Molecular and pathobiological involvement of fetuin-A in the pathogenesis of NAFLD.

The liver acts as a manufacturing unit for the production of fetuin-A, which is essential for various physiological characteristics. Scientific research has shown that a moderate upward push in fetuin-A serum levels is associated with a confirmed non-alcoholic fatty liver disease (NAFLD) diagnosis. Fetuin-A modulation is associated with a number of pathophysiological variables that cause liver problems, including insulin receptor signaling deficiencies, adipocyte dysfunction, hepatic inflammation, fibrosis, triacylglycerol production, macrophage invasion, and TLR4 activation. The focus of the present review is on the various molecular pathways, and genetic relevance of mRNA expression of fetuin-A which is correlated with progression of NAFLD. The other major area of exploration in the present review is based on the new targets for the modulation of fetuin-A, like calorie restriction and novel pharmacological agents, such as rosuvastatin, metformin, and pioglitazone which are successfully implicated in the management of various liver-related complications.

[Fetuin-A and its role in important processes in organism. From nanobacteries to nanoparticles. Attempt to summarize available information]. / Fetuina-A i jej rola w kluczowych procesach zachodzacych w organizmie. Od nanobakterii do nanoczasteczki. Próba podsumowania dostepnych informacji.

Fetuina-A, protein discovered in the fifties of the twentieth century, is intensively investigated recently as a participant in many intracellular process. The aim of this article is to summarize, comment and order previous knowledge on it, in anticipation of the publication the result of further research, which could be very important in diagnostic and treatment many illness.

Estrogen increases the transcription of human α2-Heremans-Schmid-glycoprotein by an interplay of estrogen receptor α and activator protein-1.

UNLABELLED: The expression of α2-Heremans-Schmid-glycoprotein (AHSG) was estrogen responsive in oophorectomized (OVX) osteopenic rats and HepG2 cells. Estrogen receptor α (ERα) interacted with the c-Jun/c-Fos heterodimer and indirectly associated with the -1488/-1482 activator protein-1 (AP-1) motif of the AHSG promoter. Estrogen increased c-Jun/c-Fos expression via the mitogen-activated protein kinase (MAPK) pathway. INTRODUCTION: AHSG is a hepatic secretory protein implicated in the regulation of bone homeostasis. Serum AHSG in women has been reported to decrease after menopause and increase with estrogen therapy. The detailed regulatory mechanism of estrogen on AHSG is unclear. METHODS: A postmenopausal osteoporosis model was generated in OVX rats. Skeletal parameters were determined by automatic biochemical analysis and dual X-ray absorptiometry. The expression of AHSG was evaluated by ELISA, real-time PCR, and Western blot. The 1.5-kb 5'-promoter region of AHSG was analyzed by serial truncation and luciferase assays. The putative -1488/-1482 AP-1 responsive element was identified by electrophoresis mobility shift assay (EMSA). Chromatin immunoprecipitation (ChIP), re-ChIP, and co-immunoprecipitation (Co-IP) were used to characterize the interaction of ERα and AP-1 at the -1488/-1482 AP-1 binding site. The MAPK pathway was evaluated using a specific inhibitor and active transfection. RESULTS: The expression of AHSG was estrogen responsive in both OVX rats and estradiol (E2)/ERα-treated HepG2 cells. E2/ERα most prominently increased luciferase activity of a construct with a putative -1488/-1482 AP-1 binding element. ERα interacted with the c-Jun/c-Fos heterodimer and indirectly associated with the -1488/-1482 AP-1 motif of the AHSG promoter. c-Jun/c-Fos expression was increased via the MAPK pathway by E2/ERα. CONCLUSION: Estrogen activated the transcription of AHSG through an indirect binding of ERα to the -1488/-1482 AP-1 binding element, with the c-Jun/c-Fos heterodimers.

The effects of caloric restriction on fetuin-A and cardiovascular risk factors in rats and humans: a randomized controlled trial.

OBJECTIVES: The liver-secreted protein fetuin-A is associated with insulin resistance, metabolic syndrome, type 2 diabetes and atherosclerosis. We examined the effect of caloric restriction (CR) on fetuin-A levels and concomitant changes in hepatic steatosis and cardiovascular risk factors in rats and humans. DESIGN AND SUBJECTS: We performed a randomized, controlled clinical trial to examine circulating fetuin-A levels and cardiovascular risk parameters including visceral fat area (VFA), atherogenic lipid profile, inflammatory markers, adipokines levels and brachial artery endothelial function in 76 overweight women with type 2 diabetes before and after 12 weeks of CR. In addition, the effects of CR on hepatic steatosis and fetuin-A mRNA expression were evaluated in Otuska Long Evans Tokushima Fatty (OLETF) rats, an animal model of obesity and type 2 diabetes. RESULTS: Circulating fetuin-A levels were significantly decreased after 12 weeks of CR and were accompanied by improvements in VFA, blood pressure, glucose, lipid profiles and liver function. The CR group also showed a significant decrease in apolipoprotein B, leptin and insulin resistance compared to those in the control group, although endothelial function was not different. Multiple regression analysis showed that the changes in fetuin-A levels were independently associated with CR and changes in hsCRP and adiponectin (R² = 0·156). Moreover, CR significantly reduced hepatic steatosis and fetuin-A expression, as well as weight, glucose, total cholesterol and triglyceride levels, in OLETF rats. CONCLUSION: Caloric restriction significantly reduced the hepatic expression of fetuin-A and its circulating levels and improved several cardiovascular risk factors in obese rats and humans with type 2 diabetes.

Profiling the potential tumor markers of pancreatic ductal adenocarcinoma using 2D-DIGE and MALDI-TOF-MS: up-regulation of Complement C3 and alpha-2-HS-glycoprotein.

BACKGROUND/AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with an increasing incidence worldwide. Due to lack of early diagnosis and poor prognosis, it is rather critical to improve the early diagnosis of PDAC. A comparative proteomic method was used to analyze serum proteins to find a new potential specific marker. METHODS: Comparative analysis of the pancreatic peripheral blood protein profiling from 40 pancreatic cancer patients, 10 pancreatic benign tumor patients, 10 chronic pancreatitis patients and 40 cancer-free controls. The samples were carried out by 2D-differential gel electrophoresis (2D-DIGE) and differentially expressed proteins were identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). Two up-regulated proteins were further validation by real time RT-PCR, Western blot analysis and Immunohistochemistry (IHC). RESULTS: We identified fourteen differently expressed proteins in PDAC group compared with cancer-free control group, including 9 up-regulation and 5 down-regulation proteins. Increased Complement C3 and alpha-2-HS-glycoprotein (AHSG) were further confirmed by real time RT-PCR, Western blot analysis and IHC. The expressions of Complement C3 and AHSG were higher in PDAC than that in other groups. CONCLUSIONS: These results suggest that Complement C3 and AHSG might be the potential tumor markers in PDAC screening and diagnosis. The finding of inflammation mediated factor Complement C3 revealed that inflammation might be closely related with the occurrence and development process of PDAC.

Reduced serum fetuin-A in nephrotic children: a consequence of proteinuria?

BACKGROUND: The extracellular protein fetuin-A is a potent soluble inhibitor of calcification, and its deficiency has been associated with vascular calcification in dialysis patients. In proteinuric patients, significant urinary losses of fetuin-A may cause low serum fetuin-A levels. METHODS: In a cross-sectional study, urinary/serum concentrations of fetuin-A were investigated in proteinuric children with glomerular diseases and preserved renal function (n = 58) in comparison to healthy controls (n = 246). RESULTS: Mean fetuin-A serum concentrations were clearly reduced in children with nephrotic syndrome (0.25 ± 0.14 g/l, p < 0.001), slightly reduced in children with large proteinuria (0.39 ± 0.15 g/l, p < 0.05), and comparable to controls in those with mild proteinuria (0.45 ± 0.14 vs. 0.46 ± 0.12 g/l). Fetuin-A was positively correlated with serum protein (r = 0.58), albumin (r = 0.57), and calcium (r = 0.64), but negatively correlated with proteinuria (r = -0.41), albuminuria (r = -0.46), and urinary fetuin-A excretion (r = -0.48; each p < 0.001). The fractional excretion of fetuin-A was significantly associated with the degree of proteinuria and serum fetuin-A levels. However, the urinary loss of fetuin-A and albumin in nephrotic children differed by three orders of magnitude and the mean fractional excretion of fetuin-A was only 1/10 of that of albumin (0.016 ± 0.029 vs. 0.162 ± 0.403%; p < 0.001). CONCLUSIONS: Fetuin-A is clearly reduced in children with nephrotic syndrome and associated with the degree of hypoalbuminemia. This is due to urinary fetuin-A loss and/or reduced hepatic synthesis. Persistent fetuin-A deficiency may have an impact on cardiovascular morbidity in nephrotic children.

Analysis of an Indian diabetes prevention programme on association of adipokines and a hepatokine with incident diabetes.

To study the association and possible predictive role of visfatin, resistin, fetuin-A and chemerin with incident type 2 diabetes (T2DM) among Asian Indians with prediabetes. Their association with insulin resistance, ß-cell function, glycaemia and anthropometry were also studied. This is a nested case-control study of a large 2-year prospective prevention trial in persons at high risk of developing T2DM. Baseline HbA1c values between 6.0% (42 mmol/mol) and 6.2% (44 mmol/mol) were chosen for this analysis (n = 144). At follow-up, persons with incident T2DM (HbA1c ≥ 6.5%, 48 mmol/mol) were grouped as cases (n = 72) and those reverted to normoglycaemia, (HbA1c < 5.7% (39 mmol/mol) as controls (n = 72). Insulin resistance showed the strongest association with incident T2DM ((Odds Ratio (OR): 23.22 [95%CI 6.36-84.77]; p < 0.0001). Baseline visfatin (OR: 6.56 [95%CI 2.21-19.5]; p < 0.001) and fetuin-A (OR: 1.01 [95%CI (1.01-1.04)]; p < 0.0001) independently contributed to the conversion of prediabetes to T2DM. The contribution was significantly higher when their elevated levels coexisted (OR: 12.63 [95%CI 3.57-44.63]; p < 0.0001). The area under the curve was 0.77 ± SE 0.4 (95%CI 0.69-0.85) and 0.80 ± SE 0.04 (95%CI 0.73-0.88) for visfatin (median 17.7 ng/ml, sensitivity and specificity: 75%, p < 0.0001) and fetuin-A (mean 236.2 µg/ml, sensitivity: 71%, specificity: 75%, p < 0.0001) respectively. Higher baseline visfatin and fetuin-A concentrations are strongly associated with incident T2DM and are predictive of future diabetes.

Serum Fetuin-A Levels in Patients with Bilateral Basal Ganglia Calcification.

BACKGROUND AND PURPOSE: The idiopathic basal ganglia calcification (Fahr syndrome) may occur due to senility. Fetuin-A is a negative acute phase reactant which inhibits calcium-phosphorus precipitation and vascular calcification. In this study, we aimed to evaluate whether serum fetuin-A levels correlate with bilateral basal ganglia calcification. METHOD: Forty-five patients who had bilateral basal ganglia calcification on brain CT were selected according to the inclusion and exclusion criteria, and 45 age and gender-matched subjects without basal ganglia calcification were included for the control group. Serum fetuin-A levels were measured from venous blood samples. All participants were divided into two groups; with and without basal ganglia calcification. These groups were divided into subgroups regarding age (18-32 and 33-45 years of age) and gender (male, female). RESULTS: We detected lower levels of serum fetuin-A in patients with basal ganglia calcification compared with the subjects without basal ganglia calcification. In all subgroups (female, male, 18-32 years and 33-45 years), mean fetuin-A levels were significantly lower in patients with basal ganglia calcification (p = 0.017, p = 0.014, p = 0.024, p = 0.026, p = 0.01 respectively). And statistically significantly lower levels of fetuin-A was found to be correlated with the increasing densities of calcification in the calcified basal ganglia group (p-value: <0.001). CONCLUSION: Considering the role of fetuin-A in tissue calcification and inflammation, higher serum fetuin-A levels should be measured in patients with basal ganglia calcification. We believe that the measurement of serum fetuin-A may play a role in the prediction of basal ganglia calcification as a biomarker.

Changes in plasma concentrations and mRNA expression of hepatokines fetuin A, fetuin B and FGF21 in physiological pregnancy and gestational diabetes mellitus.

We measured plasma concentrations, adipose tissue and placental mRNA expression of hepatokines fetuin A, fetuin B and fibroblast growth factor 21 (FGF21) in 12 healthy pregnant women (P group), 12 pregnant women with gestational diabetes (GDM) and 10 healthy non-pregnant women (N group) to explore their potential role in the etiopathogenesis of GDM. GDM and P group had comparable BMI, C-reactive protein (CRP) and glycated hemoglobin levels while IL-10 and TNF-alpha levels were higher in GDM group. Fetuin A and fetuin B levels were higher in pregnancy as compared to N group and decreased after delivery with no apparent influence of GDM. In contrast, the pattern of changes of circulating FGF21 levels differed between GDM and P group. Fetuin A concentrations positively correlated with CRP, TNF-alpha mRNA expression in adipose tissue and IL-6 mRNA expression in placenta. Fetuin B positively correlated with CRP. FGF21 levels correlated positively with IFN-gamma mRNA in adipose tissue and inversely with IL-8 mRNA in the placenta. Taken together, fetuin A and fetuin B levels were increased during pregnancy regardless of the presence of GDM. In contrast, FGF21 patterns differed between healthy pregnant women and GDM patients suggesting a possible role of this hepatokine in the etiopathogenesis of GDM.

FGF23-regulated production of Fetuin-A (AHSG) in osteocytes.

INTRODUCTION: AHSG, a serum glycoprotein with recognized anti-calcification activity, has also been suggested to modulate both bone formation and resorption. Though the bulk of AHSG is mostly synthesized in the liver, it has been claimed that also bone cells might produce it. However, the extent of the bone AHSG production and the potential controlling factors remain to be definitively proven. A relevant number of studies support the notion that FGF23, a bone-derived hormone, not only regulates the most important mineral metabolism (MM) related factors (phosphate, parathyroid hormone, vitamin D, etc.), but might be also involved in cardiovascular (CV) outcome, both in chronic kidney disease (CKD) patients and in the general population. Furthermore, in addition to some direct autocrine and paracrine effects in bone, FGF23 has been suggested to interact with AHSG. In this study we investigated if AHSG is really produced by bone cells, and if its bone production is related and/or controlled by FGF23, using cultured bone cells, according to a new method recently published by our group. RESULTS: Our data show that AHSG is consistently produced in osteocytes and to a far lesser extent in osteoblasts. Both FGF23 addition to the culture medium and its over-expression in osteocytes were associated with a consistent increase of both AHSG mRNA and protein, while FGF23 silencing was followed by opposite effects. Though most of these results were largely affected by the blockage of FGF23 receptors, the role of these receptors in the different experimental sets is still not completely clarified. In addition, we found that FGF23 and AHSG proteins co-localized both in cytoplasm and nucleus, which suggests a possible reciprocal interactivity. CONCLUSIONS: Our data not only confirm that AHSG is produced in bone, mainly in osteocytes, but show for the first time that its production is modulated by FGF23. Since both proteins play important roles in the bone and cardiovascular pathology, these results add new pieces to the puzzling relationship between bone and vascular pathology, in particular in CKD patients, prompting future investigations in this field.

Decreased serum fetuin-A levels and active inflammatory bowel disease.

BACKGROUND: Fetuin-A is a mediator of inflammatory response that might also be involved in the pathogenesis of inflammatory bowel disease (IBD). This study aims to assess whether serum fetuin-A levels are associated with the disease activity in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: A total of 139 patients with CD, 114 patients with UC, and 46 controls were enrolled in this study. The serum fetuin-A levels of the participants were measured using commercially available sandwich enzyme-linked immunosorbent assay. RESULTS: The patients with IBD had significantly lower serum fetuin-A levels compared with the healthy controls. The active patients with CD and patients with UC both had significantly decreased serum fetuin-A levels compared with the inactive patients with CD and patients with UC. Multivariable logistic regression analysis revealed that decreased serum fetuin-A levels were independently associated with the disease activity of CD and UC. Serum fetuin-A levels were negatively associated with C-reactive protein concentrations and white blood cell count in patients with CD but not in patients with UC. CONCLUSIONS: Decreased serum fetuin-A levels were independently associated with disease activity in patients with CD and UC. The utilization of fetuin-A concentration measurements as markers of disease activity in patients with IBD warrants further investigations.

Association between serum fetuin-A levels, carotid artery stiffness, and intima-media thickness in patients with normotensive obstructive sleep apnea syndrome.

Increased carotid intima-media thickness (cIMT) and stiffness, reflecting subclinical atherosclerosis, are associated with obstructive sleep apnea syndrome (OSAS). The relationship between serum fetuin-A, which inhibits ectopic calcification, and atherosclerosis is unclear. Therefore, we investigated the association between serum fetuin-A levels and carotid artery stiffness and cIMT in patients with normotensive OSAS (n = 50) and non-OSAS controls (n = 38). Compared with controls, there were lower fetuin-A levels (59.4 ± 6.5 vs 68.2 ± 5.8 ng/mL, P = .029), higher mean cIMT (0.73 ± 0.2 vs 0.63 ± 0.3 mm, P < .001), and greater stiffness (ß) index (7.45 ± 0.9 vs 5.2 ± 0.7, P = .001) in the OSAS group. The cIMT and stiffness (ß) index were inversely correlated with fetuin-A levels (r = -.324, P = .033; r = -.466, P < .001, respectively) and positively correlated with apnea hypopnea index (r = .498, P < .001; r = .422, P = .001, respectively) in the OSAS group. Decreased serum fetuin-A levels were associated with subclinical carotid atherosclerosis in patients with normotensive OSAS.

Direct inhibitory effects of pioglitazone on hepatic fetuin-A expression.

Fetuin-A, a circulating glycoprotein synthesized in the liver, is involved in insulin resistance and type 2 diabetes. However, regulation of fetuin-A synthesis has remained obscure. We previously reported that pioglitazone treatment significantly reduced serum fetuin-A levels in patients with type 2 diabetes. To clarify whether pioglitazone can directory inhibit hepatic fetuin-A synthesis, we investigated the effects of pioglitazone on fetuin-A expression both in vitro and in vivo. Pioglitazone treatment suppressed mRNA and protein expression of fetuin-A in Fao hepatoma cells. Interestingly, rosiglitazone but not metformin, also inhibited fetuin-A expression. In addition, GW 9662, an inhibitor of peroxisome proliferator-activated receptor (PPAR) γ, reversed pioglitazone-induced suppression of fetuin-A, suggesting that thiazolidinedione derivatives may have common characteristics with regard to fetuin-A suppression, possibly through PPARγactivation. Finally, oral administration of pioglitazone to mice for 8 weeks resulted in suppression of hepatic fetuin-A mRNA. These findings suggest that pioglitazone may partially ameliorate insulin resistance through its direct inhibitory effects on fetuin-A expression in the liver.

Associations of serum fetuin-A levels with insulin resistance and vascular complications in patients with type 2 diabetes.

OBJECTIVE: We examined the relationship between serum fetuin-A, insulin resistance (IR), metabolic syndrome (MS) and vascular complications including cardiac autonomic neuropathy (CAN) in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 172 T2DM patients were recruited and evaluated for diabetic microangiopathies (nephropathy, retinopathy and peripheral neuropathy) including CAN. Serum fetuin-A levels were measured by enzyme-linked immunosorbent assay (ELISA), and the IR was assessed by the index of homeostasis model [homeostasis model assessment-insulin resistance (HOMA-IR)]. Atherosclerotic burden was assessed by ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV). RESULTS: Serum fetuin-A levels showed significant positive correlations with HOMA-IR (r = 0.196, p = 0.022), and the mean levels of HOMA-IR were significantly increased progressively across fetuin-A tertiles (p for trend = 0.044). Serum fetuin-A showed significant positive correlations with baPWV, systolic blood pressure (BP), total cholesterol, triglycerides, serum fasting c-peptide and negative correlations with ABI. Serum fetuin-A levels were also negatively correlated with serum adiponectin and positively correlated with serum tumour necrosis factor-α (TNF-α). The mean levels of serum fetuin-A were not significantly different according to the presence of each microangiopathies including CAN. Also, the mean levels of serum fetuin-A were not different between patients with MS and without MS. CONCLUSIONS: This present study showed that levels of serum fetuin-A are significantly associated with IR and arterial stiffness assessed by baPWV, while there are no associations with each microangiopathies in patients with T2DM.

Serum fetuin-A levels related with microalbuminuria in diet-induced obese rats.

The aim of the study was to investigate the association between elevated serum fetuin-A and increased urine albumin excretion in obese rats, and whether increased urine albumin excretion was modified by improving hepatic steatosis and lipid metabolism disorder. Male Wistar rats 4 weeks in age were randomly divided into three groups and fed with normal chow (control group), high-fat chow (obesity group), or high-fat chow plus fenofibrate (fenofibrate group). After 24 weeks, both body weight and visceral fat/body weight ratio in obese rats were higher than in controls. A difference in serology markers and pathology associated with hepatic steatosis was also found among the three groups. Serum fetuin-A and the expression of NF- κ B in the liver were increased, while serum adiponectin was decreased in obese rats in comparison to controls (P < 0.01). Urinary albumin/creatinine ratio (ACR) was increased in the obesity group compared to controls (P < 0.01). The fenofibrate intervention reduced serum fetuin-A and NF- κ B expression in the liver and increased serum adiponectin compared to obese rats and was accompanied by decrease in ACR. A positive correlation was found between ACR and fetuin-A (r = 0.602, P < 0.01), and a negative correlation was found between ACR and adiponectin (r = -0.635, P < 0.01). We conclude that elevated fetuin-A levels are associated with microalbuminuria in obese rats, and abnormal albuminuria is reversible by improving hepatic steatosis.

The association of fetuin-A with cardiovascular disease mortality in older community-dwelling adults: the Rancho Bernardo study.

OBJECTIVES: The goal of this study was to evaluate the prospective association of fetuin-A levels with cardiovascular disease (CVD) mortality. BACKGROUND: Fetuin-A is a circulating inhibitor of calcium deposition in the vasculature and of insulin action in muscle and fat, and may be involved in the pathogenesis of CVD. METHODS: This is a population-based prospective study of 633 men and 1,025 women (median age = 73 years) who had fetuin-A levels and CVD risk factors evaluated in 1992 to 1996 and were followed for vital status through 2010. RESULTS: Plasma fetuin-A (g/l ± SD) was highest in women using oral estrogens (0.55 ± 0.12), intermediate for women not using oral estrogens (0.51 ± 0.10), and lowest for men (0.50 ± 0.10), p < 0.001. Lower fetuin-A levels were associated with older age, but with lower levels of other CVD risk factors including adiposity, blood pressure, lipids, triglycerides, and insulin resistance (all p < 0.01). During the median 12-year follow-up, 273 deaths were attributed to CVD. The association of fetuin-A with CVD mortality differed by diabetes status (p for interaction = 0.003). Adjusting for age, sex, oral estrogens, and lifestyle, the hazard ratio for CVD mortality comparing the lowest fetuin-A quartile with all higher values was 1.76 (95% confidence interval [CI]: 1.34 to 2.31; p < 0.001) for participants without diabetes and 0.43 (95% CI: 0.19 to 0.98; p = 0.046) for participants with diabetes. CONCLUSIONS: Low fetuin-A levels predicted greater risk for CVD mortality in older adults without diabetes, but were associated with reduced risk of CVD death in those with diabetes. Fetuin-A may provide novel insight into mechanisms leading to CVD death in those with versus without diabetes.

Fetuin A in nonalcoholic fatty liver disease: in vivo and in vitro studies.

OBJECTIVE: Fetuin A has been associated with insulin resistance and the metabolic syndrome. We therefore explored the role of fetuin A in nonalcoholic fatty liver disease (NAFLD). DESIGN: Cross-sectional and intervention studies. METHODS: We included 111 subjects with histologically proven NAFLD of whom 44 participated in a randomized, controlled trial with metformin. One hundred and thirty-one healthy subjects and 13 subjects undergoing hepatic surgery for metastatic cancer served as controls. Main outcome variables were circulating levels of fetuin A according to the presence of NAFLD, hepatic gene expression of fetuin A and key enzymes in glucose and lipid metabolism, and the effect of metformin on fetuin A levels in vivo and in vitro (HepG2 cells). RESULTS: Fetuin A levels were significantly higher in NAFLD patients compared with controls (324 ± 98 vs 225 ± 75 mg/l, P<0.001). NAFLD was a significant predictor of elevated fetuin A levels (ß=174 (95% confidence interval: 110-234)) independent of body mass index, age, sex, fasting glucose, and triglycerides. Hepatic fetuin A mRNA levels correlated significantly with hepatic mRNA levels of key enzymes in lipid (sterol regulatory element-binding protein 1c, carnitine palmitoyltransferase 1) and glucose (phosphoenol pyruvate kinase 1, glucose-6-phosphatase) metabolism. Plasma fetuin A levels decreased significantly after metformin treatment compared with placebo (-40 ± 47 vs 15 ± 82 mg/l, P = 0.008). Metformin induced a dose-dependent decrease in fetuin A secretion in vitro. CONCLUSIONS: Fetuin A levels were elevated in NAFLD. Hepatic expression of fetuin A correlated with key enzymes in glucose and lipid metabolism. Metformin decreased fetuin A levels in vitro.

Endoplasmic reticulum stress induces the expression of fetuin-A to develop insulin resistance.

Fetuin-A is a biomarker reported to be important in many metabolic disorders, including obesity, diabetes, and hepatic steatosis. Although it is well known that fetuin-A is increased in diabetes and nonalcoholic fatty liver disease (NAFLD), the levels of fetuin-A in diabetic patients with NAFLD are unknown. Furthermore, the regulation of fetuin-A expression is still obscure. In this study, a total of 180 age- and sex-matched subjects with normal glucose tolerance, NAFLD, newly diagnosed diabetes (NDD), and NDD with NAFLD were recruited. We found that the levels of fetuin-A were significantly increased in NDD with NAFLD as compared with NDD or NAFLD subjects. We further used HepG2 cells to investigate the regulation of fetuin-A. Treatment with endoplasmic reticulum (ER) stress activator, thapsigargin, increased the expression of fetuin-A mRNA and protein in a time- and dose-dependent manner. Pretreatment with ER stress inhibitor, 4-phenylbutyrate, reversed high glucose or palmitate-induced fetuin-A expression. Moreover, treatment with 4-phenylbutyrate in both streptozotocin-induced and high-fat diet-induced diabetic mice not only decreased hepatic fetuin-A levels but also improved hyperglycemia. Taken together, we found that fetuin-A levels were increased in diabetes patients with NAFLD. Moreover, ER stress induced by high glucose and palmitate increased the expression of fetuin-A and further contributed to the development of insulin resistance.

Lower fetuin-A predicts angiographic impaired reperfusion and mortality in ST-elevation myocardial infarction.

AIMS: Fetuin-A is an anti-inflammatory negative acute-phase glycoprotein, synthesized by the liver. In this study, we aimed to investigate the effects of admission fetuin-A levels on coronary and myocardial blood flow and short- and long-term prognosis in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention. METHODS AND RESULTS: One hundred eighty consecutive patients admitted with diagnosis of STEMI and 55 healthy age- and sex-matched volunteer controls were enrolled in the study. Patients with STEMI were divided into 2 groups in respect to thrombolysis in myocardial infarction myocardial perfusion grade after primary PCI: with thrombolysis in myocardial infarction myocardial perfusion grade 0-1-2 and thrombolysis in myocardial infarction myocardial perfusion grade 3. Serum levels of fetuin-A were lower in patients with STEMI than in the healthy group subjects. In-hospital and 1-year deaths were significantly higher in patients from the abnormal perfusion group. In-hospital major adverse cardiac event (MACE) and 1-year follow-up MACE also were significantly higher in patients from the abnormal perfusion group. The receiver-operating characteristic analysis indicated an optimal cut point of less than 200 µg/mL, which detects 1-year mortality with a negative predictive value of 95%. The 1-year mortality rate and 1-year MACE were significantly higher in patients with low fetuin-A level as compared with those with high fetuin-A level. CONCLUSIONS: Because low-admission fetuin-A levels are associated with impaired coronary flow in STEMI patients undergoing primary percutaneous coronary intervention, admission fetuin-A level detection may be helpful in identifying the patients at a greater risk of poor coronary blood flow and worse short- and long-term prognosis.