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Willi Jahnendechent - One of the best experts on this subject based on the ideXlab platform.
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microvasculopathy and soft tissue calcification in mice are governed by Fetuin a magnesium and pyrophosphate
PLOS ONE, 2020Co-Authors: Anne Babler, Carlo Schmitz, Theo G M F Gorgels, Andrea Buescher, Marietta Herrmann, Felix Gremse, Jürgen Floege, Willi JahnendechentAbstract:Calcifications can disrupt organ function in the cardiovascular system and the kidney, and are particularly common in patients with chronic kidney disease (CKD). Fetuin-A deficient mice maintained against the genetic background DBA/2 exhibit particularly severe soft tissue calcifications, while Fetuin-A deficient C57BL/6 mice remain healthy. We employed molecular genetic analysis to identify risk factors of calcification in Fetuin-A deficient mice. We sought to identify pharmaceutical therapeutic targets that could be influenced by dietary of parenteral supplementation. We studied the progeny of an intercross of Fetuin-A deficient DBA/2 and C57BL/6 mice to identify candidate risk genes involved in calcification. We determined that a hypomorphic mutation of the Abcc6 gene, a liver ATP transporter supplying systemic pyrophosphate, and failure to regulate the Trpm6 magnesium transporter in kidney were associated with severity of calcification. Calcification prone Fetuin-A deficient mice were alternatively treated with parenteral administration of Fetuin-A dietary magnesium supplementation, phosphate restriction, or by or parenteral pyrophosphate. All treatments markedly reduced soft tissue calcification, demonstrated by computed tomography, histology and tissue calcium measurement. We show that pathological ectopic calcification in Fetuin-A deficient DBA/2 mice is caused by a compound deficiency of three major extracellular and systemic inhibitors of calcification, namely Fetuin-A, magnesium, and pyrophosphate. All three of these are individually known to contribute to stabilize protein-mineral complexes and thus inhibit mineral precipitation from extracellular fluid. We show for the first time a compound triple deficiency that can be treated by simple dietary or parenteral supplementation. This is of special importance in patients with advanced CKD, who commonly exhibit reduced serum Fetuin-A, magnesium and pyrophosphate levels.
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soft tissue calcification in mice is governed by Fetuin a pyrophosphate and magnesium
bioRxiv, 2019Co-Authors: Anne Babler, Carlo Schmitz, Andrea Buscher, Theo G M F Gorgels, Marietta Herrmann, Felix Gremse, Jürgen Floege, Willi JahnendechentAbstract:Abstract Objective Soft tissue calcifications are mostly benign adaptations to ageing, injury or inflammation. However, calcifications can disrupt organ function in the cardiovascular system and the kidney, and are particularly common in patients with chronic kidney disease (CKD). Fetuin-A deficient mice maintained against the genetic background DBA/2 exhibit severe soft tissue calcifications with premature ageing and organ failure, while Fetuin-A deficient C57BL/6 mice remain healthy. Approach and Results We studied the calcification in progeny of an intercross of Fetuin-A deficient DBA/2 and C57BL/6 mice. We analyzed by DNA sequencing and gene expression analysis candidate risk genes involved in the strong calcification phenotype of Fetuin-A deficient DBA/2 mice. We determined that a hypomorphic mutation of the Abcc6 gene, a liver ATP transporter supplying systemic pyrophosphate, and failure to regulate expression of the TRPM6 magnesium transporter in kidney were associated with severity of calcification. Calcification prone Fetuin-A deficient mice were alternatively treated with dietary phosphate restriction, magnesium supplementation, or by parenteral administration of Fetuin-A or pyrophosphate. All treatments markedly reduced soft tissue calcification, demonstrated by computed tomography, histology and calcium measurement of affected tissues. Conclusions We show that pathological ectopic calcification in Fetuin-A deficient DBA/2 mice is caused by a compound deficiency of three major systemic inhibitors of calcification, namely Fetuin-A, pyrophosphate, and magnesium, identifying these compounds as therapeutic targets in the treatment of calcifications. This is of special importance in patients with advanced CKD, who commonly exhibit reduced serum Fetuin-A, pyrophosphate and magnesium levels.
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Fetuin a and cystatin c are endogenous inhibitors of human meprin metalloproteases
Biochemistry, 2010Co-Authors: Jana Hedrich, Willi Jahnendechent, Daniel Lottaz, Irene Yiallouros, Katharina Meyer, Christoph BeckerpaulyAbstract:Meprin α and β, zinc metalloproteinases, play significant roles in inflammation, including inflammatory bowel disease (IBD), possibly by activating cytokines, like interleukin 1β, interleukin 18, or tumor growth factor α. Although a number of potential activators for meprins are known, no endogenous inhibitors have been identified. In this work, we analyzed the inhibitory potential of human plasma and identified bovine Fetuin-A as an endogenous meprin inhibitor with a K(i) (inhibition constant) of 4.2 × 10(-5) M for meprin α and a K(i) of 1.1 × 10(-6) M meprin β. This correlated with data obtained for a Fetuin-A homologue from carp (nephrosin inhibitor) that revealed a potent meprin α and β inhibition (residual activities of 27 and 22%, respectively) at a carp Fetuin concentration of 1.5 × 10(-6) M. Human Fetuin-A is a negative acute phase protein involved in inflammatory diseases, thus being a potential physiological regulator of meprin activity. We report kinetic studies of Fetuin-A with the proteolytic enzymes astacin, LAST, LAST_MAM, trypsin, and chymotrypsin, indeed demonstrating that Fetuin-A is a broad-range protease inhibitor. Fetuin-A inhibition of meprin α activity was 40 times weaker than that of meprin β activity. Therefore, we tested cystatin C, a protein structurally closely related to Fetuin-A. Indeed, cystatin C was an inhibitor for human meprin α (K(i) = 8.5 × 10(-6) M) but, interestingly, not for meprin β. Thus, the identification of Fetuin-A and cystatin C as endogenous proteolytic regulators of meprin activity broadens our understanding of the proteolytic network in plasma.
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a shielding topology stabilizes the early stage protein mineral complexes of Fetuin a and calcium phosphate a time resolved small angle x ray study
ChemBioChem, 2009Co-Authors: Christophe N Rochette, Alexander Heiss, Sabine Rosenfeldt, Theyencheri Narayanan, Matthias Ballauff, Willi JahnendechentAbstract:: We report on the earliest stages of the formation of complexes of calcium phosphate in the presence of the serum protein alpha(2)-HS glycoprotein/Fetuin-A termed calciprotein particles (CPPs). Time-resolved small-angle X-ray scattering (TR-SAXS) and stopped-flow analysis were used to monitor the growth of protein mineral particles nucleating from supersaturated salt solutions. It was found that Fetuin-A did not influence the formation of mineral nuclei. However, Fetuin-A did prevent the aggregation of nuclei and thus mineral precipitation. Hence, Fetuin-A shielded spontaneously formed mineral nuclei, leading to stable calciprotein particles in the first stage of mineralization. Fetuin-A is therefore critically required during the earliest stages of the formation of protein-mineral complexes in order to prevent uncontrolled mineralization.
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hierarchical role of Fetuin a and acidic serum proteins in the formation and stabilization of calcium phosphate particles
Journal of Biological Chemistry, 2008Co-Authors: Alexander Heiss, Cora Schafer, Thomas Eckert, Anke Aretz, Walter Richtering, Wim Van Dorp, Willi JahnendechentAbstract:The serum protein Fetuin-A is a potent systemic inhibitor of soft tissue calcification. Fetuin-A is highly effective in the formation and stabilization of protein-mineral colloids, referred to as calciprotein particles (CPPs). These particles ripen in vitro in a two-step process, indicated by a morphological conversion from spheres to larger prolate ellipsoids. Using a combined light scattering and electron microscopic imaging approach we determined that the second-stage particles resulted from a highly anisotropic outgrowth of the first-stage particles. Electron microscopy of ascites fluid from a patient with calcifying peritonitis revealed particles reminiscent of secondary CPPs. Thus, CPPs form in the body and undergo the two-step ripening at least in pathological conditions. Unlike in vitro generated CPPs, ascites-derived CPPs contained little Fetuin-A but large amounts of albumin. This prompted us to study the role of Fetuin-A combined with other serum proteins in CPP formation. Fetuin-A was indispensable for primary CPP formation. Albumin and acidic proteins in general greatly enhanced the Fetuin-A triggered formation of secondary CPPs and, thus, substituted substantial amounts of Fetuin-A without loss of inhibition of calcium phosphate precipitation. Thus, direct mineral deposition from solute in the body is unlikely even at low Fetuin-A serum levels as long as sufficient bulk acidic protein is available. Collectively Fetuin-A and other acidic bulk plasma proteins may be considered as mineral chaperones mediating the stabilization, safe transport, and clearance in the body of calcium and phosphate as colloidal complexes, thus, preventing ectopic calcification.
Heiner Boeing - One of the best experts on this subject based on the ideXlab platform.
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circulating Fetuin a and risk of type 2 diabetes a mendelian randomization analysis
Diabetes, 2018Co-Authors: Janine Kroger, Karina Meidtner, Norbert Stefan, Marcela Guevara, Nicola D Kerrison, Eva Ardanaz, Dagfinn Aune, Heiner Boeing, Miren DorronsoroAbstract:Fetuin-A, a hepatic-origin protein, is strongly positively associated with risk of type 2 diabetes in human observational studies, but it is unknown whether this association is causal. We aimed to study the potential causal relation of circulating Fetuin-A to risk of type 2 diabetes in a Mendelian randomization study with single nucleotide polymorphisms located in the Fetuin-A-encoding AHSG gene. We used data from eight European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study including 10,020 incident cases. Plasma Fetuin-A concentration was measured in a subset of 965 subcohort participants and 654 case subjects. A genetic score of the AHSG single nucleotide polymorphisms was strongly associated with Fetuin-A (28% explained variation). Using the genetic score as instrumental variable of Fetuin-A, we observed no significant association of a 50 µg/mL higher Fetuin-A concentration with diabetes risk (hazard ratio 1.02 [95% CI 0.97, 1.07]). Combining our results with those from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (12,171 case subjects) also did not suggest a clear significant relation of Fetuin-A with diabetes risk. In conclusion, although there is mechanistic evidence for an effect of Fetuin-A on insulin sensitivity and secretion, this study does not support a strong, relevant relationship between circulating Fetuin-A and diabetes risk in the general population.
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plasma Fetuin a concentration genetic variation in the ahsg gene and risk of colorectal cancer
International Journal of Cancer, 2015Co-Authors: Heiner Boeing, Katharina Nimptsch, Krasimira Aleksandrova, Juergen Janke, Youngae Lee, Mazda Jenab, So Yeon Kong, Konstantinos K TsilidisAbstract:Fetuin-A, also referred to as alpha 2-Heremans-Schmid glycoprotein (AHSG), is a liver protein known to inhibit insulin actions. Hyperinsulinemia is a possible risk factor for colorectal cancer; however, the role of Fetuin-A in the development of colorectal cancer is unclear. We investigated the association between circulating Fetuin-A and colorectal cancer risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Fetuin-A concentrations were measured in prediagnostic plasma samples from 1,367 colorectal cancer cases and 1,367 matched controls. In conditional logistic regression models adjusted for potential confounders, the estimated relative risk (95% confidence interval) of colorectal cancer per 40 mg/mL higher Fetuin-A concentrations (approximately one standard deviation) was 1.13 (1.02-1.24) overall, 1.21 (1.05-1.39) in men, 1.06 (0.93-1.22) in women, 1.13 (1.00-1.27) for colon cancer and 1.12 (0.94-1.32) for rectal cancer. To improve causal inference in a Mendelian Randomization approach, five tagging single nucleotide polymorphisms of the AHSG gene were genotyped in a subset of 456 case-control pairs. The AHSG allele-score explained 21% of the interindividual variation in plasma Fetuin-A concentrations. In instrumental variable analysis, genetically raised Fetuin-A was not associated with colorectal cancer risk (relative risk per 40 mg/mL genetically determined higher Fetuin-A was 0.98, 95% confidence interval: 0.73-1.33). The findings of our study indicate a modest linear association between Fetuin-A concentrations and risk of colorectal cancer but suggest that Fetuin-A may not be causally related to colorectal cancer development.
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abstract 2200 plasma Fetuin a concentration genetic variation in the ahsg gene and risk of colorectal cancer
Cancer Research, 2014Co-Authors: Katharina Nimptsch, Heiner Boeing, Krasimira Aleksandrova, Youngae Lee, Mazda Jenab, Konstantinos K Tsilidis, Jurgen Janke, Bas Buenodemesquita, Elisabete Weiderpass Vainio, Eugene JansenAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Fetuin-a, also referred to as α2-Heremans-Schmid glycoprotein (AHSG) is a liver protein that inhibits insulin actions. High circulating Fetuin-a concentrations have been associated with insulin resistance and hyperinsulinemia, which pose risk factors for colorectal cancer. Experimental studies have also shown that Fetuin-a mediates the adhesion of tumor cells, an important step in tumor growth through which Fetuin-a could influence colorectal cancer risk independent of the insulin axis. With this study, we aimed to investigate the prospective association between circulating Fetuin-a and risk of colorectal cancer. In addition, we examined potential causality of observed associations by using single nucleotide polymorphisms (SNPs) in the AHSG gene as relatively unbiased proxies for Fetuin-a levels in a Mendelian Randomization approach. Methods: Fetuin-a levels were measured in plasma samples from a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) comprising 1367 cases and 1367 matched controls (matching variables included age, sex, study center and fasting status). In a subset of 456 case-control pairs, five tagging SNPs in the AHSG gene (rs2248690, rs2070633, rs2070635, rs4917 and rs6787344) were genotyped. The association between circulating Fetuin-a and risk of colorectal cancer was investigated using conditional logistic regression models (controlled for matching factors and multivariable adjusted for education, physical activity, smoking, alcohol consumption, dietary factors and body fatness) estimating incidence rate ratios (RRs) and 95% confidence intervals (CI). The association between genetically raised Fetuin-a and risk of colorectal cancer was estimated by instrumental variable analysis using two-stage least squares regression. Results: Higher Fetuin-a concentrations were associated with a moderately higher risk of colorectal cancer: The estimated RRs (95% CI) per 40 µg/mL higher Fetuin-a were 1.11 (1.01, 1.22) overall, 1.18 (1.03, 1.37) in men, 1.05 (0.92, 1.21) in women, 1.11 (0.99, 1.25) for colon cancer and 1.10 (0.92, 1.30) for rectal cancer. In the subset of participants with available data on both plasma Fetuin-a and AHSG SNPs, the AHSG allele score explained 21% of the inter-individual variation in plasma Fetuin-a. When using the AHSG-score as instrumental variable in a Mendelian randomization approach, there was no association between genetically determined Fetuin-a and risk of colorectal cancer: RR (95% CI) per 40 µg/mL genetically determined higher Fetuin-a was 0.98 (0.73, 1.33) overall, 1.04 (0.68, 1.60) in men and 0.93 (0.62, 1.42) in women. Conclusion: This is the first prospective study relating circulating Fetuin-a to risk of colorectal cancer. Our findings suggest that high Fetuin-a concentrations are associated with a moderately higher risk of colorectal cancer, but that Fetuin-a is probably not a causal factor. Citation Format: Katharina Nimptsch, Krasimira Aleksandrova, Heiner Boeing, Jurgen Janke, Young-Ae Lee, Mazda Jenab, Bas Bueno-De-Mesquita, Konstantinos K. Tsilidis, Elisabete Weiderpass Vainio, Eugene HJM Jansen, Timothy J. Key, Antonia Trichopoulou, Kim Overvad, Elio Riboli, Tobias Pischon, European Prospective Investigation into Cancer andNutrition (EPIC). Plasma Fetuin-a concentration, genetic variation in the AHSG gene and risk of colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2200. doi:10.1158/1538-7445.AM2014-2200
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impact of the adipokine adiponectin and the hepatokine Fetuin a on the development of type 2 diabetes prospective cohort and cross sectional phenotyping studies
PLOS ONE, 2014Co-Authors: Norbert Stefan, Andreas Fritsche, Hansgeorg Joost, Qi Sun, Jurgen Machann, Fritz Schick, Felicia Gerst, Charlotte Jeppesen, Heiner BoeingAbstract:Background: Among adipokines and hepatokines, adiponectin and Fetuin-A were consistently found to predict the incidence of type 2 diabetes, both by regulating insulin sensitivity. Objective: To determine to what extent circulating adiponectin and Fetuin-A are independently associated with incident type 2 diabetes in humans, and the major mechanisms involved. Methods: Relationships with incident diabetes were tested in two cohort studies: within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study (628 cases) and the Nurses' Health Study (NHS; 470 cases). Relationships with body fat compartments, insulin sensitivity and insulin secretion were studied in the Tubingen Lifestyle Intervention Program (TULIP; N=358). Results: Circulating adiponectin and Fetuin-A, independently of several confounders and of each other, associated with risk of diabetes in EPIC-Potsdam (RR for 1 SD: adiponectin: 0.45 (95% CI 0.37-0.54), Fetuin-A: 1.18 (1.05-1.32)) and the NHS (0.51 (0.42-0.62), 1.35 (1.16-1.58)). Obesity measures considerably attenuated the association of adiponectin, but not of Fetuin-A. Subjects with low adiponectin and concomitantly high Fetuin-A had the highest risk. Whereas both proteins were independently (both p,1.8610 27 ) associated with insulin sensitivity, circulating Fetuin-A (r= 20.37, p=0.0004), but not adiponectin, associated with insulin secretion in subjects with impaired glucose tolerance. Conclusions: We provide novel information that adiponectin and Fetuin-A independently of each other associate with the diabetes risk. Furthermore, we suggest that they are involved in the development of type 2 diabetes via different mechanisms, possibly by mediating effects of their source tissues, expanded adipose tissue and nonalcoholic fatty liver. Citation: Stefan N, Sun Q, Fritsche A, Machann J, Schick F, et al. (2014) Impact of the Adipokine Adiponectin and the Hepatokine Fetuin-A on the Development of
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association of ahsg gene polymorphisms with Fetuin a plasma levels and cardiovascular diseases in the epic potsdam study
Circulation-cardiovascular Genetics, 2009Co-Authors: Eva Fisher, Norbert Stefan, Andreas Fritsche, Hansulrich Haring, Hansgeorg Joost, Matthias B Schulze, Kathrin Saar, Dagmar Drogan, Norbert Hubner, Heiner BoeingAbstract:Background— Elevated circulating levels of Fetuin-A in blood have been associated with increased risk of cardiovascular disease. The goal of our study was to prospectively investigate the potential causal nature of the association between Fetuin-A levels and myocardial infarction (MI) and ischemic stroke by applying a Mendelian randomization approach. Methods and Results— Five tagging single-nucleotide polymorphisms (rs2248690, rs2070633, rs2070635, rs4917, and rs6787344) capturing the common genetic variation of the Fetuin-A coding gene α2-Heremans-Schmid glycoprotein ( AHSG ) were genotyped in a case-cohort comprising 214 MI cases, 154 ischemic stroke cases, and 2152 persons who remained free of cardiovascular disease events in the European Prospective Investigation into Cancer and Nutrition-Potsdam study. One single-nucleotide polymorphism (rs6787344) was discarded because of Hardy-Weinberg disequilibrium. All AHSG tagging single-nucleotide polymorphisms were associated with Fetuin-A plasma levels ( P T showed the strongest association, explaining 21.2% of the phenotypic variance independent of potential confounding factors (+35.5 μg/mL increase per C-allele, P =2×10−121). Furthermore, the rs4917 C-allele showed a significant association with MI (adjusted hazard rate ratio [RR] 1.34, 95% CI 1.05 to 1.70, P =0.02). Based on this association, the expected RR for MI corresponding to 1 SD in Fetuin-A was 1.54 and, thus, strikingly matches the previously observed association between Fetuin-A plasma levels and MI risk (RR 1.59). Conclusions— These data provide evidence for the causal nature of the recently reported association between Fetuin-A plasma levels and MI risk, thereby suggesting an involvement of Fetuin-A in the pathogenesis of cardiovascular disease. Received April 2, 2009; accepted August 5, 2009. # CLINICAL PERSPECTIVE {#article-title-2}
Katsuhito Mori - One of the best experts on this subject based on the ideXlab platform.
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Fetuin-A: a multifunctional protein.
Recent patents on endocrine metabolic & immune drug discovery, 2011Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki InabaAbstract:Sixty-six years have elapsed since the discovery of Fetuin in 1944, but its importance in mammalian physiology has only recently been appreciated. Fetuin, first isolated from fetal bovine serum and now most commonly known as either Fetuin-A, alpha-2-HS-glycoprotein (recommended name by UniprotKB and PIR), or α2-Heremans-Schmid glycoprotein, functions as an important component of diverse normal and pathological processes, including vascular calcification and bone metabolism regulation, insulin resistance, protease activity control, keratinocytes migration, and breast tumor cell proliferative signaling. Fetuin-A has also been identified as a biomarker for neurodegenerative disease. Here, we summarize recent publications focusing on the structural and functional properties of Fetuin-A. The emerging importance of Fetuin-A for both diagnosis and therapeutics has come to the attention of the pharmaceutical industry. Therefore, we will discuss the status of patents based on Fetuin-A.
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effects of pioglitazone on serum Fetuin a levels in patients with type 2 diabetes mellitus
Metabolism-clinical and Experimental, 2008Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki Inaba, Hidenori Koyama, Takahiro Araki, Hisayo Yokoyama, Megumi Teramura, Eiko Lee, Tetsuo Shoji, Yoshiki NishizawaAbstract:Abstract Fetuin-A (α2-Heremans-Schmid glycoprotein), a circulating glycoprotein, can inhibit insulin signaling both in vivo and in vitro. Recently, we and another independent group have shown that Fetuin-A is positively associated with insulin resistance in humans. Furthermore, it has been reported that higher Fetuin-A levels are associated with metabolic syndrome and atherogenic lipid profiles. These data suggest that Fetuin-A might be a regulator of insulin resistance and/or metabolic syndrome. However, it is not clear how Fetuin-A levels are regulated. To address this, we investigated the effects of representative insulin-sensitizing therapies such as pioglitazone, metformin, and aerobic exercise on Fetuin-A levels. Twenty-seven patients with type 2 diabetes mellitus were divided into pioglitazone-treated (Pio), metformin-treated (Met), and exercise-treated (Ex) groups. Ten patients in the Pio group and 9 patients in the Met group took 15 or 30 mg/d pioglitazone or 500 or 750 mg/d metformin, respectively, for 6 months. Eight patients in the Ex group underwent a 3-month aerobic exercise program. Serum Fetuin-A levels were measured before and after each intervention. Intervention significantly decreased hemoglobin A1c in all groups. After treatment, serum Fetuin-A levels significantly decreased in the Pio group (291.2 ± 57.7 to 253.1 ± 43.9 μg/mL, P = .006), whereas there were no changes in serum Fetuin-A after intervention in either the Met or the Ex groups. We hypothesize that pioglitazone could partially ameliorate insulin resistance via modulating Fetuin-A levels.
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association of serum Fetuin a with carotid arterial stiffness
Clinical Endocrinology, 2007Co-Authors: Katsuhito Mori, Masanori Emoto, Koka Motoyama, Hidenori Koyama, Takahiro Araki, Hisayo Yokoyama, Megumi Teramura, Eiko Lee, Tetsuo Shoji, Masaaki InabaAbstract:Summary Objective Fetuin-A is a circulating glycoprotein which is well characterized as an inhibitor of ectopic calcification. Vascular calcification commonly found in chronic kidney disease (CKD) patients is a predictor of cardiovascular death. Recently, several groups have demonstrated that low Fetuin-A levels are associated with mortality in uraemic patients, possibly through regulation of vascular calcification. However, the physiological significance of Fetuin-A in atherosclerosis remains unknown, except in specific conditions, such as vascular calcification in CKD patients. The objective of this study was to investigate the association between serum Fetuin-A levels and arterial stiffness, a functional property of atherosclerosis, in healthy subjects. Patients and measurements The study subjects comprised 141 healthy subjects. We measured serum Fetuin-A levels and stiffness parameter β for the common carotid artery, which was assessed by ultrasound using a phase-locked echo-tracking system. Results Simple regression analyses indicated that serum Fetuin-A levels were significantly correlated with stiffness parameter β (r = 0·200, P = 0·018). Multiple regression analyses showed that, besides age, Fetuin-A (β = 0·166, P = 0·033) independently contribute to the stiffness parameter β (R2 = 0·310, P < 0·0001). Conclusions Serum Fetuin-A level is associated with carotid arterial stiffness, independent of known atherogenic factors in healthy subjects.
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association of serum Fetuin a with insulin resistance in type 2 diabetic and nondiabetic subjects
Diabetes Care, 2006Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki Inaba, Hidenori Koyama, Takahiro Araki, Hisayo Yokoyama, Megumi Teramura, Tetsuo Shoji, Y NishizawaAbstract:Fetuin-A (α2-Heremans Schmid glycoprotein) is a circulating glycoprotein that can inhibit insulin receptor autophosphorylation and subsequent downstream signaling in vitro (1, 2). Recently, it has been reported (3) that Fetuin-A–deficient mice demonstrate enhanced insulin sensitivity. These data indicate that Fetuin-A might be a negative regulator of insulin signaling. However, the physiological significance of Fetuin-A in insulin resistance in humans remains unclear. To address this, we investigated the relationship of serum Fetuin-A levels and insulin resistance in nondiabetic ( n = 160) and type 2 diabetic ( n = 161) subjects. Serum Fetuin-A was measured by an enzyme-linked immunosorbent assay kit (BioVender Laboratory Medicine, …
Masaaki Inaba - One of the best experts on this subject based on the ideXlab platform.
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Fetuin-A: a multifunctional protein.
Recent patents on endocrine metabolic & immune drug discovery, 2011Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki InabaAbstract:Sixty-six years have elapsed since the discovery of Fetuin in 1944, but its importance in mammalian physiology has only recently been appreciated. Fetuin, first isolated from fetal bovine serum and now most commonly known as either Fetuin-A, alpha-2-HS-glycoprotein (recommended name by UniprotKB and PIR), or α2-Heremans-Schmid glycoprotein, functions as an important component of diverse normal and pathological processes, including vascular calcification and bone metabolism regulation, insulin resistance, protease activity control, keratinocytes migration, and breast tumor cell proliferative signaling. Fetuin-A has also been identified as a biomarker for neurodegenerative disease. Here, we summarize recent publications focusing on the structural and functional properties of Fetuin-A. The emerging importance of Fetuin-A for both diagnosis and therapeutics has come to the attention of the pharmaceutical industry. Therefore, we will discuss the status of patents based on Fetuin-A.
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effects of pioglitazone on serum Fetuin a levels in patients with type 2 diabetes mellitus
Metabolism-clinical and Experimental, 2008Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki Inaba, Hidenori Koyama, Takahiro Araki, Hisayo Yokoyama, Megumi Teramura, Eiko Lee, Tetsuo Shoji, Yoshiki NishizawaAbstract:Abstract Fetuin-A (α2-Heremans-Schmid glycoprotein), a circulating glycoprotein, can inhibit insulin signaling both in vivo and in vitro. Recently, we and another independent group have shown that Fetuin-A is positively associated with insulin resistance in humans. Furthermore, it has been reported that higher Fetuin-A levels are associated with metabolic syndrome and atherogenic lipid profiles. These data suggest that Fetuin-A might be a regulator of insulin resistance and/or metabolic syndrome. However, it is not clear how Fetuin-A levels are regulated. To address this, we investigated the effects of representative insulin-sensitizing therapies such as pioglitazone, metformin, and aerobic exercise on Fetuin-A levels. Twenty-seven patients with type 2 diabetes mellitus were divided into pioglitazone-treated (Pio), metformin-treated (Met), and exercise-treated (Ex) groups. Ten patients in the Pio group and 9 patients in the Met group took 15 or 30 mg/d pioglitazone or 500 or 750 mg/d metformin, respectively, for 6 months. Eight patients in the Ex group underwent a 3-month aerobic exercise program. Serum Fetuin-A levels were measured before and after each intervention. Intervention significantly decreased hemoglobin A1c in all groups. After treatment, serum Fetuin-A levels significantly decreased in the Pio group (291.2 ± 57.7 to 253.1 ± 43.9 μg/mL, P = .006), whereas there were no changes in serum Fetuin-A after intervention in either the Met or the Ex groups. We hypothesize that pioglitazone could partially ameliorate insulin resistance via modulating Fetuin-A levels.
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association of serum Fetuin a with carotid arterial stiffness
Clinical Endocrinology, 2007Co-Authors: Katsuhito Mori, Masanori Emoto, Koka Motoyama, Hidenori Koyama, Takahiro Araki, Hisayo Yokoyama, Megumi Teramura, Eiko Lee, Tetsuo Shoji, Masaaki InabaAbstract:Summary Objective Fetuin-A is a circulating glycoprotein which is well characterized as an inhibitor of ectopic calcification. Vascular calcification commonly found in chronic kidney disease (CKD) patients is a predictor of cardiovascular death. Recently, several groups have demonstrated that low Fetuin-A levels are associated with mortality in uraemic patients, possibly through regulation of vascular calcification. However, the physiological significance of Fetuin-A in atherosclerosis remains unknown, except in specific conditions, such as vascular calcification in CKD patients. The objective of this study was to investigate the association between serum Fetuin-A levels and arterial stiffness, a functional property of atherosclerosis, in healthy subjects. Patients and measurements The study subjects comprised 141 healthy subjects. We measured serum Fetuin-A levels and stiffness parameter β for the common carotid artery, which was assessed by ultrasound using a phase-locked echo-tracking system. Results Simple regression analyses indicated that serum Fetuin-A levels were significantly correlated with stiffness parameter β (r = 0·200, P = 0·018). Multiple regression analyses showed that, besides age, Fetuin-A (β = 0·166, P = 0·033) independently contribute to the stiffness parameter β (R2 = 0·310, P < 0·0001). Conclusions Serum Fetuin-A level is associated with carotid arterial stiffness, independent of known atherogenic factors in healthy subjects.
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association of serum Fetuin a with insulin resistance in type 2 diabetic and nondiabetic subjects
Diabetes Care, 2006Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki Inaba, Hidenori Koyama, Takahiro Araki, Hisayo Yokoyama, Megumi Teramura, Tetsuo Shoji, Y NishizawaAbstract:Fetuin-A (α2-Heremans Schmid glycoprotein) is a circulating glycoprotein that can inhibit insulin receptor autophosphorylation and subsequent downstream signaling in vitro (1, 2). Recently, it has been reported (3) that Fetuin-A–deficient mice demonstrate enhanced insulin sensitivity. These data indicate that Fetuin-A might be a negative regulator of insulin signaling. However, the physiological significance of Fetuin-A in insulin resistance in humans remains unclear. To address this, we investigated the relationship of serum Fetuin-A levels and insulin resistance in nondiabetic ( n = 160) and type 2 diabetic ( n = 161) subjects. Serum Fetuin-A was measured by an enzyme-linked immunosorbent assay kit (BioVender Laboratory Medicine, …
Konstantinos K Tsilidis - One of the best experts on this subject based on the ideXlab platform.
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plasma Fetuin a concentration genetic variation in the ahsg gene and risk of colorectal cancer
International Journal of Cancer, 2015Co-Authors: Heiner Boeing, Katharina Nimptsch, Krasimira Aleksandrova, Juergen Janke, Youngae Lee, Mazda Jenab, So Yeon Kong, Konstantinos K TsilidisAbstract:Fetuin-A, also referred to as alpha 2-Heremans-Schmid glycoprotein (AHSG), is a liver protein known to inhibit insulin actions. Hyperinsulinemia is a possible risk factor for colorectal cancer; however, the role of Fetuin-A in the development of colorectal cancer is unclear. We investigated the association between circulating Fetuin-A and colorectal cancer risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Fetuin-A concentrations were measured in prediagnostic plasma samples from 1,367 colorectal cancer cases and 1,367 matched controls. In conditional logistic regression models adjusted for potential confounders, the estimated relative risk (95% confidence interval) of colorectal cancer per 40 mg/mL higher Fetuin-A concentrations (approximately one standard deviation) was 1.13 (1.02-1.24) overall, 1.21 (1.05-1.39) in men, 1.06 (0.93-1.22) in women, 1.13 (1.00-1.27) for colon cancer and 1.12 (0.94-1.32) for rectal cancer. To improve causal inference in a Mendelian Randomization approach, five tagging single nucleotide polymorphisms of the AHSG gene were genotyped in a subset of 456 case-control pairs. The AHSG allele-score explained 21% of the interindividual variation in plasma Fetuin-A concentrations. In instrumental variable analysis, genetically raised Fetuin-A was not associated with colorectal cancer risk (relative risk per 40 mg/mL genetically determined higher Fetuin-A was 0.98, 95% confidence interval: 0.73-1.33). The findings of our study indicate a modest linear association between Fetuin-A concentrations and risk of colorectal cancer but suggest that Fetuin-A may not be causally related to colorectal cancer development.
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abstract 2200 plasma Fetuin a concentration genetic variation in the ahsg gene and risk of colorectal cancer
Cancer Research, 2014Co-Authors: Katharina Nimptsch, Heiner Boeing, Krasimira Aleksandrova, Youngae Lee, Mazda Jenab, Konstantinos K Tsilidis, Jurgen Janke, Bas Buenodemesquita, Elisabete Weiderpass Vainio, Eugene JansenAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Fetuin-a, also referred to as α2-Heremans-Schmid glycoprotein (AHSG) is a liver protein that inhibits insulin actions. High circulating Fetuin-a concentrations have been associated with insulin resistance and hyperinsulinemia, which pose risk factors for colorectal cancer. Experimental studies have also shown that Fetuin-a mediates the adhesion of tumor cells, an important step in tumor growth through which Fetuin-a could influence colorectal cancer risk independent of the insulin axis. With this study, we aimed to investigate the prospective association between circulating Fetuin-a and risk of colorectal cancer. In addition, we examined potential causality of observed associations by using single nucleotide polymorphisms (SNPs) in the AHSG gene as relatively unbiased proxies for Fetuin-a levels in a Mendelian Randomization approach. Methods: Fetuin-a levels were measured in plasma samples from a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) comprising 1367 cases and 1367 matched controls (matching variables included age, sex, study center and fasting status). In a subset of 456 case-control pairs, five tagging SNPs in the AHSG gene (rs2248690, rs2070633, rs2070635, rs4917 and rs6787344) were genotyped. The association between circulating Fetuin-a and risk of colorectal cancer was investigated using conditional logistic regression models (controlled for matching factors and multivariable adjusted for education, physical activity, smoking, alcohol consumption, dietary factors and body fatness) estimating incidence rate ratios (RRs) and 95% confidence intervals (CI). The association between genetically raised Fetuin-a and risk of colorectal cancer was estimated by instrumental variable analysis using two-stage least squares regression. Results: Higher Fetuin-a concentrations were associated with a moderately higher risk of colorectal cancer: The estimated RRs (95% CI) per 40 µg/mL higher Fetuin-a were 1.11 (1.01, 1.22) overall, 1.18 (1.03, 1.37) in men, 1.05 (0.92, 1.21) in women, 1.11 (0.99, 1.25) for colon cancer and 1.10 (0.92, 1.30) for rectal cancer. In the subset of participants with available data on both plasma Fetuin-a and AHSG SNPs, the AHSG allele score explained 21% of the inter-individual variation in plasma Fetuin-a. When using the AHSG-score as instrumental variable in a Mendelian randomization approach, there was no association between genetically determined Fetuin-a and risk of colorectal cancer: RR (95% CI) per 40 µg/mL genetically determined higher Fetuin-a was 0.98 (0.73, 1.33) overall, 1.04 (0.68, 1.60) in men and 0.93 (0.62, 1.42) in women. Conclusion: This is the first prospective study relating circulating Fetuin-a to risk of colorectal cancer. Our findings suggest that high Fetuin-a concentrations are associated with a moderately higher risk of colorectal cancer, but that Fetuin-a is probably not a causal factor. Citation Format: Katharina Nimptsch, Krasimira Aleksandrova, Heiner Boeing, Jurgen Janke, Young-Ae Lee, Mazda Jenab, Bas Bueno-De-Mesquita, Konstantinos K. Tsilidis, Elisabete Weiderpass Vainio, Eugene HJM Jansen, Timothy J. Key, Antonia Trichopoulou, Kim Overvad, Elio Riboli, Tobias Pischon, European Prospective Investigation into Cancer andNutrition (EPIC). Plasma Fetuin-a concentration, genetic variation in the AHSG gene and risk of colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2200. doi:10.1158/1538-7445.AM2014-2200