israeli sand rat) and its homologue for humans is SelS/AD-015. The present study analyzed mRNA expression of SelS in omental adipose tissue biopsies from patients with type 2 diabetes mellitus (T2DM), and age- and weight-matched nondiabetic patients, the relationship of SelS mRNA with Homa-IR and serum SAA level.p><p>METHODSHuman omental adipose tissues from ten cases of type 2 diabetic patients and twelve cases of nondiabetic individuals were analyzed for the expression level of SelS mRNA by semiquantitative polymerase chain reaction (PCR), Homa-IR estimated by standard formula and SAA level by enzyme-linked immunosorbent assay (ELISA).p><p>RESULTSSelS mRNA expression, Homa-IR and serum SAA were higher in T2DM sufferers than in nondiabetic control group. SelS mRNA level was positively correlated with Homa-IR and SAA level in each group.p><p>CONCLUSIONSSelS protein may be involved in insulin resistance in Chinese with T2DM by acting as the SAA receptor, thus playing an important role in the development of T2DM and atherosclerosis.p>
Adipose Tissue ; metabolism ; Adult ; Aged ; Base Sequence ; Diabetes Mellitus, Type 2 ; metabolism ; Female ; Humans ; Insulin Resistance ; Male ; Membrane Proteins ; genetics ; Molecular Sequence Data ; Omentum ; metabolism ; RNA, Messenger ; analysis ; Selenoproteins ; genetics ; Serum Amyloid A Protein ; analysis

<p>OBJECTIVETo study the cell biological mechanism of sodium selenite improving insulin sensitivity in pubertal rats with insulin resistance.p><p>METHODSThe content of inositol 1,4,5-trisphosphate (IP3) was examined by anion resin chromatography, and mRNA levels of phosphatidylinositol 3-kinase regulatory subunits (PI3Kp85 alpha) and Se-P were detected by RT-PCR in hepatocyte isolated from pubertal rats with insulin resistance.p><p>RESULTSThe mRNA levels of Se-P and PI3Kp85 alpha and content of IP3 in isolated hepatocyte decreased in pubertal male rats with insulin resistance. The above indices increased and reached normal level in rats supplied with selenium. The response to insulin stimulation in isolated hepatocyte in rats with selenium supply was similar to that in the control group, and both groups had higher response than those with high-fat diet. Alone when inhibited by wortmannin, the concentration of IP3 increased slightly in rats with selenium supply, but still was lower than that in the control group.p><p>CONCLUSIONSThese results indicate that the effect of selenium improving insulin sensitivity may be related to phosphatidylinositol PI3K signalling pathway. The effect of regulation of IP3 by selenium is not as effective as that by insulin, which may explain the difference of effect between selenium and insulin.p>
Animals ; Cell Separation ; Hepatocytes ; cytology ; metabolism ; Inositol 1,4,5-Trisphosphate ; analysis ; Insulin ; pharmacology ; Insulin Resistance ; Male ; Phosphatidylinositol 3-Kinases ; analysis ; Proteins ; analysis ; RNA, Messenger ; analysis ; Rats ; Rats, Wistar ; Selenoproteins ; Signal Transduction ; Sodium Selenite ; pharmacology

Objective: Physical exercise can provide many health benefits in humans. Exercise-induced reactive oxygen species (ROS) formation and its downstream signaling cascades are reported to induce mitochondrial biogenesis in exercising tissues. Selenoprotein P (SELENOP) is the antioxidant hepatokine whose hypersecretion is associated with various metabolic diseases. It was reported to impair exercise-induced reactive oxygen species signaling and inhibit subsequent mitochondrial biogenesis in mice. However, the relationship between selenoprotein P and mitochondrial dynamics in humans has not yet been reported. While reduction of plasma selenoprotein P becomes an attractive therapeutic target for metabolic diseases, the role of regular exercise in this regard is still unknown. This study aimed to analyze the influence of regular habitual exercise on plasma selenoprotein P levels and its association with leucocyte mitochondrial DNA copy number in healthy young adults. Methodology: Plasma selenoprotein P levels and leucocyte mitochondrial DNA copy numbers were compared in 44 regularly exercising subjects and 44 non-exercising controls, and the correlation between the two parameters was analyzed. Plasma selenoprotein P levels were measured by Enzyme-linked Immunosorbent Assay, and leucocyte mitochondrial DNA copy numbers were measured using the qPCR method. Results: The regular-exercise group had lower plasma selenoprotein P levels with higher leucocyte mitochondrial DNA copy numbers than the non-exercise group. There was a tendency of negative correlation between the two variables in our studied population. Conclusion Regular habitual exercise has a beneficial effect on reducing plasma selenoprotein P levels while raising mitochondrial DNA copy numbers.
mitochondria ; physical exercise ; reactive oxygen species ; selenoprotein P

Non-alcoholic fatty liver disease, which is considered a hepatic manifestation of metabolic syndrome, independently increases the risks of developing cardiovascular disease (CVD) and type 2 diabetes mellitus. Recent emerging evidence suggests that a group of predominantly liver-derived proteins called hepatokines directly affect the progression of atherosclerosis by modulating endothelial dysfunction and infiltration of inflammatory cells into vessel walls. Here, we summarize the role of the representative hepatokines fibroblast growth factor 21, fetuin-A, and selenoprotein P in the progression of CVD.
alpha-2-HS-Glycoprotein ; Atherosclerosis ; Cardiovascular Diseases* ; Diabetes Mellitus, Type 2 ; Fatty Liver ; Fibroblast Growth Factors ; Obesity* ; Selenoprotein P

BACKGROUND: Selenoprotein P (SEPP1) and fetuin-A, both circulating liver-derived glycoproteins, are novel biomarkers for insulin resistance and nonalcoholic fatty liver disease. However, the effect of exendin-4 (Ex-4), a glucagon-like peptide-1 receptor agonist, on the expression of hepatokines, SEPP1, and fetuin-A, is unknown. METHODS: The human hepatoma cell line HepG2 was treated with palmitic acid (PA; 0.4 mM) and tunicamycin (tuni; 2ug/ml) with or without exendin-4 (100 nM) for 24 hours. The change in expression of PA-induced SEPP1, fetuin-A, and endoplasmic reticulum (ER) stress markers by exendin-4 treatment were evaluated using quantitative real-time reverse transcription polymerase chain reaction and Western blotting. Transfection of cells with AMP-activated protein kinase (AMPK) small interfering RNA (siRNA) was performed to establish the effect of exendin-4-mediated AMPK in the regulation of SEPP1 and fetuin-A expression. RESULTS: Exendin-4 reduced the expression of SEPP1, fetuin-A, and ER stress markers including PKR-like ER kinase, inositol-requiring kinase 1alpha, activating transcription factor 6, and C/EBP homologous protein in HepG2 cells. Exendin-4 also reduced the expression of SEPP1 and fetuin-A in cells treated with tunicamycin, an ER stress inducer. In cells treated with the AMPK activator 5-aminoidazole-4-carboxamide ribonucleotide (AICAR), the expression of hepatic SEPP1 and fetuin-A were negatively related by AMPK, which is the target of exendin-4. In addition, exendin-4 treatment did not decrease SEPP1 and fetuin-A expression in cells transfected with AMPK siRNA. CONCLUSION: These data suggest that exendin-4 can attenuate the expression of hepatic SEPP1 and fetuin-A via improvement of PA-induced ER stress by AMPK.
Activating Transcription Factor 6 ; alpha-2-HS-Glycoprotein* ; AMP-Activated Protein Kinases* ; Blotting, Western ; Carcinoma, Hepatocellular ; Cell Line ; Endoplasmic Reticulum ; Endoplasmic Reticulum Stress* ; Fatty Liver ; Glucagon-Like Peptide 1 ; Glycoproteins ; Hep G2 Cells ; Humans ; Insulin Resistance ; Palmitic Acid ; Phosphotransferases ; Polymerase Chain Reaction ; Reverse Transcription ; RNA, Small Interfering ; Selenoprotein P ; Transfection ; Tunicamycin ; Biomarkers ; Glucagon-Like Peptide-1 Receptor