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

Type 2 diabetes (T2D) is rapidly spreading throughout the world. It's an insidious disease and still treated in an indirect manner without having specific drug target. In majority cases T2D is treated with drugs that address type 1 diabetes, majority of drugs aim to increase insulin release although the root cause for T2D is not the dearth of insulin release, it occurs in the later stage of disease development. T2D silently progressed in the patient; it begins with insulin resistance that takes place due to the loss of insulin sensitivity. Though insulin resistance is the centre of pathogenesis, our treatment of the disease has not yet addressed it. It is now a fact that insulin resistance is manifested by lipid and fatty acids (FAs) play a critical role in blunting insulin sensitivity. Our understanding is still poor in deciphering how lipid impose insulin insensitivity, majority of workers suggest it is because of insulin signaling defects which implements insulin function in inhibiting glucose to the cell from circulation. Number of long chain saturated FA has been shown to produce insulin signaling defects. However, we really need further investigation to find specific target(s) for FA induced damage. In addition to these information, a new dimension of T2D is getting attractive is fetuin-A/alpha2-Heremans-Schmid Glycoprotein, a secretary protein from liver. Its gene locus has been identified as T2D susceptible. Fetuin-A's excess expression occurs by FA and it disrupts adipocyte function. It has been shown to be associated with T2D especially in obesity. In this review, we briefly discuss the present status on the mechanistic understanding of lipid induced insulin resistance that leads to T2D. More we understand the mechanism; opportunity to fight the battle with T2D will be increasing. Since, this field is now vast; we covered a few major events.
Adipocytes ; alpha-2-HS-Glycoprotein ; Fatty Acids ; Glucose ; Glycoproteins ; Hypogonadism ; Insulin ; Insulin Resistance ; Liver ; Mitochondrial Diseases ; Obesity ; Ophthalmoplegia

BACKGROUND: Coronary artery calcification is frequently seen in hemodialysis patients. The development and progression of coronary artery calcification is similar to osteogenesis, and a naturally occurring serum inhibitor of calcification may be involved. The aim of this study was to evaluate the relationship between coronary artery calcification, bone remodeling related factor, serum osteoprotegerin (OPG), calcification inhibitor and the serum fetuin-A levels in hemodialysis patients. METHODS: A total of 51 hemodialysis patient were assessed for their coronary artery calcium (CAC) scores with using multirow spiral computed tomography and measuring the serum OPG level, the serum fetuin-A level, the biochemical markers of inflammation, the lipid profile and the mineral metabolism. RESULTS: The mean serum OPG level was 3,561+/-1,160 pg/mL and the mean serum fetuin-A level was 28.5+/-4.1 mg/dL. The CAC scores were significantly correlated with the duration of dialysis (p=0.0225), hs-CRP (p=0.0392), serum phosphate (p=0.0341), Ca x P (p=0.0434), the serum OPG level (p=0.0026) and LDL-cholesterol (p=0.0438), after adjusting for age, gender, BMI, smoking history and the presence of diabetes. Multiple regression analysis showed that the CAC scores were significantly associated with the serum OPG level (p<0.0001) and the serum phosphate level (p=0.0003). The subgroup of the patients with a CAC score greater than 400 (the severe CAC group) had significantly higher OPG levels and lower fetuin-A levels than the groups of the patients with lower CAC scores. CONCLUSIONS: Our data suggest that the CAC scores in the patients undergoing hemodialysis were related with higher serum OPG and higher serum phosphate levels. The serum fetuin-A level was significantly lower in the patients with severe coronary artery calcification.
alpha-2-HS-Glycoprotein* ; Biomarkers ; Bone Remodeling ; Calcium ; Coronary Disease ; Coronary Vessels* ; Dialysis ; Humans ; Inflammation ; Kidney Failure, Chronic* ; Metabolism ; Osteogenesis ; Osteoprotegerin* ; Renal Dialysis ; Smoke ; Smoking ; Tomography, Spiral Computed

Coronary artery calcification is associated with the increased cardiovascular mortality and the extent of atheromatous plaque, especially in the hemodialysis patients. Vascular calcification was in the past considered a passive process, a degenerative consequence of aging or the result of disrupted mineral balance in the patients with chronic renal failure. It is now understood that calcium deposition in the vasculature is an active and regulated process similar to bone formation. In this issue of JKMS, Kim et al. investigate the clinical association between osteoprotegerin, an osteoclast inhibitory factor which was reported to be associated with coronary artery calcification, and fetuin-A, a systemic ectopic calcification inhibitory factor, with coronary artery calcification (CAC) score obtained from multi-slice CT. They showed that the high serum osteoprotegerin level is associated with increased CAC score and serum fetuin-A level is significantly lowered in the severe CAC score group. These results show that serum osteoprotegerin or fetuin-A level might be used as serum markers for the determination of the severity of coronary artery calcification. However, the role of serum osteoprotegerin in the formation of vascular calcification is uncertain and the pathophysiologic mechanism is not uncovered yet. Some studies suggested that the osteoprotegerin level is associated with vascular stiffness. Lower fetuin-A level is known to be a prognostic factor of cardiovascular disease mortality from several epidemiologic studies and a confirmed anti-calcifying agents in vitro experiments. In interpreting this issue of Kim et al., it is important that increased serum osteoprotegerin level might be associated with not vascular calcification but other vascular malfunction such as arterial stiffness. In conclusion, more sophisticated study needed for the clarification of the role of calcification-associated serum markers in the process of vascular calcification.
Aging ; alpha-2-HS-Glycoprotein ; Biomarkers* ; Calcium ; Cardiovascular Diseases ; Coronary Vessels* ; Humans ; Kidney Failure, Chronic ; Mortality ; Osteoclasts ; Osteogenesis ; Osteoprotegerin ; Renal Dialysis ; Vascular Calcification ; Vascular Stiffness

OBJECTIVETo examine the relationship between reduction of serum fetuin A and coronary artery calcification (CAC) in patients starting hemodialysis.

METHODSTwenty-nine patients on chronic hemodialysis (duration of hemodialysis less than 6 months) were enrolled in this study. Serum fetuin A and such potential CAC-related risk factors as C-reactive protein (CRP), Ca, P, iPTH, body mass index (BMI) were examined. CAC was detected by multislice spiral CT scan (MSCT) and quantified by the modified Agaston's scoring system. All the 29 patients were followed up for 18 months to appraise the cardiovascular events defined as cardiac failure, angina pectoris or myocardial infarction.

RESULTSEleven patients (78.57%) were found to have CAC as detected by MSCT in low serum fetuin A (below the average serum concentration of 0.71 g/L) group, a rate significantly higher than that in high serum fetuin A group (7 patients, 46.67%, P<0.05). Serum fetuin A in these 29 patients was related with CAC score (Pearson correlation coefficient of -0.734, P=0.001) and stepwise regression analysis indicated that serum fetuin A (standardized beta=-0.568, P=0.003) and age (standardized beta=0.416, P=0.019) were independently correlated to CAC. Such factors as CRP, Ca, P, iPTH, Chol, TG, HDL-C, LDL-C, BMI and blood pressure were excluded from the regression equation. Reduction of serum fetuin A was associated with cardiovascular events (Spearman's rho -0.758, P<0.01). No significant difference was found between low and high serum fetuin A groups by Kaplan-Meier survival analysis (P=0.065).

CONCLUSIONReduced serum fetuin A may be a potential risk factor of coronary artery calcification, and can contribute to cardiovascular events in patients starting hemodialysis.

Adult ; Aged ; Blood Proteins ; metabolism ; Calcinosis ; blood ; etiology ; Coronary Vessels ; pathology ; Female ; Humans ; Male ; Middle Aged ; Renal Dialysis ; adverse effects ; Risk Factors ; alpha-2-HS-Glycoprotein

OBJECTIVETo identify the single nucleotide polymorphisms (SNPs) of the alpha2-Heremans-Schmid glycoprotein (AHSG) gene and assess their association with the AHSG serum level.

METHODSThe SNPs of the AHSG gene were identified from 30 unrelated Han individuals from Guangzhou area by resequencing. Linkage disequilibrium(LD) was performed to observe the linkage disequilibrium pattern. Then tagSNPs were genotyped in 192 Han individuals from Beijing and 424 Han individuals from Guangzhou area. Finally, luciferase reporter gene assay was performed to determine whether the SNPs affected the promoter activity. Serum AHSG concentrations were measured in the 192 subjects from Beijing using ELISA.

RESULTSEight SNPs were detected in total. The linkage disequilibrium profile in the Guangzhou Han population was different from that in the Beijing Han population. However, the allele and genotype frequencies of tagSNPs between the two Han populations were not significantly different. The reporter gene assay showed that the -799A allele had significantly higher promoter activity than the -799T allele. Multiple regression analysis revealed that only the rs2248690 SNP was an independent contributor to serum AHAG concentration.

CONCLUSIONThe rs2248690 SNP in the promoter region of the AHSG gene might affect the AHSG gene transcription.

Blood Proteins ; genetics ; metabolism ; Enzyme-Linked Immunosorbent Assay ; Genotype ; Linkage Disequilibrium ; Polymorphism, Single Nucleotide ; genetics ; Serum ; chemistry ; alpha-2-HS-Glycoprotein

OBJECTIVETo explore the dynamic changes of fetuin-A expression and the influences of the changes on liver damage, hepatocyte apoptosis and inflammation in a mouse fulminant hepatic failure (FHF) model.

METHODSThe changes of fetuin-A expression were investigated by semi-quantitative RT-PCR and Western blot. Immunohistochemical staining was used in TNFa and fetuin-A detection. Hepatocyte apoptosis was detected by TUNEL.

RESULTSFetuin-A mRNA expression decreased after the FHF model was established for 3 hours (compared with the normal group, P less than 0.01), while the protein expression decreased after nine hours (compared with the normal group, P less than 0.01). Fetuin-A expressions were negatively correlated with the liver pathological scores and TNFa levels.

CONCLUSIONIn our mouse FHF model, fetuin-A is a possible protective factor for liver damage.

Animals ; Blood Proteins ; metabolism ; Female ; Liver ; metabolism ; pathology ; Liver Failure ; metabolism ; pathology ; Mice ; Mice, Inbred BALB C ; alpha-2-HS-Glycoprotein

OBJECTIVE: The aim of this study was to compare serum fetuin-A levels and oxidative stress markers, as indicators of insulin resistance, in women with polycystic ovary syndrome (PCOS) and in healthy controls. METHODS: This prospective case-control study included 46 patients with PCOS and 48 age- and body mass index–matched control women. Levels of serum hormones, fetuin-A, and oxidative stress markers were measured in blood samples taken during the early follicular period from each participant. RESULTS: Follicle-stimulating hormone (FSH), luteinising hormone (LH), total testosterone levels, and the LH/FSH ratio were found to be significantly higher in women with PCOS than in controls. Serum total antioxidant status, total oxidant status, and oxidative stress index parameters all indicated significantly higher levels of oxidative stress in PCOS patients than in controls. Serum fetuin-A levels, which were analyzed as an indicator of insulin resistance, were higher in the PCOS group than in the control group (210.26±65.06 µg/mL and 182.68±51.20 µg/mL, respectively; p=0.024). CONCLUSION: The data obtained from the present study suggest that higher levels of both serum fetuin-A and oxidative stress markers might be related with PCOS.
alpha-2-HS-Glycoprotein* ; Case-Control Studies ; Female ; Follicle Stimulating Hormone ; Humans ; Insulin Resistance ; Oxidative Stress* ; Polycystic Ovary Syndrome* ; Prospective Studies ; Testosterone

BACKGROUND: Visfatin is an adipokine produced by visceral adipose tissue and has insulin-mimicking effects. Fetuin-A is a hepatic secretory protein that binds the insulin receptor and inhibits insulin action both in vivo and in vitro. The authors of the present study aimed to investigate the levels of serum visfatin and fetuin-A and their correlation with hemoglobin A1c (HbA1c) and urine albumin levels in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 40 obese patients with T2DM (11 males and 29 females; age, 54.47+/-10.83 years and 23 obese nondiabetic controls (8 males and 15 females; age, 53.04+/-11.33 years) were included in the study. Age, sex, and body mass index were similar in the 2 groups. Serum visfatin and fetuin-A levels were measured by enzyme-linked immunosorbent assay. HbA1c and urine albumin levels were measured by high performance liquid chromatography and nephelometric method, respectively. RESULTS: Serum levels of visfatin in patients with T2DM (4.03+/-2.44 ng/mL) were similar to the control group (3.65+/-3.02 ng/mL). Serum fetuin-A levels were significantly lower in patients with T2DM than the controls (298.75+/-78.86 and 430.73+/-94.46 microg/mL, respectively). HbA1c levels were significantly higher in the T2DM group compared with controls (7.33+/-1.32 and 5.44+/-0.84%, respectively). Correlations between visfatin, fetuin-A and HbA1c levels were not observed. CONCLUSION: The present study suggests fetuin-A may play a role in the pathogenesis of T2DM.
Adipokines ; Albuminuria ; alpha-2-HS-Glycoprotein ; Body Mass Index ; Chromatography, Liquid ; Diabetes Mellitus, Type 2 ; Enzyme-Linked Immunosorbent Assay ; Hemoglobins ; Humans ; Insulin ; Intra-Abdominal Fat ; Male ; Nicotinamide Phosphoribosyltransferase ; Receptor, Insulin

BACKGROUND: Fetuin-A is a hepatokine that involved in the pathogenesis of insulin resistance. Previous epidemiological studies have found a positive association between blood fetuin-A and type 2 diabetes mellitus (T2DM) risk among Caucasians and African Americans. We aimed to investigate the prospective relationship between fetuin-A and T2DM in an Asian population for the first time. METHODS: A nested case-control study was established within a prospective cohort of Chinese living in Singapore. At blood collection (1999 to 2004), all participants were free of diagnosed T2DM and aged 50 to 79 years. At subsequent follow-up (2006 to 2010), 558 people reported to have T2DM and were classified as incident cases, and 558 controls were randomly chosen from the participants who did not develop T2DM to match with cases on age, sex, dialect group, and date of blood collection. Plasma fetuin-A levels were measured retrospectively in cases and controls using samples collected at baseline. Conditional logistic regression models were used to compute the odds ratio (OR) and 95% confidence interval (CI). Restricted cubic spline analysis was used to examine a potential non-linear association between fetuin-A levels and T2DM risk. RESULTS: Compared with those in the lowest fetuin-A quintile, participants in the highest quintile had a two-fold increased risk of developing T2DM (OR, 2.06; 95% CI, 1.21 to 3.51). A non-linear association was observed (P nonlinearity=0.005), where the association between fetuin-A levels and T2DM risk plateaued at plasma concentrations around 830 µg/mL. CONCLUSION: There is a positive association between plasma fetuin-A levels and risk of developing T2DM in this Chinese population.
African Americans ; alpha-2-HS-Glycoprotein ; Asian Continental Ancestry Group ; Case-Control Studies ; Cohort Studies ; Diabetes Mellitus, Type 2 ; Epidemiologic Studies ; Epidemiology ; Follow-Up Studies ; Humans ; Insulin Resistance ; Logistic Models ; Odds Ratio ; Plasma ; Prospective Studies ; Retrospective Studies ; Singapore