Serum galectin-3 levels in patients with nonalcoholic fatty liver disease

Objectives

Galectin-3 might serve as a biomarker of human metabolic alterations. We measured serum levels of galectin-3 in patients with nonalcoholic fatty liver disease (NAFLD) and examined their association with clinical and histological phenotypes.

Design and methods

Serum levels of galectin-3 were assayed in 71 patients with biopsy-proven NAFLD and 39 controls.

Results

Serum galectin-3 levels did not differ in patients with NAFLD (median 4.1 ng/mL; interquartile range: 1.5–5.5 ng/mL) compared with healthy controls (median 3.1 ng/mL; interquartile range: 0.8–7.5 ng/mL, P = 0.93). Among patients with NAFLD, however, serum galectin-3 levels correlated significantly with BMI (r = 0.267, P < 0.05). This association persisted after adjustment for potential confounders (β = 0.30; t = 2.11, P < 0.05).

Conclusions

Although galectin-3 was modestly associated with BMI, our results do not support the hypothesis that levels of this molecule are altered in patients with NAFLD.     

非酒精性脂肪性肝病模型大鼠饮食或二甲双胍干预后肝视黄醇结合蛋白4表达

背景：目前关于血清视黄醇结合蛋白4在非酒精性脂肪性肝病中的表达水平仍存在争议。目的：研究饮食或二甲双胍干预对非酒精性脂肪性肝病大鼠肝脏视黄醇结合蛋白4表达的影响。方法：将50只SD大鼠随机分为6组,8周对照组,正常饮食8周后处死;8周高脂组,高脂饮食8周制作非酒精性脂肪性肝病模型,随后处死;16周对照组,正常饮食16周后处死;16周高脂组,高脂饮食16周后处死;饮食干预组,8周高脂饮食后再正常饮食8周,随后处死;二甲双胍治疗组,8周高脂饮食后,继续8周高脂饮食,同时给予二甲双胍灌胃治疗,随后处死。采用ELISA法检测血清视黄醇结合蛋白4水平及生化指标,免疫组织化学法、Western blotting法、RT-PCR法检测肝脏组织视黄醇结合蛋白4表达。结果与结论：高脂饮食成功建立非酒精性脂肪性肝病大鼠模型,随造模时间延长,大鼠肝脏由单纯性脂肪肝逐渐进展成为脂肪性肝炎。饮食干预可改善高脂饮食引发的肝组织视黄醇结合蛋白4表达下降、肝功能异常、脂代谢紊乱和胰岛素抵抗,二甲双胍治疗仅改善了高脂饮食引发的肝脂肪变。结果表明肝组织视黄醇结合蛋白4表达的改变可能在非酒精性脂肪性肝病发病中起一定作用,饮食干预应作为防治非酒精性脂肪性肝病的基本措施,二甲双胍可以改善非酒精性脂肪性肝病的肝脂肪变。     

Serum adipocyte fatty acid-binding protein levels are associated with nonalcoholic fatty liver disease in type 2 diabetic patients

OBJECTIVE—Adipocyte fatty acid–binding protein (A-FABP) is a major cytoplasmic protein in adipocytes and macrophages and is closely associated with metabolic syndrome, type 2 diabetes, and atherosclerosis. Here, we investigated whether A-FABP was associated with nonalcoholic fatty liver disease (NAFLD) in type 2 diabetes.RESEARCH DESIGN AND METHODS—We enrolled 181 type 2 diabetic patients. Clinical and biochemical metabolic parameters were measured. The severity of NAFLD was measured by ultrasound. A-FABP, adiponectin, and retinol-binding protein-4 (RBP-4) were determined by enzyme-linked immunosorbent assay.RESULTS—A-FABP levels, defined as more than a moderate degree of fatty liver compared with men, those without metabolic syndrome, and those without NAFLD, were higher in women, patients with metabolic syndrome, and patients with overt NAFLD, respectively. Adiponectin was decreased according to the severity of NAFLD, but RBP-4 showed no difference. Age- and sex-adjusted A-FABP showed positive correlations with BMI, waist-to-hip ratio, waist circumference, triglycerides, γ-glutamyltransferase, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), A1C, and C-reactive protein (CRP) but showed negative correlation with HDL cholesterol. The odds ratio (OR) for the risk of overt NAFLD with increasing levels of sex-specific A-FABP was significantly increased (OR 2.90 [95% CI 1.15–7.29] vs. 7.87 [3.20–19.38]). The OR in the highest tertile of A-FABP remained significant after adjustments for BMI, waist circumference, A1C, HDL cholesterol, triglycerides, HOMA-IR, CRP, and hepatic enzymes.CONCLUSIONS—Our study demonstrates that serum A-FABP is significantly associated with NAFLD in type 2 diabetes, independent of BMI, waist circumference, HOMA-IR, A1C, triglycerides, HDL cholesterol, and CRP.Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic elevation of hepatic enzymes in the general population without known liver disease. NAFLD is observed in 20–30% of the total population (1) and in 75% of type 2 diabetic patients (2,3) in developed countries. NAFLD is characterized by hepatic insulin resistance. In epidemiologic studies, NAFLD has been reported to be closely associated with obesity, dyslipidemia, and diabetes (4–6). In prospective studies, NAFLD was a risk factor for type 2 diabetes and cardiovascular disease independent of the classic risk factors (7,8). Hence, NAFLD is considered a hepatic manifestation of metabolic syndrome.Adipocyte fatty acid–binding protein (A-FABP; also known as FABP-4 or aP2) is a major cytoplasmic protein and is involved in the regulation of lipid metabolism. A-FABP is expressed abundantly in mature adipocytes and activated macrophages. A-FABP binds fatty acid ligands with high affinity and functions in intracellular fatty acid trafficking, regulation of lipid metabolism, and modulation of gene expression (9,10). In obese mice lacking A-FABP, dyslipidemia and peripheral insulin resistance are improved and β-cell function is preserved (11). Boord et al. (12) reported that combined adipocyte-macrophage fatty acid–binding protein deficiency improves glucose and lipid metabolism, reduces atherosclerosis, and improves survival in apoE^-/- mice. In cross-sectional studies, A-FABP was closely associated with obesity and metabolic syndrome (13,14). In prospective studies, A-FABP levels predicted the development of metabolic syndrome and type 2 diabetes (15,16). Furthermore, Yeung et al. (17) reported that A-FABP levels were independently associated with carotid atherosclerosis. Tuncman et al. (18) reported that individuals with an aP2 variant had lower triglycerides and a reduced risk of coronary heart disease and obesity-induced type 2 diabetes. These findings suggested that A-FABP is closely associated with insulin resistance and plays a central role in the development of metabolic syndrome, type 2 diabetes, and atherosclerosis. Maeda et al. (19) demonstrated protection against fatty liver disease in mice lacking aP2 and mal1 on high-fat diet. However, a relationship between A-FABP and NAFLD, a hepatic manifestation of metabolic syndrome, has not yet been established in a human study.We hypothesized that patients with NAFLD might have higher A-FABP levels and that A-FABP might show a positive correlation with the severity of NAFLD on ultrasound. To test this hypothesis, we investigated the relationship between serum A-FABP levels and NAFLD in type 2 diabetic patients.     

Serum retinol binding protein 4 in patients with familial partial lipodystrophy

ObjectiveTo determine Retinol Binding Protein 4 (RBP4) levels in patients with Familial Partial Lipodystrophy (FPLD).MethodsTen patients with FPLD and a control group (9 patients) were selected to participate in the study.ResultsRBP4-log levels were lower in patients with FPLD in comparison to control group (1.52  ±  0.32 vs 1.84 ± 0.25, p = 0.029). A statistical trend was observed between Waist-to-Hip Ratio and RBP4-log (r = - 0.44, p = 0.054).ConclusionRBP4 levels are decreased in FPLD.     

血清视黄醇结合蛋白4和非酒精性脂肪性肝病的相关性

目的分析非酒精性脂肪性肝病（NAFLD）患者血清视黄醇结合蛋白4（RBP4）水平,探讨血清RBP4与NAFLD发病的相关性。方法分别测定324例NAFLD患者和200名健康对照者血清RBP4、肌酐（Cr）、三酰甘油（TG）、胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、空腹葡萄糖（Glu）水平,比较各指标在2组中的差异。结果 NAFLD组血清RBP4水平[（58.42±20.74）mg/L]明显高于对照组[（39.1±7.1）mg/L]（P〈0.01）;Logistic回归分析显示血清RBP4是与NAFLD发病相关的独立危险因子（预期比数比为1.138,P〈0.05）,Pearson相关分析提示血清RBP4水平与Cr、TC、TG、LDL-C水平呈正相关（r分别为0.270、0.393、0.175、0.158,P均0.057）,与HDL-C水平呈负相关（r=-0.186,P〈0.05）。结论血清RBP4水平与NAFLD患病相关,并且与Cr、TC、TG、LDL-C、HDL-C具有相关性。     

Serum levels of osteoprotegerin in the spectrum of nonalcoholic fatty liver disease

Abstract

Objective. Osteoprotegerin (OPG) is a member of the tumor necrosis factor superfamily with pleiotropic effects on inflammation, endocrine function and the immune system. Reduced OPG levels are related to insulin resistance. We tested the hypothesis that serum levels of OPG may be associated with nonalcoholic fatty liver disease (NAFLD). Material and methods. Four groups of patients were enrolled in the present study: subjects with definite nonalcoholic steatohepatitis (NASH, n = 56), borderline NASH (n = 26), simple fatty liver (n = 17) and healthy controls without evidence of liver disease (n = 58). Serum levels of OPG were measured by ELISA. Results. Concentrations of OPG were significantly lower in patients with definite NASH (median: 45 pg/mL, p < 0.001) and borderline NASH (57 pg/mL, p < 0.001) than in controls (92 pg/mL). The area under the ROC curve for distinguishing between steatohepatitis (definite NASH plus borderline NASH) and healthy controls using OPG was 0.82. The use of a cut-off level < 74 pg/mL for serum OPG levels yielded sensitivity and specificity values of 75.6% and 75.9%, respectively. Conclusions. Serum osteoprotegerin concentrations are reduced in patients with the more severe forms of NAFLD and may serve as a noninvasive biomarker to identify patients with NASH.     

维持性血液透析患者血清视黄醇结合蛋白4的水平变化

目的观察终末期肾病维持性血液透析患者血清视黄醇结合蛋白4(RBP4)的水平变化及其与营养不良和血脂的关系。方法选择我院终末期肾病维持性血液透析患者48例及30例健康体检者,测定两组尿素氮(BUN)、肌酐(Cr)、尿酸(UA)、甘油三脂(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、白蛋白(Alb)、总蛋白(TP)及RBP4的浓度,分析RBP4与所测定指标的关系。结果①与对照组相比,维持性血液透析患者TP、Alb、TC、HDL-C、LDL-C的水平是降低的,TP(64.33±4.42)g/L vs(70.25±4.94)g/L,Alb(38.98±6.07)g/L vs(45.23±7.67)g/L,TC(4.20±1.83)mmol/L vs(5.29±1.09)mmol/L,HDL-C(1.37±0.52)mmol/Lvs(1.62±0.43)mmol/L,LDL-C(2.99±1.02)mmol/L vs(4.08±1.14)mmol/L(均P<0.01)。②维持性血液透析患者的RBP4的水平明显高于正常对照组,(43.58±5.42)μg/L vs(32.42±6.71)μg/L,且与BUN、Cr、UA呈正相关(r=0.651、0.671、0.449,P<0.01),与HDL-C、Alb呈负相关(r=-0.289、-0.249,P<0.05)。结论维持性血液透析患者存在有营养不良及脂代谢紊乱,RBP4可能参与营养不良及脂代谢紊乱。     

非酒精性脂肪肝肝纤维化评分与脂肪肝及胰岛素抵抗的相关性研究

目的分析非酒精性脂肪肝肝纤维化评分（NAFLDFS）与非酒精性脂肪肝（NAFLD）及胰岛素抵抗（瓜）的相关性。方法以来自江苏徐州地区的2622例健康体检人群为研究对象,检测受试者的血清谷丙转氨酶（“r）,谷草转氨酶（AsT）,血小板计数（PLT）,血清白蛋白（ALB）,空腹血糖（FBG）,餐后2h血糖（PBG）,空腹胰岛素（Fins）等相关生化指标,计算出NAFLDFS及胰岛素抵抗指数（HOMA2-IR）,将研究对象按非酒精性脂肪肝纤维化评分的低诊断阈值（～1．455）及高诊断阈值（0．676）分成三组,A1组：NAFLDFS〈-1．455;A2组：0．676≥NAFLDFS≥-1．455和A3组NAFLDFS〉0．676。Pearson分析肝纤维化评分与各指标相关性;运用二元Logistic回归计算NAFLDFS与NAFLD、IR的风险性。结果随着NAFLDFS值增高,年龄（Age）、体重（Weight）、体重指数（BMI）、腰围（wc）、臀围（Hip）、糖化血红蛋白（HbAlc）、颈围（NC）、FBG、PBG、Fins、收缩压（SBP）、舒张压（DBP）、总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白（LDL-C）水平逐渐增高,且三组问的差异有统计学意义;而ALT、AST、PLT、ALB、高密度脂蛋白（HDL．c）随着NAFLDFS值的增高而减小。Pearson分析显示Age、NC、WC、Hip、Weight、BMI、HbAlc、FBG、PBG、PLT与NAFLDFS正相关。随着NAFLDFS值的增加,NAFLD与取的患病风险（OR）也增加。NAFLD的患病风险由1．22（OR=1．22）增加到1．79（OR=1．79）：IR的患病风险由1．13（OR=1．13）增加到1．91（OR=1．91）;进一步校正性别及年龄后,NAFLD的患病风险由1．15（OR=1．15）增加到1．53（OR=1．53）;IR的患病风险由1．15（OR=1．15）增加到2．02（OR=2．02）。结论NAFLDFS与NAFLDF及瓜密切相关,在临床上可将其作为简易评价NAFLD及IR的指标。     

A simpler diagnostic formula for screening nonalcoholic fatty liver disease

ObjectiveTo increase the accuracy of non-invasive diagnosis of nonalcoholic fatty liver disease (NAFLD), clinical and laboratory NAFLD indicators were integrated into a diagnostic formula.MethodsA total of 141 patients with clinically diagnosed NAFLD and 30 healthy controls were enrolled. We collected case history, body weight, height and mass index (BMI), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase, blood urea nitrogen and blood uric acid (UA), serum creatinine, plasma total cholesterol, triglyceride, low density lipoprotein, glycosylated hemoglobin, fasting plasma glucose, fasting insulin, ultrasonic tests, Fibroscans, and other data. Linear correlation, multiple linear regressions, and receiver operating characteristic (ROC) curve methods were used to process and analyze the collected data. The performance of Fibroscan and our diagnostic formula was compared in reference to the findings of liver biopsy.ResultsThe identified NAFLD diagnostic indices consisted of BMI, ALT, AST and UA. A regression formula was proposed as: CAP = 113.163 + 0.252 * ALT + 6.316 * BMI. Diagnosis of the area under the ROC curve was 0.927, the sensitivity was 87.68%, and specificity was 90%. The cutoff was 277.67 (p < 0.01). The accuracy of the NAFLD diagnosis with the proposed formula was significantly higher than FibroScan (82.6% vs 69.6%; p = 0.005).ConclusionsNAFLD diagnosis with the proposed formula demonstrated both high sensitivity and specificity, and its accuracy was significantly higher than FibroScan. This formula only utilized non-invasive clinical and laboratory findings and the calculation was simple. It can be conveniently used for clinical diagnosis of NAFLD.     

非酒精性脂肪性肝病与代谢综合征的相关性分析

目的:分析非酒精性脂肪性肝病(NAFLD)的临床及生化特征,以探讨NAFLD与代谢综合征(MS)的相关性。方法:对2248例在青岛大学医学院附属青岛市市立医院体检中心进行健康体检的人群,进行身高、体重、腰围、血压、血脂、空腹血糖、血尿酸等指标检测,空腹行腹部B超检查。结果:NAFLD组中肥胖、中心性肥胖、高血压、血脂异常、糖代谢异常、高尿酸血症的检出率明显高于对照组(P<0.01),Logistic回归分析显示腰围、甘油三酯、空腹血糖、体重指数、性别与NAFLD密切相关,NAFLD组中MS伴发率明显高于对照组(48.62%vs19.13%,P<0.01)。结论:NFALD与MS密切相关,NAFLD患者具有MS各组分集聚的特征,应重视NAFLD对心脑血管疾病的影响。     

PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) has now become the leading cause of chronic liver disease with its growing incidence worldwide. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 C > G reflects one of the critical genetic factors that confers high-risk to NAFLD. However, the role of PNPLA3 polymorphism in NAFLD treatment remains uncertain. Here, the present review reveals that NAFLD patients with G-allele at PNPLA3 rs738409 (PNPLA3 148M variant) are sensitive to therapies of lifestyle modification, dipeptidyl peptidase-4 inhibitors, and bariatric surgery. They exhibit much significant reduction of liver fat content, in concurrence with weigh loss and abolished insulin resistance, as compared to those of C-allele carriers. In contrast, patients bearing PNPLA3 rs738409 C-allele (PNPLA3 148I variant), instead of G-allele, demonstrate greater beneficial effects by omega-3 poly-unsaturated fatty acids and statin intervention. Improved adipose tissue-liver interaction and decrease in intrahepatic triglyceride efflux may contribute to the PNPLA3 rs738409 related diversities in therapeutic efficacy. Therefore, PNPLA3 rs738409 underlies the response to a variety of treatments, which warrants a personalized, precise medicine in NAFLD on the basis of genotype stratification.     

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

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.     

Urine liver fatty acid binding protein and chronic kidney disease progression

Excretion of the tubular protein liver fatty acid binding protein (L-FABP) is a potential novel biomarker of renal dysfunction. We examined whether urine L-FABP excretion adds prognostic information to the well-established risk markers, blood pressure (BP), albumin excretion and baseline GFR, regarding progression of chronic kidney disease (CKD). In a prospective study design a cohort of 74 stage 3-4 CKD patients (age 61?±?13 years) were included. Glomerular filtration ratio (GFR, ⁵¹Cr-EDTA-clearance), 24-hour ambulatory BP, 24-hour urinary albumin/creatinine ratio (UAC) and urinary L-FABP/creatinine ratio (U-L-FABP/C) were determined at baseline and after 18 months of follow-up. For comparison 25 age-matched healthy controls were included. The U-L-FABP/C was elevated in CKD patients when compared to controls (mean U-L-FABP/C 2.3 [95% CI 1.7–2.9] μg/mmol vs 0.6 [0.5–0.7] μg/mmol, p?<?.001). In CKD patients, log U-L-FABP/C at baseline and at follow-up were positively associated (Pearson correlation coefficient r?=?0.74, p?<?.001). Baseline log U-L-FABP/C was negatively correlated with baseline GFR (r?=??0.32, p?<?.001) and directly correlated with UAC (r?=?0.67, p?<?.001). The relative change in GFR from baseline to follow-up correlated with baseline UAC (p?<?.001), 24-hour systolic BP (p?=?0.05) and log U-L-FABP/C (p?<?.001). Using multiple regression analysis adjusting for baseline GFR, UAC, BP, age and gender, baseline log U-L-FABP/C was associated with a decline in GFR only in patients with UAC <3?mg/mmol (n?=?29, p?=?0.001) and not in patients with UAC ≥3?mg/mmol (n?=?44, p?=?0.21). In conclusion urine L-FABP/C is permanently elevated in CKD patients, but only associated with GFR decline in those without albuminuria.