Fatih Eren

Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease

Eur J Clin Invest 2010; 40 (10): 887–892

Serum levels of omentin, chemerin and adipsin in patients with biopsy-proven nonalcoholic fatty liver disease

Abstract Objective. The novel adipokines omentin, chemerin, and adipsin are associated with insulin resistance and the components of the metabolic syndrome. We assayed circulating levels of these molecules and examined their association with clinical, biochemical, and histological phenotypes in patients with nonalcoholic fatty liver disease (NAFLD). Material and methods. Serum levels of omentin, chemerin, and adipsin were assayed by enzyme-linked immunosorbent assay in 99 patients with biopsy-proven NAFLD and 75 control subjects. We analyzed associations between adipokines and the characteristics of patients with NAFLD using multivariable linear regression models. Results. Adipsin levels did not differ between patients and controls, whereas both omentin and chemerin levels were significantly higher in patients with biopsy-proven NAFLD than in controls (both p values <0.001). Serum omentin levels were significantly associated with C-reactive protein (r = 0.29, p < 0.01) and the degree of hepatocyte ballooning (r = 0.27, p < 0.01), whereas chemerin showed a modest association with liver fibrosis (r = 0.22, p = 0.04). After stepwise linear regression analysis adjusting for potential confounders, serum omentin levels retained their independent significance as a predictor of hepatocyte ballooning in patients with NAFLD (β = 1.42; t = 2.79, p < 0.01). Conclusions. Our results suggest that serum omentin levels are raised in patients with NAFLD regardless of potential confounders and represent an independent predictor of hepatocyte ballooning.

Serum levels of vaspin, obestatin, and apelin-36 in patients with nonalcoholic fatty liver disease.

The novel adipokines vaspin, obestatin, and apelin-36 are associated with insulin resistance and the components of the metabolic syndrome. We assayed circulating levels of these molecules and examined their association with clinical, biochemical, and histologic phenotypes in patients with nonalcoholic fatty liver disease (NAFLD). Serum levels of vaspin, obestatin, and apelin-36 were assayed by enzyme-linked immunosorbent assay in 91 patients with biopsy-proven NAFLD and 81 controls. We analyzed associations between adipokines and the characteristics of patients with NAFLD using multivariable linear regression models. Univariable analysis showed that concentrations of vaspin and apelin-36 were significantly higher in patients with NAFLD than in controls, whereas no differences in obestatin levels were found. Serum vaspin levels showed a statistically significant association with C-reactive protein (r = 0.378, P < .001) and liver fibrosis scores (r = 0.401, P < .001), whereas apelin-36 levels showed a modest association with homeostasis model assessment of insulin resistance (r = 0.204, P < .01). After stepwise linear regression analysis, serum vaspin levels were the only independent predictor of liver fibrosis scores in patients with NAFLD (β = 0.37, t = 3.99, P < .01). Serum vaspin levels are raised in patients with NAFLD regardless of potential confounders and represent an independent predictor of liver fibrosis scores. These findings support further investigation of this novel adipokine in metabolic liver diseases.

Melatonin ameliorates methionine- and choline-deficient diet-induced nonalcoholic steatohepatitis in rats.

Abstract:  Nonalcoholic steatohepatitis (NASH) may progress to advanced fibrosis and cirrhosis. Mainly, oxidative stress and excessive hepatocyte apoptosis are implicated in the pathogenesis of progressive NASH. Melatonin is not only a powerful antioxidant but also an anti‐inflammatory and anti‐apoptotic agent. We aimed to evaluate the effects of melatonin on methionine‐ and choline‐deficient diet (MCDD)‐induced NASH in rats. Thirty‐two male Wistar rats were divided into four groups. Two groups were fed with MCDD while the other two groups were fed a control diet, pair‐fed. One of the MCDD groups and one of the control diet groups were administered melatonin 50 mg/kg/day intraperitoneally, and the controls were given a vehicle. After 1 month the liver tissue oxidative stress markers, proinflammatory cytokines and hepatocyte apoptosis were studied by commercially available kits. For grading and staging histological lesions, Brunt et al.’s system was used. Melatonin decreased oxidative stress, proinflammatory cytokines and hepatocyte apoptosis. The drug ameliorated the grade of NASH. The present study suggests that melatonin functions as a potent antioxidant, anti‐inflammatory and antiapoptotic agent in NASH and may be a therapeutic option.

Circulating vaspin levels and epicardial adipose tissue thickness are associated with impaired coronary flow reserve in patients with nonalcoholic fatty liver disease

BACKGROUND Patients with nonalcoholic fatty liver disease (NAFLD) have a reduced coronary flow reserve (CFR) and an increased risk of cardiovascular disease. The fat cells that surround coronary arteries may play a central and underrecognized role in development of cardiovascular disease through the systemic secretion of adipokines. We therefore evaluated the relation of epicardial fat thickness, serum levels of epicardial fat-related adipokines (chemerin and vaspin), and CFR in patients with NAFLD. METHODS We investigated 54 patients with biopsy-proven NAFLD and 56 age- and sex-matched controls. CFR and epicardial fat thickness (EFT) were measured by transthoracic echocardiography. Serum levels of chemerin and vaspin were measured by ELISA. RESULTS EFT was significantly higher (0.64 ± 0.13 vs. 0.54 ± 0.10 cm, P<0.001) and CFR significantly lower (2.11 ± 0.45 vs. 2.52 ± 0.62, P < 0.001) in patients with NAFLD than in controls. Serum levels of vaspin and chemerin were both significantly increased in patients with NAFLD compared with controls. Stepwise regression analysis showed that EFT (β=-0.53, t=-3.7, P<0.001), serum vaspin levels (β=-0.30, t=-2.5, P=0.014), and liver fibrosis (β=-0.31, t=-2.11, P=0.041), in the order they entered into the model, were independent predictors of CFR in NAFLD patients. CONCLUSION Our data suggest the presence of a complex interplay between EFT, serum vaspin, and liver histology in promoting an impaired hyperemic stimulation of coronary blood flow in patients with NAFLD.

Local delivery of chitosan/VEGF siRNA nanoplexes reduces angiogenesis and growth of breast cancer in vivo.

Vascular endothelial growth factor (VEGF) is the important angiogenic factor associated with tumor growth and metastasis in a wide variety of solid tumors. The aim of this study is to investigate the tumor suppressive effect of chitosan/small interfering RNA (siRNA)-VEGF nanoplexes in the rat breast cancer model. Chitosan/siRNA nanoplexes (siVEGF-A, siVEGFR-1, siVEGFR-2) and NRP-1 were prepared in a 15 to1 ratio and injected (intratumorally) into the breast-tumor-bearing Sprague-Dawley rats. Tumor volumes were measured during 21 days. To investigate the effect of chitosan/siRNA nanoplexes on VEGF expression in tumors, VEGF was analyzed with immunohistochemistry and western blotting. The mRNA levels of VEGF in tumor samples were determined with real-time PCR (RT-PCR). After siRNA treatment, a marked reduction in tumor volumes was measured in complex-injected rats (97%). Free siRNA injection showed lower tumor inhibition. Reduction of VEGF protein was also shown with western blotting and immunohistochemistry. Similar results were obtained with RT-PCR also. These results indicate that the chitosan/siRNA targeting to VEGF nanoplexes have a remarkably suppressive effect on VEGF expression and tumor volume in breast cancer model of rats.

Preliminary evidence of a reduced serum level of fibroblast growth factor 19 in patients with biopsy-proven nonalcoholic fatty liver disease.

OBJECTIVES We sought to determine whether serum concentrations of fibroblast growth factor 19 (FGF19) - an ileum-derived enterokine which plays a role in the control of glucose and lipid homeostasis - are altered in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD). DESIGN AND METHODS Serum levels of FGF19 were measured using enzyme-linked immunosorbent assay in 91 patients with biopsy-proven NAFLD and 74 controls. RESULTS FGF19 levels were significantly lower in patients with biopsy-proven NAFLD (median: 130pg/mL) than in controls (median: 210pg/mL, P<0.001). Serum FGF19 levels were significantly but modestly associated with hepatocyte ballooning scores in univariate analysis (r=-0.25, P<0.05) but not after adjustment for potential confounders (β=-0.18; t=1.78, P=0.08). CONCLUSIONS This pilot study suggests that serum FGF19 levels are decreased in patients with NAFLD but are not independently associated with liver histology findings.

Serum osteocalcin levels in patients with nonalcoholic fatty liver disease: Association with ballooning degeneration

Abstract Our aim was to examine the relation of serum osteocalcin (OCN) levels with the clinical, biochemical, and histological characteristics of patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD). We carried out a case-control study including 99 patients with biopsy-proven NAFLD and 75 age- and sex-matched controls. Concentrations of OCN were measured in aprotinin-treated serum samples using a solid-phase enzyme amplified sensitivity immunoassay. Serum OCN levels were significantly lower in patients with NAFLD than in healthy controls. In patients with NAFLD, serum OCN levels were inversely associated with ALT (r =−0.36, p < 0.001), AST (r =−0.39, p < 0.001), HOMA-IR (r =−0.30, p < 0.01) and the degree of hepatocyte ballooning (r =−0.20, p < 0.05). Serum OCN was the only independent predictor of the degree of hepatocyte ballooning in NAFLD patients (β =−0.24; t = −2.146, p < 0.05). Compared with controls, NAFLD patients have a decrease in serum OCN concentrations, which is significantly associated with serum transaminases and the extent of hepatocyte ballooning.

Serum levels of adipokines in patients with chronic HCV infection: relationship with steatosis and fibrosis.

BACKGROUND AND AIMS Hepatic steatosis and fibrosis are common histological findings in patients with chronic hepatitis C virus (HCV) infection. In this study we sought to determine whether serum levels of three adipokines (leptin, adiponectin and resistin) show any biochemical correlation with hepatic steatosis and fibrosis in patients with chronic HCV infection. METHODS We examined a total of 51 patients with chronic HCV infection (22 males and 29 females, mean BMI: 27.4+/-5kg/m(2)) and 24 healthy control subjects (10 males and 14 females, mean BMI: 23.2+/-3kg/m(2)). Liver steatosis and fibrosis were scored on biopsies. Serum levels of leptin, adiponectin and resistin were determined by ELISA. RESULTS HCV genotypes were 1b in 41 patients (80.4%), 3a in three patients (5.9%), 2a in two patients (3.9%), 1a in two patients (3.9%), 1c in one patient (2%), and 2b in one patient (2%). Serum levels of leptin, resistin, and the leptin-to-adiponectin ratio were significantly higher in patients with chronic HCV infection than in controls. Steatosis and fibrosis were detected in 33.3% and 70.5% of chronic HCV patients, respectively. No significant association with serum adipokine levels and degree of steatosis was evident. Low serum levels of resistin were associated with the presence of fibrosis independently of potential confounders. CONCLUSIONS Patients with chronic HCV infection display elevated levels of adipokines in their sera. Reduced concentrations of resistin may be a biochemical marker of fibrosis in this patient group.

Serum progranulin as an independent marker of liver fibrosis in patients with biopsy-proven nonalcoholic fatty liver disease

Background: Elevated progranulin levels are associated with visceral obesity, elevated plasma glucose, and dyslipidemia. Progranulin has not been previously investigated as a biomarker of nonalcoholic fatty liver disease (NAFLD). We sought to determine whether serum progranulin levels are altered in patients with biopsy-proven NAFLD and if they are associated with their clinical, biochemical, and histological characteristics. Subjects and methods: We measured serum progranulin levels in 95 patients with biopsy-proven NAFLD and 80 age- and sex-matched controls. The potential associations between progranulin and the characteristics of NAFLD patients were examined by multiple linear regression analysis. Results: Serum progranulin levels were significantly higher in NAFLD patients (34 ± 13 ng/mL) than in controls (28 ± 7 ng/mL, P < 0.001). In NAFLD patients, serum progranulin levels were associated with lipid levels and the degree of hepatic fibrosis. After adjustment for potential confounders, serum progranulin remained an independent predictor of the degree of hepatic fibrosis in NAFLD patients (β = 0.392; t =2.226, P < 0.01). Conclusions: Compared with controls, NAFLD patients have higher serum progranulin concentrations, which are closely associated with lipid values and the extent of hepatic fibrosis.