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Objective　To investigate the value of serum Fetuin-A and Fetuin-B combined with Homeostasis Model Assessment of Insulin Resistance （HOMA-IR） in predicting nonalcoholic fatty liver disease （NAFLD). Methods　A total of 120 patients with NAFLD who attended Department of Gastroenterology, The First Affiliated Hospital of Dali University, from June 2020 to June 2021, and 120 healthy individuals who underwent physical examination at Physical Examination Center during the same period of time were enrolled as subjects, and clinical data were collected from all subjects. The serum levels of Fetuin-A and Fetuin-B were measured. The independent-samples t test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups； the multivariate Logistic regression analysis was used to assess the risk factors for NAFLD. The receiver operating characteristic （ROC） curve was plotted to evaluate the predictive efficacy of Fetuin-A and Fetuin-B combined with HOMA-IR in NAFLD patients. Results　Compared with the healthy control group, the NAFLD group had significantly higher levels of body mass index, systolic blood pressure, diastolic blood pressure, alanine aminotransferase, aspartate aminotransferase, fasting blood glucose, fasting insulin, triglycerides, HOMA-IR, Fetuin-A, and Fetuin-B （all P<0.05). The multivariate Logistic regression analysis showed that Fetuin-A （odds ratio ［OR］=1.010, 95% confidence interval［ CI］： 1.001 — 1.020, P<0.05), Fetuin-B（ OR=1.113, 95%CI： 1.021 — 1.214, P<0.05), and HOMA-IR（ OR= 24.053, 95%CI： 2.624 — 220.470, P<0.05） were independent risk factors for NAFLD. The ROC curve analysis showed that Fetuin-A, Fetuin-B or HOMA-IR alone had an area under the ROC curve （AUC） of 0.637 （95%CI： 0.551 — 0.722), 0.853 （95%CI： 0.796 — 0.912), and 0.837（ 95%CI： 0.763 — 0.912), respectively, and Fetuin-A combined with Fetuin-B, Fetuin-A combined with HOMA-IR, and Fetuin-B combined with HOMA-IR had an AUC of 0.853 （95%CI： 0.795 — 0.911), 0.843 （95%CI： 0.770 — 0.916), 0.922 （95%CI： 0.877 — 0.967), respectively, while the combination of these three indicators had an AUC of 0.922 （95%CI： 0.877 — 0.966). Conclusion　Fetuin-A and Fetuin-B have a certain value in predicting NAFLD, and Fetuin-B combined with HOMA-IR tends to have a higher predictive value. [ABSTRACT FROM AUTHOR]

Background: Fetuin-B, a cytokine that regulates lipid metabolism, has recently been linked to cardiovascular diseases such as coronary heart disease. In this study, we discussed the relationship between fetuin-B and essential hypertension. Method: A bioinformatics analysis of fetuin-B was performed. A total of 206 with essential hypertension and 180 age- and-sex-matched healthy sub jects were enrolled. Plasma fetuin-B, endothelin 1 (ET-1), nitric oxide (NO), and adiponectin (ADI) levels were measured using ELISA kits. Results: Bioinformatics analysis has revealed that fetuin-B plays an important role in pathways such as lipid metabolism. Compared with healthy subjects, serum fetuin-B levels in patients with essential hypertension were significantly increased. Correlation analysis showed that the serum fetuin-B level was positively correlated with systolic blood pressure (SBP), diastolic blood pressure, body mass index, fat percentage in vivo, waist–hip ratio, intima–media thickness, low-density lipoprotein cholesterol (LDL-C), glutamyl transpeptidase, alanine transaminase, albumin, fasting blood glucose (FBG), glycated hemoglobin, and ET-1 in the overall study subjects (all P < 0.05) and negatively correlated with HDL-C, ADI, and NO (all P < 0.05). Multivariate linear regression analysis showed that SBP, FBG, LDL-C, ADI, and ET-1 were independent factors affecting serum fetuin-B. A binary logistic regression analysis showed that fetuin-B was an independent risk factor for primary hypertension (odds ratio: 1.060, 95% CI: 1.034–1.086, P < 0.001). Receiver operating characteristic curve analysis was used to evaluate the predictive value of fetuin-B for primary hypertension, and the optimal cutoff point was 83.14 μg/mL (sensitivity 77.4%, specificity 63.3%) (area under the curve) = 0.7738, 95% CI 0.7276–0.8200, P < 0.001). Conclusion: Elevated fetuin-B levels are associated with an increased risk of essential hypertension.

To investigate the expression, source, role, and mechanism of Fetuin-B (FETUB) in diabetic retinopathy (DR). ELISA and immunofluorescence were used to analyze the concentration of FETUB in plasma, aqueous fluid, and tissue specimens of patients with DR and healthy controls. Immunofluorescence, q-PCR, and western blotting were used to examine the expression of FETUB in DR mice and cells cultured with different concentrations of glucose. BV2 microglia cell line and DR mice were treated using FETUB recombination protein and FETUB shRNA to explore the function of FETUB in DR by q-PCR, western blotting, and immunofluorescence. FETUB concentrations in plasma, aqueous fluid, and tissue specimens were significantly increased in DR patients. The mice in DR group had a higher concentration of FETUB in the retina and liver tissues than those in the control group, and the expression of FETUB was increased in both ARPE19 and BV2 cells under a high-glucose environment. The ratio of p-P65 (Phospho-P65)/P65 and the expression levels of TNF-α, VEGF, and ionized calcium binding adaptor molecule (IBA)-1 were increased in BV2 cells cultured with FETUB recombinant protein, while they were decreased in BV2 cells transfected with FETUB shRNA. Immunofluorescence staining showed that there were more IBA-1+ activated microglia in the retinas of the FETUB recombination protein group than in the retinas of the DR group, and there were fewer IBA-1+ activated microglia in the retinas of the FETUB shRNA group than in the retinas of the DR group. FETUB sourced from endocrine, autocrine, and paracrine pathways could promote inflammation in DR by activating the NF-κB pathway and microglia. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVE: Non-alcoholic fatty liver is one of the most common causes of chronic liver disease and is considered as one of the hepatic manifestations of metabolic syndrome, and since one of the effective treatments for this disease is exercise, the aim of this study was to evaluate the changes in Fetuin-B and retinol binding protein 4 (RBP4) during eight weeks of high-intensity interval training (HIIT) in women with fatty liver. METHODS: This experimental study was performed on 25 women with fatty liver disease in the age range of 30-50 years in two groups of training (n=13) and control (n=12). The training group was included in the intermittent high-intensity exercise protocols (8 weeks and four sessions per week and each session for 48 to 60 minutes) and the control group participated in the study without any intervention. Fetuin-B and RBP4 were evaluated and compared by ELISA using a kit made by Elabscience Inc. FINDINGS: The results of the present study showed that the levels of Fetuin-B in the training group (752.50±191.23) had a significant decrease compared to the control group (1141.90±227.23) (p=0.001). Moreover, RBP4 had a significant decrease in the training group (25.42±1.11) compared to the control group (30.33±3.09) (p=0.001). CONCLUSION: The results of the study showed that a course of high-intensity interval training can be a suitable and preventive strategy to improve Fetuin-B and RBP4 levels in women with fatty liver.

Aim: We aimed to investigate the value of follicular fluid fetuins‐A and ‐B to predict successful IVF and pregnancy outcomes in infertile women with poor, normal, and high ovarian reserve. Methods: The follicular fluid of 96 infertile women who underwent intra‐cytoplasmic sperm injection (ICSI) procedure was analyzed. Fetuins‐A and ‐B levels were examined and compared in those who could achieve pregnancy and those who could not. Receiver operating characteristic curve analyzes were used to determine cut‐off and statistically significant associations for fetuins‐A and ‐B. Results: Follicular fluid fetuin‐A levels were higher in cases with weak ovarian reserve (OR) (p < 0.05) and higher in patients who did not achieve clinical pregnancy (p < 0.05). Conversely, the follicular fluid fetuin‐B levels were lower in cases with poor OR (p < 0.05) and were lower in patients who did not achieve a clinical pregnancy (p < 0.05). A follicular fluid fetuin‐A concentration ≤ 19.12 ng/mL had a sensitivity and specificity of 94.74% and 93.1%, respectively, at predicting clinical pregnancy. While the follicular fluid fetuin‐B concentration >24.7 ng/mL had sensitivity and specificity of 71.1% and 51.7%, respectively, for clinical pregnancy prediction. Conclusion: Overall, high levels of follicular fluid fetuin‐A may be independently associated with unsuccessful IVF irrespective of OR grouping. A low level of follicular fetuin‐B was also associated with failed IVF. The sensitivity and specificity were found to be higher for fetuin‐A in predicting clinical pregnancy. Therefore, the follicular fluid fetuin‐A may be more predictive for successful IVF and clinical pregnancy outcomes than follicular fluid fetuin‐B. [ABSTRACT FROM AUTHOR]

Introduction: Decreased physical activity is one of the main causes of the obesity epidemic. In the process of obesity, the secretion of some hepato-adipokines increases and causes metabolic disorders. Exercise plays an important role in improving the complications of obesity by regulating the levels of selected hepato-adipokine. The purpose of this study was to examine the effects of three types of resistance training methods on selected hepato-adipokine and lipid profiles in men with obesity. Materials and Methods: The sample of the study included 44 sedentary men with obesity divided into 4 groups of traditional resistance training (TRT), circuit resistance training (CRT), and interval resistance training (IRT) as well as one control group. Fetuin-A, Fetuin-B, high-density lipoproteins (HDL), low-density lipoproteins (LDL), total cholesterol (TC), and triglyceride (TG) were measured using the ELISA method. Results: The results of the mixed model ANOVA analysis showed a significant interaction between the type of training used and time at the levels of Fetuin-A (F (1, 40) = 94273.16, P = 0.001, ES = 1.00) and Fetuin-B (F (1, 40) = 49697.67, P = 0.001, ES = 0.99. In addition, within-group comparisons showed that lipid profile improved in TRT and CRT groups compared to the pretest (P = 0.001), while in the IRT group this improvement was not significant (P > 0.05). Conclusion: The result of the present study shows that three models of resistance training reduced the select hepato-adipokines level in comparison to the control group. However, IRT and CRT had the greatest effect on reducing Fetuin-A and Fetuin-B, respectively. [ABSTRACT FROM AUTHOR]

Objective: PCOS women are characterized by insulin resistance and have higher tendency to the development of hepatic steatosis. Fetuin-B has been introduced as a hepatokine/ adipokine, which is increased in hepatic steatosis and may be connected with glucose metabolism disturbances. The aim of the study was to evaluate the relationships between serum fetuin-B concentration and indices of insulin resistance, insulin secretion and markers of liver steatosis in PCOS women in comparison to the control group. Patients and methods: The study group included 108 women – 57 women with PCOS and 51 women matched for age and BMI as a control group. Serum concentration of fetuin-B was estimated. Homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment β cell function (HOMA-β) were calculated. Fatty liver index (FLI), lipid accumulation product (LAP) and visceral adiposity index (VAI) were used as markers of liver steatosis. Results: We found higher serum concentration of fetuin-B and FLI in PCO S women in comparison to the control group (all P < 0.05). We observed a positive relationship between serum fetuin-B concentration and HOMA-β (r = 0.43, P = 0.01), HOMA-IR (r = 0.31, P = 0.01), FLI (r = 0.29, P = 0.02), VAI (r = 0.29, P = 0.02) and LAP (r = 0.32, P = 0.01) in PCOS women. We also noticed a relationship between HOMA-IR and FLI (r = 0.42, P = 0.01), VAI (r = 0.38, P = 0.004) and LAP (r = 0.41, P = 0.001) in this group. Multiple regression analysis revealed that HOMA-β (β = 0.39, P = 0.002) and LAP (β = 0.27, P = 0.02) were independently connected with serum fetuin-B levels in women with PCOS. Conclusions: Serum fetuin-B levels are higher in women with PCOS and are in dependently connected with HOMA-β and hepatic steatosis.

Background and Aims Fetuin-B has been reported to be involved in glucose and lipid metabolism and associated with the occurrence of diabetes. The main purpose of this study is to explore the changes of circulating fetuin-B in young women with pre-diabetes and to analyze the relationship between fetuin-B and the occurrence and development of IR. Methods A total of 304 women were enrolled in this study and subjected to both OGTT and EHC. A subgroup of 26 overweight/obese womenwas treated with Lira for 24 weeks. serum fetuin-B concentrations were measured by ELISA. Results In IGT and IR-NG groups, serum fetuin-B levels were higher than those in the NGT group. The serum fetuin-B levels in the IGT group were higher than those in the IR-NG group. serum fetuin-B was positively correlated with BMI, WHR, 2h-BG, FIns, HbA1c, and HOMA2-IR, but negatively correlated with the M-value in all study populations. Multiple stepwise regression analysis showed that the M-value was independently and inversely associated with serum fetuin-B. Logistic regression analysis showed that serum fetuin-B was independently associated with IGT and significantly increased the risk of IGT. During the OGTT, serum fetuin-B increased significantly in the NGT group, but there were no significant changes in other groups. During the EHC, serum fetuin-B increased in the IGT group, but there was no change in other groups. After Lira intervention, serum fetuin-B decreased significantly in IGT women. Conclusions serum fetuin-B levels are elevated in young women with IR or IGT and may be associated with IR.

Nanoparticles have gained importance in various biomedical field viz cosmetics, diagnostics, therapeutics, and food additives. Due to small size, NPs penetrate tissues and cells, thereby interacting with biomolecules such as proteins and nucleic acids. This raises the major concern to investigate the effect of NPs in a living system. Previously, we reported downregulation of Fetuin-B in rat plasma, with the increasing dose level of NP-Fe4(P2O7)3, in rats treated with NP-Fe4(P2O7)3 as a food-fortificant. In the present study, we validated the dose response of Fetuin-B in rats exposed to NP-Fe4(P2O7)3, NP-ZnO, and NP-SiO2. Fetuin-B showed similar dose responses in all the groups irrespective of their physicochemical properties. Previously, we hypothesized that the immune response was triggered upon exposure to NP-Fe4(P2O7)3 in vivo, which led to the differential regulation of Fetuin-B. To evaluate the hypothesis, immunological response was assessed in rats by estimating the pro-inflammatory cytokines in plasma. We observed Interleukin-1α and Interleukin-1β increased with the increasing dose levels of the three NPs. The impact of NPs on the proteomic profile in the kidney tissues of rats exposed to three NPs, showed differential spatial distribution of α-Enolase across the medulla and the cortex region with respect to the control group, suggesting an overexpression of α-Enolase. Overexpression of α-Enolase might be an indicative of cellular apoptosis in response to cytotoxicity caused due to NP perforation across the cellular membrane. In the present study, we propose that Fetuin-B might be considered a plasma biomarker to detect nanotoxicity at an early stage in a living system. [ABSTRACT FROM AUTHOR]

Context/objective: Fetuin-B is a hepatokine/adipokine implicated in glucose homeostasis and lipid metabolism. We sought to assess whether cord blood fetuin-B levels are altered in gestational diabetes mellitus (GDM) and the association with fetal growth factors and lipids., Study Design, Population, and Outcomes: In a nested case-control study of 153 pairs of neonates of mothers with GDM and euglycemic pregnancies in the Shanghai Birth Cohort, we assessed cord blood fetuin-B in relation to fetal growth factors and lipids [high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterols (TC) and triglycerides (TG)]., Results: Cord blood fetuin-B concentrations were higher in the newborns of GDM vs. euglycemic mothers (mean ± SD: 2.35±0.96 vs 2.05±0.73 mg/L, P=0.012), and were positively correlated with LDL (r=0.239, P<0.0001), TC (r=0.230, P=0.0001), insulin-like growth factor-Ⅰ [IGF-Ⅰ (r=0.137, P=0.023)] and IGF-Ⅱ (r=0.148, P=0.014) concentrations. Similar associations were observed adjusting for maternal and neonatal characteristics., Conclusions: The study is the first to demonstrate that fetuin-B levels are elevated in fetal life in GDM, and that fetuin-B affects lipid metabolic health during fetal life in humans. The secretion of fetuin-B appears to be related to the secretion of insulin-like growth factors (IGF-Ⅰ and IGF-Ⅱ)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Patients with type 2 diabetes mellitus (T2DM) are more susceptible to acute myocardial ischemia/reperfusion (MI/R) injury. However, the mechanism remains largely elusive. Clinical observation showed that high levels of hepatokine fetuin-B (FetB) in plasma are significantly associated with both diabetes and coronary artery diseases. This study was aimed to determine whether FetB mostly derived from liver exacerbates MI/R-induced injury and the underlying mechanisms in T2DM. Mice were given high-fat diet and streptozotocin to induce T2DM model and subjected to 30 min MI followed by reperfusion. Diabetes caused increased hepatic FetB expression and greater myocardial injury as evidenced by increased apoptosis and myocardial enzymes release following MI/R. In T2DM hearts, insulin-induced phosphorylations of insulin receptor substrate 1 at Tyr608 site and Akt at Ser473 site and glucose transporter 4 membrane translocation were markedly reduced. Interaction between FetB and insulin receptor-β subunit (IRβ) was enhanced assessed by immunoprecipitation analysis. More importantly, FetB knockdown via AAV9 alleviated MI/R injury and improved cardiac insulin-induced signaling in T2DM mice. Conversely, upregulation of FetB in normal mice caused exacerbated MI/R injury and impairment of insulin-mediated signaling. In cultured neonatal mouse cardiomyocytes, incubation of FetB significantly reduced tyrosine kinase activity of IR and insulin-induced glucose uptake, and increased hypoxia/reoxygenation-induced apoptosis. Furthermore, FoxO1 knockdown by siRNA suppressed FetB expressions in hepatocytes treated with palmitic acid. In conclusion, upregulated FetB in diabetic liver contributes to increased MI/R injury and cardiac dysfunction via directly interacting with IRβ and consequently impairing cardiac insulin signaling. • Hepatokine fetuin-B is significantly upregulated in diabetes. • Upregulated fetuin-B exacerbates MI/R injury in diabetes and suppression of fetuin-B exerts cardiac protective effects. • Fetuin-B interacts with insulin receptor-β subunit, impairs cardiac insulin signaling and consequently causes MI/R injury. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVE: Non-alcoholic fatty liver is one of the most common causes of chronic liver disease and is considered as one of the hepatic manifestations of metabolic syndrome, and since one of the effective treatments for this disease is exercise, the aim of this study was to evaluate the changes in Fetuin-B and retinol binding protein 4 (RBP4) during eight weeks of high-intensity interval training (HIIT) in women with fatty liver. METHODS: This experimental study was performed on 25 women with fatty liver disease in the age range of 30-50 years in two groups of training (n=13) and control (n=12). The training group was included in the intermittent highintensity exercise protocols (8 weeks and four sessions per week and each session for 48 to 60 minutes) and the control group participated in the study without any intervention. Fetuin-B and RBP4 were evaluated and compared by ELISA using a kit made by Elabscience Inc. FINDINGS: The results of the present study showed that the levels of Fetuin-B in the training group (752.50±191.23) had a significant decrease compared to the control group (1141.90±227.23) (p=0.001). Moreover, RBP4 had a significant decrease in the training group (25.42±1.11) compared to the control group (30.33±3.09) (p=0.001). CONCLUSION: The results of the study showed that a course of high-intensity interval training can be a suitable and preventive strategy to improve Fetuin-B and RBP4 levels in women with fatty liver. [ABSTRACT FROM AUTHOR]

Background: Hepatokines such as fibroblast growth factor 21 (FGF21), leukocyte cell-derived chemotaxin 2 (LECT2), fetuin-A, fetuin-B, and selenoprotein P (SeP) are liver-derived proteins that are modulated by chronic energy status and metabolic disease. Emerging data from rodent and cell models indicate that hepatokines may be sensitive to acute nutritional manipulation; however, data in humans are lacking.Objective: The aim was to investigate the influence of hyperenergetic, high-fat feeding on circulating hepatokine concentrations, including the time course of responses.Methods: In a randomized, crossover design, 12 healthy men [mean ± SD: age, 24 ± 4 y; BMI (kg/m2), 24.1 ± 1.5] consumed a 7-d hyperenergetic, high-fat diet [HE-HFD; +50% energy, 65% total energy as fat (32% saturated, 26% monounsaturated, 8% polyunsaturated)] and control diet (36% total energy as fat), separated by 3 wk. Whole-body insulin sensitivity was assessed before and after each diet using oral-glucose-tolerance tests. Fasting plasma concentrations of FGF21 (primary outcome), LECT2, fetuin-A, fetuin-B, SeP, and related metabolites were measured after 1, 3, and 7 d of each diet. Hepatokine responses were analyzed using 2-factor repeated-measures ANOVA and subsequent pairwise comparisons.Results: Compared with the control, the HE-HFD increased circulating FGF21 at 1 d (105%) and 3 d (121%; P ≤ 0.040), LECT2 at 3 d (17%) and 7 d (32%; P ≤ 0.004), and fetuin-A at 7 d (7%; P = 0.028). Plasma fetuin-B and SeP did not respond to the HE-HFD. Whole-body insulin sensitivity was reduced after the HE-HFD by 31% (P = 0.021).Conclusions: Acute high-fat overfeeding augments circulating concentrations of FGF21, LECT2, and fetuin-A in healthy men. Notably, the time course of response varies between proteins and is transient for FGF21. These findings provide further insight into the nutritional regulation of hepatokines in humans and their interaction with metabolic homeostasis. This study was registered at clinicaltrials.gov as NCT03369145. [ABSTRACT FROM AUTHOR]

Fetuin-B is a serum protein linked to the regulation of physiological or pathophysiological events such as fertility, energy metabolism, and liver disease. Recently, fetuin-B has been reported to be involved in the modulation of the rupture of atherosclerotic plaques associated with acute myocardial infarction. However, the exact mechanism involved in the modulation of atherosclerotic plaque rupture event by fetuin-B is not fully elucidated yet. In the present study, we investigated whether fetuin-B could influence atherosclerotic plaque rupture through vascular smooth muscle cells (VSMCs). Immunoprecipitation assay using membrane proteins from VSMCs revealed that fetuin-B tightly bound to transforming growth factor-β receptor (TGF-βR). Fetuin-B treatment elevated TGF-βR signals (e.g., phosphorylation of Smad2 and Smad3) in VSMCs. Fetuin-B also stimulated nuclear translocation of phosphorylated Smads. Phosphorylation of Smad and its nuclear translocation by treatment with fetuin-B were inhibited in VSMCs by treatment with SB431542, a selective inhibitor of TGF-βR. Fetuin-B enhanced expression levels of plasminogen activator inhibitor-1 (PAI-1) and matrix metalloproteinase-2 (MMP-2) in VSMCs through its epigenetic modification including recruitments of both histone deacetylase 1 and RNA polymerase II. These epigenetic alterations in VSMCs were also inhibited by treatment with SB431542. In vivo administration of fetuin-B protein increased expression levels of PAI-1 and MMP-2 in the vascular plaque. However, these increases in expression were inhibited by the administration of SB43154. These results indicate that fetuin-B may modulate vascular plaque rupture by promoting expression of PAI-1 and MMP-2 in VSMCs via TGF-βR-mediated Smad pathway. [ABSTRACT FROM AUTHOR]

Background: There is no evidence available on the association of Fetuin-B with chronic kidney disease (CKD), and mechanisms linking nonalcoholic fatty liver disease (NAFLD) to CKD are not fully understood. We aimed to explore the independent associations and potential mechanisms of Fetuin-B and NAFLD with CKD. Methods: A cross-sectional study of 1,072 Chinese adults who underwent serum Fetuin-B test and hepatic ultrasonography scanning was conducted in Xiamen, China. CKD was defined as estimated glomerular filtration rate < 60 mL/min/1.73 m2 and/or the presence of albuminuria. Results: Subjects with CKD showed significantly higher prevalence of NAFLD (69.5 vs. 57.2%, p < 0.001) and serum Fetuin-B levels (4.32 ± 1.45 vs. 4.05 ± 1.36 µg/mL, p = 0.007) than their controls. Increased serum Fetuin-B was also significantly associated with increased levels of fasting insulin and homeostasis model assessment – insulin resistance (both p values < 0.05). NAFLD and higher serum Fetuin-B were significantly associated with increased risk of CKD, and the unadjusted ORs (95% CIs) were 1.701 (1.256–2.303, p = 0.001) and 1.213 (1.053–1.399, p = 0.008, per SD increase of Fetuin-B), respectively. With adjustment for potential confounding factors, including metabolic/insulin resistance syndrome, NAFLD but not serum Fetuin-B was still significantly associated with increased risk of CKD, and the adjusted ORs (95% CIs) were 1.820 (1.327–2.496, p < 0.001) and 1.116 (0.959–1.298, p = 0.153, per SD increase of Fetuin-B), respectively. Conclusions: Fetuin-B might link NAFLD to CKD via inducing insulin resistance, and NAFLD contributes independently to the pathogenesis of CKD via multiple mechanisms besides of metabolic/insulin resistance syndrome. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the relationship between serum/follicular fluid fetuin-B levels and fertilization outcomes in conventional IVF cycles. Methods: A prospective cohort study of conventional IVF treatments including 78 cycles with low fertilization rates (two pronuclei [2PN] rate < 30%; LF group) and 104 cycles performed during the same period with 2PN rate > 70% (high fertilization group, HF). To calculate the required sample size, a two-sample t test power analysis was applied to data from our pilot study, using PASS 11.0 software. Fetuin-B was measured using a commercial sandwich enzyme-linked immunosorbent assay. Results: Serum fetuin-B and follicular fluid fetuin-B were positively correlated (r = 0.703, P < 0.001). Compared to the HF group, the LF group had significantly lower levels of fetuin-B, both in serum (5.81 ± 1.53 vs. 7.19 ± 1.42, P < 0.001) and follicular fluid (5.06 ± 1.29 vs. 6.16 ± 1.52, P < 0.001). The serum fetuin-B level from cycles with polypronuclear (PPN) zygotes was significantly lower when compared to cycles without PPN zygotes (6.82 ± 1.65 vs. 6.10 ± 1.43, P = 0.006). However, serum fetuin-B level was not correlated with preimplantation embryo development or clinical pregnancy. Conclusion: Serum fetuin-B level is correlated with fertilization rate in conventional IVF and it may be used as a predictive marker of fertilization in IVF treatment. [ABSTRACT FROM AUTHOR]

Objectives: To investigate liver-derived plasma protein fetuin B levels in healthy pregnant women and pregnant women with intrahepatic cholestasis of pregnancy (ICP).Materials and Methods: Forty women with ICP and 40 healthy pregnant women were included in this cross-sectional study. The serum fetuin B levels of these patients were analyzed. The patients were followed up to delivery.Results: Maternal age, gravida, parity, BMI at assessment, and gestational age at blood sampling were similar between the ICP and control groups (p > .05). However, the gestational age at delivery and the birth weight were significantly lower in the ICP group (p < .05). Total bile acid (TBA) levels and liver function tests were significantly higher in the ICP group than in the control group (p < .0001 and < .0001, respectively). In addition, serum fetuin B concentrations were significantly higher in the ICP group than in the control group (p < .0001). The best cutoff for fetuin B serum concentration was 5540.2 pg/mL. Serum values greater than this threshold had 80% sensitivity and 65% specificity for the diagnosis of ICP.Conclusions: Serum fetuin B was higher in patients with ICP compared to healthy pregnant women and might be a new biomarker. [ABSTRACT FROM AUTHOR]

Coronary artery disease (CAD) is the leading cause of death worldwide. Earlier detection of CAD improves treatment outcomes and secondary prevention. The circulating fetuin-B protein is considered to be a promising biomarker for the early detection of CAD. However, a facile and reliable clinical test for fetuin-B is still lacking. Herein, we describe a reliable fluorescent biosensor for detecting fetuin-B in plasma that combines quantum dots-doped polystyrene nanoparticles with an immunochromatographic assay strip (QNPs-ICAS). The QNPs served as detection signals in the QNPs-ICAS sensor system, which was based on a double-antibody sandwich structure. Under optimum experimental conditions, the biosensor exhibited a broad linear range of 1–200 ng mL−1 and a low detection limit of 0.299 ng mL−1. Furthermore, the proposed immunosensor demonstrated high sensitivity, satisfactory selectivity, good reproducibility, and excellent recovery. Finally, the performance and applicability of our QNPs-based ICAS system were validated in clinical samples using a commercial ELISA kit with excellent correlations (r = 0.98451, n = 116). To conclude, the proposed sensor served as a rapid, sensitive, and accurate method for detecting fetuin-B in actual clinical samples, thereby demonstrating its potential for preliminary CAD screening and diagnosis. A reliable fluorescent biosensor for detecting fetuin-B in plasma that combines quantum dots-doped polystyrene nanoparticles with an immunochromatographic assay strip (QNPs-ICAS). The QNPs served as detection signals in the QNPs-ICAS sensor system, which was based on a double-antibody sandwich structure. [Display omitted] • A rapid and sensitive QNPs-ICAS was established for detection of fetuin-B. • The QNPs was used to enhance fluorescence signals and improve detection limit. • A linear dynamic concentration range of 1–200 ng mL−1 with a detection limit of 0.299 ng mL−1 for fetuin-B. • The proposed method exhibited satisfactory selectivity, reproducibility, and recovery. • The sensor was feasible for fetuin-B determination in real samples. [ABSTRACT FROM AUTHOR]

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Abstract Aims To assess circulating fetuin-B concentrations in subjects with different degrees of glucose tolerance and to analyze the association of fetuin-B concentrations with insulin resistance and the first phase of glucose-stimulated insulin secretion. Methods Plasma fetuin-B concentrations were analyzed in 149 subjects with normal glucose tolerance (NGT, n = 54), impaired glucose regulation (preDM, n = 42) and newly diagnosed type-2 diabetes mellitus (nT2DM, n = 53). Intravenous glucose tolerance tests (IVGTTs) and biochemical parameters were also assessed in all participants. Results Plasma fetuin-B concentrations were significantly higher in nT2DM patients compared with NGT and preDM subjects (both P < 0.001) and positively correlated with FPG, 2hPG, HOMA-IR, HbA 1c , hsCRP, FINS and TG (P < 0.05), but negatively correlated with AIR, AUC, GDI and fasting Belfiore index (P < 0.01). After adjusting for age and gender, all correlations remained statistically significant (P < 0.05). Multivariate logistic regression analysis revealed that plasma fetuin-B concentrations were significantly correlated with nT2DM after controlling for age, gender, BMI, WHR, blood pressure and lipid profiles. Conclusion Patients with nT2DM have significantly higher concentrations of plasma fetuin-B compared with NGT subjects and plasma fetuin-B is strongly associated with glucose and lipid metabolism, chronic inflammation and first-phase glucose-stimulated insulin secretion and insulin resistance. [ABSTRACT FROM AUTHOR]

Abstract Maternal undernutrition during pregnancy (MUN) often leads to low birth weight (LBW) neonates that have a reduced total nephron endowment, leaving these neonates susceptible to kidney disease throughout their lives. For reasons unknown, these LBW neonates have impaired kidney development due to a severe reduction in renal SIX2+ stem cells during nephrogenesis. Using a mouse model of MUN, we investigated SIX2+ stem cell reduction in the LBW neonate. Significant upregulation of the protein fetuin-B (measured by PCR and immunoblotting) in the MUN mother's placenta, organs and circulation yielded a 3-fold increase of this protein in the embryonic kidney. Recombinant fetuin-B, administered to healthy pregnant mothers at the concentration equivalent to that in the MUN mother, crossed the placenta and reduced both SIX2+ stem cells by 50% and nephron formation by 66% in embryonic kidneys (measured by immunofluorescence and the physical dissector/fractionator stereological method). Administration of fetuin-B to kidney explants yielded similar reductions in renal SIX2+ stem cells and nephron formation. Fetuin-B treatment of isolated embryonic renal SIX2+ stem cell primary cultures 1) increased NF-kB activity and apoptosis, 2) reduced cell proliferation due to upregulated p21 nuclear activity and subsequent cell cycle arrest, and 3) enhanced generation of reactive oxygen species (measured by fluorescence microscopy). In conclusion, MUN increases fetuin-B in the developing embryonic kidney. The increase in fetuin-B blunts nephrogenesis by reducing SIX2+ stem cells by promoting their apoptosis (via NF-kB upregulation), blunting their proliferative renewal (via p21 upregulation) and enhancing oxidative stress. Highlights • MUN causes LBW neonates to have reduced nephrons and prone to kidney disease. • MUN upregulates fetuin-B release from the mother's placenta, lungs, liver&kidneys. • Upregulated fetuin-B crosses the placenta into the embryonic circulation&kidney. • Fetuin-B reduces SIX2+ renal stem cells in the developing embryonic kidney. • Fetuin-B induced SIX2+ cell reduction impairs nephron formation in the LBW neonate. [ABSTRACT FROM AUTHOR]

Objective Laboratory models suggested that Fetuin-B impaired insulin action in myotubes and hepatocytes and caused glucose intolerance in mice. We aimed to explore the independent associations and pathways among serum Fetuin-B, nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Methods A cross-sectional study of 1318 obese adults who underwent serum Fetuin-B test and hepatic ultrasonography scanning was conducted in Xiamen, China. Multivariable logistic regression was used to calculate adjusted odds ratio (OR) and 95% confidence intervals (CI) of serum Fetuin-B level and NAFLD for T2D in different models with adjustment for potential confounders. Structural equation modeling (SEM) was used to examine the paths among NAFLD, serum Fetuin-B, metabolic/insulin resistance syndrome and T2D. Results Subjects with T2D or NAFLD showed significantly increased serum Fetuin-B levels compared to their controls (4.25 ± 1.35 vs. 4.08 ± 1.38 µg/ml for diabetes; and 4.26 ± 1.41 vs. 4.07 ± 1.33 µg/ml for NAFLD; both p-values < 0.05). NAFLD and higher serum Fetuin-B were significantly associated with higher risk of T2D with adjustment for sociodemographic and lifestyle habits; and the adjusted ORs (95%CIs) were 2.90 (2.17–3.87, p < 0.001) and 1.16 (1.01–1.32, p = 0.032), respectively. With further adjustment for metabolic/insulin resistance syndrome (BMI, systolic and diastolic BP, triglyceride, total cholesterol, HDL- and LDL-cholesterol, HOMA-IR and serum uric acid), NAFLD but not serum Fetuin-B was significantly associated with increased risk of T2D (ORs (95%CIs): 1.58 (1.12–2.21, p = 0.009) and 1.07 (0.92–1.23, p = 0.384), respectively). A one pathway model by using SEM fitted well (χ 2  = 497.92, p < 0.001; CFI = 0.965; TLI = 0.926; and RMSEA = 0.097) and showed that NAFLD increased serum Fetuin-B and elevated Fetuin-B increased fasting insulin level, which in turn induced insulin resistance and T2D. Besides, NAFLD increased the risk of T2D directly in addition to its indirect effects of inducing metabolic/insulin resistance syndrome which in turn increased the risk of T2D. Conclusions Fetuin-B links NAFLD to T2D via inducing insulin resistance, and NAFLD contributes to the pathogenesis of T2D via multiple mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: Background: Fetuin‐B impairs insulin action in myotubes and hepatocytes and causes glucose intolerance in mice. This study explored the correlation between serum fetuin‐B and intrahepatic triglyceride (IHTG) content, and the association between fetuin‐B and the risk of insulin resistance in the general adult population. Methods: A cross‐sectional study of 1318 obese adults who underwent serum fetuin‐B testing and hepatic ultrasonography was conducted in Xiamen, China. The IHTG content was determined in 428 subjects by magnetic resonance spectroscopy. Results: Non‐alcoholic fatty liver disease prevalence was significantly higher in those with the highest serum fetuin‐B concentrations and the highest IHTC content (Tertile 3) than in subjects in Tertiles 1 and 2 (62.6% vs 60.7% and 54.3%, respectively [P = 0.032], and 15.3% vs 12.8% and 12.7%, respectively [P = 0.049]). There was a significant association between increasing serum fetuin‐B tertiles and both increasing fasting insulin concentrations (mean [± SD] 11.9 ± 6.8, 12.7 ± 7.6, and 13.3 ± 6.4 mIU/L in Tertiles 1, 2 and 3, respectively; P = 0.006) and prevalence of insulin resistance (54.4%, 58.9%, and 64.5% in Tertiles 1, 2 and 3, respectively; P = 0.010). In linear regression analysis, IHTG content was independently and positively correlated with serum fetuin‐B (regression coefficient 0.015; P = 0.045). With adjustment for potential confounders, serum fetuin‐B was independently associated with increased risk of insulin resistance, with an adjusted odds ratio per standard deviation increase in fetuin‐B of 1.14 (95% confidence interval 1.01–1.30; P = 0.031). Conclusions: The results demonstrate the role of fetuin‐B linking liver fat accumulation to insulin resistance in humans. [ABSTRACT FROM AUTHOR]

The liver is a central regulator of whole body glucose, and lipid homeostasis and hepatokines, like fetuin-A, have been identified as markers and mediators of fatty liver-induced cardiometabolic risk. The closely related protein fetuin-B was shown to be upregulated in the fatty liver and to impact on glucose homeostasis in mice. In the present study we aimed to test the relevance of these findings in humans. In 55 subjects, hepatic mRNA expression of both hepatokines, fetuin-A and fetuin-B, associated positively with liver triglyceride content, whereas only fetuin-A expression associated with the homeostatic model assessment of insulin resistance. In 220 subjects who underwent precise metabolic phenotyping, circulating fetuin-A, but not fetuin-B, associated positively with liver fat content, and negatively with insulin sensitivity, measured during the oral glucose tolerance test (OGTT) and during the euglycemic, hyperinsulinemic clamp. Both circulating fetuin-A and fetuin-B correlated positively with the glucose area under the curve during the OGTT, but after additional adjustment for insulin sensitivity this relationship remained significant only for fetuin-B. In conclusion, despite the fact that the two hepatokines, fetuin-A and fetuin-B, are upregulated in the state of hepatic steatosis in humans, it appears that they differently impact on glucose homeostasis. Our data are in agreement with observations that fetuin-A can alter insulin signaling and that fetuin-B may regulate glucose homeostasis via so far unknown effects, possibly on glucose effectiveness. [ABSTRACT FROM AUTHOR]

Study Question: Is serum fetuin-B associated with the fertilization rate in in vitro fertilization (IVF)?Summary Answer: Serum fetuin-B increased during IVF cycles when oocytes could be fertilized while remained unchanged in fertilization failure.What Is Known Already: Fetuin-B deficiency in mice causes premature zona pellucida hardening mediated by the zona protease ovastacin. Thus fetuin-B deficiency renders females infertile.Study Design, Size, Duration: We determined the human serum fetuin-B reference range, studying longitudinally, over the course of one month, five male and seven female volunteers without hormone treatment and four female volunteers on varying hormonal contraception. We sampled blood and determined serum fetuin-B, luteinizing hormone (LH), estradiol (E2) and progesterone (P4). In addition, we determined serum fetuin-B and estradiol in eight women undergoing intracytoplasmatic sperm injection (ICSI, nine ICSI cycles) and 19 women undergoing IVF (21 IVF cycles) after ovarian stimulation with recombinant human follicular stimulating hormone (rFSH) and/or a combined medication of FSH and LH. At least three blood samples were analyzed in each cycle. We compared serum fetuin-B and follicular fluid fetuin-B in nine patients by measuring follicular fetuin-B in pooled follicular fluid, and in fluid obtained from individual follicles. Samples were drawn from January 2012 to March 2014.Participants/materials, Setting, Method: All volunteers and patients gave informed consent. Fetuin-B was measured employing a commercial sandwich enzyme-linked immunosorbent assay. Serum fetuin-B was determined as duplicates in 5 male (34 ± 14.6 years) and 11 female volunteers (29.4 ± 4.1 years) as well as in female volunteers on hormonal contraception (30.0 ± 6.5 years). The duplicate standard deviation was 4.0 ± 2.3%. The contraceptive drugs were mono or combined preparations containing 0-0.03 mg ethinyl estradiol, and 0.15-3.0 mg of various progestins. In addition, serum fetuin-B was determined as triplicates in 27 female patients undergoing conventional IVF (19) or ICSI (8). The triplicate standard deviation was 3.3 ± 1.8%. IVF was declared as 'successful', if at least one oocyte was fertilized, and 'unsuccessful', if no oocyte could be fertilized. Patient age was 34.4 ± 4.4 years in successful IVF, and 35.4 ± 3.3 years in unsuccessful IVF. Serum and follicular fluid of patients undergoing controlled ovarian hyperstimulation were analyzed. Serum was drawn at the day of follicle aspiration.Main Results and the Role Of Chance: Serum fetuin-B and follicular fluid fetuin-B were not significantly different in six out of nine patients suggesting, in principle, free exchange of fetuin-B between serum and follicular fluid. Thus serum fetuin-B may be used as a proxy of follicular fluid fetuin-B. Serum fetuin-B increased during successful IVF cycles (n = 15, P < 0.0001), but did not change in unsuccessful IVF cycles (n = 6, P = 0.118) despite increased estradiol levels (P = 0.0019 and P = 0.0254, respectively).Limitations, Reasons For Caution: The female volunteers self-reported their respective hormone medication. Medication was verified by serum estradiol, LH and progesterone measurements. For oocyte harvesting, the vaginal wall was punctured once only to minimize co-morbidity. Low grade cross-contamination of individual follicular fluid aspirates and contamination of the follicular fluid with small amounts of blood were inevitable. Samples were routinely checked for the presence of hemoglobin that would suggest blood contamination. Only samples containing <250 erythrocyte equivalents/µl were used for analysis.Wider Implications Of the Finding: Serum fetuin-B may be used as a marker to predict the fertilization success in IVF. Fetuin-B levels attained during IVF stimulation may help to make an informed decision whether oocytes should be fertilized by IVF or by ICSI to overcome the zona pellucida as a barrier.Study Funding/competing Interests: The research was supported by a grant from Deutsche Forschungsgemeinschaft and by the START program of the Medical Faculty of RWTH Aachen University. J.F., E.D., J.N., B.R. and W.J.-D. declare that they are named inventors on the RWTH Aachen University patent application EP 13157317.2, 'Use of fetuin-B for culture of oocytes', applied for by RWTH Aachen University. [ABSTRACT FROM AUTHOR]

The rupture of an atherosclerotic plaque is one of the main causes of coronary artery thrombotic occlusion, leading to myocardial infarction. However, the exact mechanism and causal risk factors for plaque rupture remain unclear. To identify a potential molecule that can influence atherosclerotic plaque rupture, we investigated protein expression in serum from patients with acute myocardial infarction (AMI) and stable angina (SA), using proteomic analysis. The expression of six proteins, including fibrinogen, fetuin-B, keratin 9, proapolipoprotein and fibrinogen, were altered in serum from patients with AMI compared with serum from those with SA. Of these, fetuin-B, proapolipoprotein, fibrinogen ? -B-chain precursors and fibrinogen expression were greater in serum from patients with AMI than from patients with SA. Increased fetuin-B expression in serum from AMI patients was also confirmed by Western blot analysis. Treatment with recombinant human fetuin-B increased the migration in monocytes and macrophages in a concentration-dependent manner. Fetuin-B also affected vascular plaque-stabilizing factors, including lipid deposition and cytokine production in macrophages, the activation of matrix metalloproteinase (MMP)-2 in monocytes, and the activation of apoptosis and MMP-2 in vascular smooth muscle cells. Moreover, in vivo administration of fetuin-B decreased the collagen accumulation and smooth muscle cell content and showed an increased number of macrophages in the vascular plaque. From these results, we suggest that fetuin-B may act as a modulator in the development of AMI. This study may provide a therapeutic advantage for patients at high risk of AMI. [ABSTRACT FROM AUTHOR]

Objectives: To assess circulating fetuin A and fetuin B levels in participants with and without Gestational Diabetes Mellitus (GDM) and to find out their correlations with other different parameters relating to gestational diabetes in Saudi women., Methods: A total of 123 Saudi pregnant women (N: 46 GDM and N: 77 healthy control) were included in this observational study. Fasting blood samples were collected to assess serum lipids, insulin and fetuin A and fetuin B. Serum fetuin A and fetuin B were quantified by commercially available kits., Results: The median value of fetuin A was slight lower in GDM patients [2003 pg/ml (866-3369)] than in the control group [2015 pg/ml (1060-2951)] without significant difference (P=0.95). The median value of fetuin B was also slight lower in GDM patients [3292 ng/ml (782-6740)] than the control group [3514 ng/ml (364-14854)] but without significant difference (P=0.564). There was a significant inverse correlation between fetuin B and total cholesterol in control group., Conclusions: The present study did not find a significant association between fetuins A and B with GDM or insulin resistance, but there was a significant inverse correlation between fetuin B and total cholesterol in the control group, reflecting good glucose control and adequate use of lipids in the nutrition of the fetus. Further research is required in the future to understand fetuin's role in the progression of GDM in Saudi women., Competing Interests: None., (AJTR Copyright © 2023.)

The zinc-dependent metalloprotease meprin α is predominantly expressed in the brush border membrane of proximal tubules in the kidney and enterocytes in the small intestine and colon. In normal tissue homeostasis meprin α performs key roles in inflammation, immunity, and extracellular matrix remodelling. Dysregulated meprin α is associated with acute kidney injury, sepsis, urinary tract infection, metastatic colorectal carcinoma, and inflammatory bowel disease. Accordingly, meprin α is the target of drug discovery programs. In contrast to meprin β, meprin α is secreted into the extracellular space, whereupon it oligomerises to form giant assemblies and is the largest extracellular protease identified to date (~6 MDa). Here, using cryo-electron microscopy, we determine the high-resolution structure of the zymogen and mature form of meprin α, as well as the structure of the active form in complex with a prototype small molecule inhibitor and human fetuin-B. Our data reveal that meprin α forms a giant, flexible, left-handed helical assembly of roughly 22 nm in diameter. We find that oligomerisation improves proteolytic and thermal stability but does not impact substrate specificity or enzymatic activity. Furthermore, structural comparison with meprin β reveal unique features of the active site of meprin α, and helical assembly more broadly., (© 2022. The Author(s).)

Abstract: Between April and September every year, many dogs in Finland are bitten by Vipera berus berus, also known as the European adder, the only venomous snake in the area. Exposure to snake bite venom causes local and systemic symptoms and in severe cases can lead to death. Urine samples were collected from four dogs bitten by V. berus berus and treated in the intensive care unit of the Veterinary Teaching Hospital at the University of Helsinki. The inclusion criteria were a strong suspicion of an adder bite no more than two days before admission and clinical signs of an adder bite. Exclusion criteria were defined as ongoing treatment with glucocorticoids or a known history of liver or kidney diseases. Six privately owned, healthy dogs were obtained as controls. Samples were subjected to 2D-DIGE analysis. Image analysis was performed with DeCyder 7.0 2D software, and protein spots demonstrating a minimum 1.5-fold difference in average spot volume ratios between envenomed and control dogs with a Student''s t-test p-value of less than 0.05 were picked and identified using LC–MS/MS. In 2D-DIGE analysis, seven proteins were significantly (p < 0.05) over-expressed in the urine of dogs bitten by V. berus berus compared to the control group. From these, five proteins were identified: beta-2-microglobulin (b2MG), alpha-1-antitrypsin (AAT), albumin, fetuin-B and superoxide dismutase (SOD1). Results indicate that envenomation by V. berus berus alter the urinary protein profile in dogs. [Copyright &y& Elsevier]

Background: Our recent proteomic study has shown that plasma protein levels of fetuin-B (Ft-B) and zinc-α2-glycoprotein (ZAG) are significantly elevated in obesity-resistant (OR) rats exposed to a high fat diet. Time profiling of the plasma concentrations of Ft-B and ZAG in OR rats has shown stable regulation of these proteins throughout the entire period of rat breeding. Methods: To firmly establish roles for these proteins in lipogenesis, we efficiently knocked down (KD) the genes FETUB and AZGP1 encoding Ft-B and ZAG, respectively, using siRNA in Chang liver cells. Results: Reduced expression of FETUB and AZGP1 led to a significant increase in the expression of lipogenic genes, thereby resulting in higher lipid levels in both KD cells. Collectively with our previous findings, we confirmed that Ft-B was similarly regulated with Ft-A, in that their plasma protein levels were commonly reduced in diet-induced obese rats. Conclusion: Our results provide a possible relationship between reduced plasma protein levels of Ft-B and ZAG and higher risk of diet-induced obesity through impaired fatty acid metabolism in hepatocytes. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Studies of mouse models for multistage carcinogenesis have led to the identification of a susceptibility locus for skin tumor development (Skts9) in the proximal region of mouse chromosome 16. This chromosome region shows a loss of heterozygosity or an allelic imbalance in mouse skin and pancreatic islet carcinoma, and has been associated with angiogenesis. The microsatellite marker D16Mit2, which has the strongest linkage to skin tumor susceptibility, was used to screen a bacterial artificial chromosome (BAC) library, leading to the identification of the histidine-rich glycoprotein (Hrg) and Fetuin-B as the most tightly linked genes. These genes are members of a cystatin-like superfamily that includes the neighboring genes Kng and Ahsg/Fetuin. Overexpression of Fetuin-B in skin squamous carcinoma cells led to suppression of tumor growth in nude mice. The neighboring genes Kng and Ahsg also have potential roles in angiogenesis and (or) tumor development, and several genes in this locus may be candidates for the Skts9 gene. [ABSTRACT FROM AUTHOR]