osteoprotegerin and Non-alcoholic-Fatty-Liver-Disease

To summarize evidence on the potential involvement of the osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B (NF-κΒ) ligand (RANKL)/receptor activator of NF-κΒ (RANK) axis in the pathogenesis of metabolic diseases.. The OPG-RANKL-RANK axis, which has been originally involved in bone remodeling and osteoporosis, is now recognized as a potential contributor in the pathogenesis of obesity and its associated comorbidities, i.e., type 2 diabetes mellitus and nonalcoholic fatty liver disease. Besides bone, OPG and RANKL are also produced in adipose tissue and may be involved in the inflammatory process associated with obesity. Metabolically healthy obesity has been associated with lower circulating OPG concentrations, possibly representing a counteracting mechanism, while elevated serum OPG levels may reflect an increased risk of metabolic dysfunction or cardiovascular disease. OPG and RANKL have been also proposed as potential regulators of glucose metabolism and are potentially involved in the pathogenesis of type 2 diabetes mellitus. In clinical terms, type 2 diabetes mellitus has been consistently associated with increased serum OPG concentrations. With regard to nonalcoholic fatty liver disease, experimental data suggest a potential contribution of OPG and RANKL in hepatic steatosis, inflammation, and fibrosis; however, most clinical studies showed reduction in serum concentrations of OPG and RANKL. The emerging contribution of the OPG-RANKL-RANK axis to the pathogenesis of obesity and its associated comorbidities warrants further investigation by mechanistic studies and may have potential diagnostic and therapeutic implications.

Topics: Diabetes Mellitus, Type 2; Humans; Ligands; NF-kappa B; Non-alcoholic Fatty Liver Disease; Obesity; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Concomitantly with the increase in the prevalences of overweight/obesity, nonalcoholic fatty liver disease (NAFLD) has worldwide become the main cause of chronic liver disease in both adults and children. Patients with fatty liver display features of metabolic syndrome (MetS), like insulin resistance (IR), glucose intolerance, hypertension and dyslipidemia. Recently, epidemiological studies have linked obesity, MetS, and NAFLD to decreased bone mineral density and osteoporosis, highlighting an intricate interplay among bone, adipose tissue, and liver. Osteoprotegerin (OPG), an important symbol of the receptor activator of nuclear factor-B ligand/receptor activator of nuclear factor kappa B/OPG system activation, typically considered for its role in bone metabolism, may also play critical roles in the initiation and perpetuation of obesity-related comorbidities. Clinical data have indicated that OPG concentrations are associated with hypertension, left ventricular hypertrophy, vascular calcification, endothelial dysfunction, and severity of liver damage in chronic hepatitis C. Nonetheless, the relationship between circulating OPG and IR as a key feature of MetS as well as between OPG and NAFLD remains uncertain. Thus, the aims of the present review are to provide the existent knowledge on these associations and to discuss briefly the underlying mechanisms linking OPG and NAFLD.

Topics: Animals; Comorbidity; Humans; Liver; Non-alcoholic Fatty Liver Disease; Obesity; Osteoprotegerin; Prevalence; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction

Growing evidence suggests complex interplay between nonalcoholic fatty liver disease (NAFLD) and bone health. The present study's aim was to examine the impact of metformin treatment on circulating osteoprotegerin (OPG) in patients with NAFLD, a population in which this relationship has not yet been studied.. In a randomized, placebo-controlled study, 63 patients with NAFLD were assigned to one of two groups: Group 1 received daily metformin; Group 2 received a placebo. Metabolic parameters, insulin resistance markers and OPG levels were examined at baseline and at the end of the study.. In the placebo group, liver function and OPG levels did not change during the study. Among metformin-treated patients, significant declines in OPG and alkaline phosphatase were observed. CRP and ALT decreased marginally during the 4-month treatment period. While at baseline circulating OPG levels did not differ significantly between the groups, by the end of the study OPG was significantly lower in patients treated with metformin than in the placebo group (p < 0.0001). Delta OPG was significantly greater in the metformin group than the placebo group (p = 0.001). In the general linear model, metformin treatment was the only significant independent predictor of endpoint and delta OPG.. Metformin treatment was associated with a significant decrease in OPG levels in patients with NAFLD. The effect on OPG was associated with exposure to metformin per se.. NCT01084486.

Topics: Adult; Aged; Alkaline Phosphatase; Double-Blind Method; Down-Regulation; Female; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Non-alcoholic Fatty Liver Disease; Osteoprotegerin; Treatment Outcome

Postmenopausal estrogen decline increases the risk of developing nonalcoholic steatohepatitis (NASH), and it might accelerate progression to cirrhosis and hepatocellular carcinoma.. This study aimed to investigate a novel therapy for postmenopausal women who are diagnosed with NASH.. Seven-week-old female C57BL/6 J mice were divided into three experimental groups as follows: (1) sham operation (SHAM group), (2) ovariectomy (OVX group), and (3) ovariectomy + 0.02% astaxanthin (OVX + ASTX group). These three groups of mice were fed a choline-deficient high-fat (CDHF) diet for 8 weeks. Blood serum and liver tissues were collected to examine liver injury, histological changes, and hepatic genes associated with NASH. An in vitro study was performed with the hepatic stellate cell line LX-2.. The administration of ASTX significantly improved pathological NASH with suppressed steatosis, inflammation, and fibrosis, in comparison with those in the OVX-induced estrogen deficiency group. As a result, liver injury was also attenuated with reduced levels of alanine aminotransferase and aspartate transaminase. In addition, our study found that ASTX supplementation decreased hepatic osteoprotegerin (OPG) in vivo, a possible factor that contributes to NASH development. In vitro, this study further confirmed that ASTX has an inhibitory effect on the secretion of OPG in LX-2 human hepatic stellate cells.. Our findings suggest that ASTX alleviates CDHF-OVX-induced pathohistological NASH with downregulated OPG, possibly via suppression of the transforming growth factor beta pathway. ASTX could has promise for use in postmenopausal women diagnosed with NASH.

Topics: Animals; Choline; Diet; Diet, High-Fat; Down-Regulation; Estrogens; Female; Fibrosis; Humans; Liver; Liver Cirrhosis; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Osteoprotegerin

Clinical studies have shown that osteoprotegerin (OPG) is reduced in patients with nonalcoholic steatohepatitis (NASH), but the underlying mechanisms are unclear. The current study focuses on the role of OPG in the NASH pathogenesis. OPG knockout mice and wild-type control mice fed a methionine choline-deficient diet (MCD) for 4 weeks resulted in an animal model of NASH. Measurement of triglycerides (TG) in serum and liver to assess steatosis. Hematoxylin eosin (HE), Sirius Red and Masson staining were used to assess the liver damage. Transcriptome sequencing analysis, qPCR and western blot were to analyze changes in lipid metabolism and inflammation-related indicators in the liver. In vivo knockout of OPG resulted in a reduction of TG levels in the liver and a significant increase in serum ALT and AST. The expression of inflammatory factors and fibrosis genes was significantly upregulated in the livers of OPG knockout mice. Transcriptome sequencing analysis showed that OPG knockout significantly enhanced MCD diet-induced activation of the mitogen-activated protein kinase (MAPK) signaling pathway. Mechanistically, OPG may inhibit MAPK signaling pathway activity by upregulating the expression of dual specificity phosphatase 14 (DUSP14), thereby reducing inflammatory injury. OPG could regulate the activity of the MAPK signaling pathway via DUSP14, thus regulating the expression of some inflammatory factors in NASH, it may be a promising target for the treatment of NASH.

Topics: Animals; Choline; Choline Deficiency; Diet; Dual-Specificity Phosphatases; Liver; Methionine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinases; Non-alcoholic Fatty Liver Disease; Osteoprotegerin; Racemethionine

Pathogenesis of the beginning and progression of nonalcoholic fatty liver disease (NAFLD) has not been clarified exactly. The osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) axis seems to play an imperative function in the onset and progression of this disease. The goal of the present study was to investigate the peripheral blood mononuclear cell (PBMC) expression and plasma levels of RANKL and OPG cytokines in NAFLD patients and compare them with healthy group. Plasma levels of OPG and RANKL were determined with ELISA kits in 57 men with NAFLD and 25 healthy men as controls. Biochemical and anthropometric parameters tests were also evaluated in the study groups. RANKL and OPG mRNA contents were evaluated by quantitative RT-PCR. OPG contents were markedly decreased in NAFLD patients as compared with healthy patients [1.43 (1.05-5.45)] versus [2.94 (1.76-4.73)] ng/mL; P = 0.007). The levels of RANKL were significantly reduced in NAFLD patients [74.00 (56.26-203.52) ng/mL] than in healthy patients [119.37 (83.71-150.13) ng/mL]; (P = 0.03). Also, OPG and RANKL gene expression were significantly decreased in NAFLD patients in comparison with the control group (P < 0.05). Moreover, receiver operating characteristic curve indicated that OPG may have a good capability to discriminate between NAFLD patients and normal individuals. A positive correlation was observed between OPG and RANKL in plasma sample (r = 0.495) (P = 0.000). Decreased plasma levels and gene expression of RANKL and OPG cytokines in NAFLD patients indicate that there is a relationship between these cytokines and the pathology of NAFLD disease. Confirmation of this association as well as the mechanism and role of these cytokines in NAFLD require further studies.

Topics: Adult; Case-Control Studies; Humans; Ligands; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Osteoprotegerin; Receptor Activator of Nuclear Factor-kappa B; RNA, Messenger

To investigate the relationship between osteocalcin and osteoprotegerin as bone markers and inflammatory biomarkers such as adiponectin, leptin, tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6) in children with nonalcoholic fatty liver disease (NAFLD).. This study included 40 obese children with NAFLD as the patient group and 40 healthy obese children of matched age, sex and BMI as the control group. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting blood glucose, fasting insulin, Homeostatic model assessment method of insulin resistance (HOMA-IR), lipid profile, osteocalcin, osteoprotegerin, adiponectin, leptin, TNF-α, and IL-6 were measured in all participants.. Children with NAFLD had a significant decrease in osteocalcin, osteoprotegerin and adiponectin level with a significant increase in TNF-α and IL-6 levels. We also found a significant positive correlation between osteocalcin level and adiponectin levels but a significant negative correlation of osteocalcin with each of leptin and TNF-α. However, there was a significant negative correlation between osteoprotegerin levels and both TNF-α and IL-6 levels. Moreover, adiponectin and TNF-α were significant predictors for osteocalcin, and IL-6 was a significant predictor for osteoprotegerin.. Adiponectin, leptin, TNF-α, and IL-6 have potential association with the changes of osteocalcin and osteoprotegerin levels in children with NAFLD.

Topics: Adipokines; Adiponectin; Alanine Transaminase; Aspartate Aminotransferases; Biomarkers; Blood Glucose; Body Mass Index; Case-Control Studies; Child; Cytokines; Humans; Inflammation; Insulin; Insulin Resistance; Interleukin-6; Male; Non-alcoholic Fatty Liver Disease; Obesity; Osteocalcin; Osteoprotegerin; Tumor Necrosis Factor-alpha

Previous cross-sectional studies have established that circulating osteoprotegerin (OPG) levels are associated with nonalcoholic fatty liver disease (NAFLD). However, the role of OPG in metabolic diseases, such as diabetes and NAFLD, is still unclear. In the current study, we demonstrated that hepatic OPG expression was downregulated in NAFLD individuals and in obese mice. OPG deficiency decreased lipid accumulation and expression of CD36 and peroxisome proliferator-activated receptor-γ (PPAR-γ) in the livers of OPG

Topics: Animals; CD36 Antigens; Extracellular Signal-Regulated MAP Kinases; Fatty Liver; Hepatocytes; Humans; Liver; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Obesity; Osteoprotegerin; Phosphorylation; PPAR gamma; Signal Transduction

Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor (TNF) receptor superfamily, is a decoy receptor for the receptor activator of nucleus factor-κB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). OPG has an effect on systemic insulin sensitivity and glucose homeostasis. The objective of this study was to evaluate the relationship between plasma osteoprotegerin (OPG) levels and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes.. A case-control study was performed with 746 patients with type 2 diabetes. Of the study population, 367 patients had B-mode ultrasound-proven NAFLD and 379 were controls. The plasma OPG levels were measured using ELISA methods. NAFLD was diagnosed by hepatic ultrasound after the exclusion of alcohol abuse and other liver diseases.. The OPG levels were significantly decreased in patients with NAFLD (2.3±1.1μg/L vs. 2.8±1.3μg/L, p=3.75×10(5)) compared to controls. Pearson correlation analysis showed that the OPG levels were associated with age and systolic blood pressure (both p<0.05). The participants in the lowest OPG quartile had a significantly increased risk for NAFLD (OR=3.49, 95% CI 1.86-6.94) after adjusting for potential cofounders.. The plasma OPG level is negatively associated with NAFLD independent of potential cofounders.

Topics: Age Factors; Aged; Asian People; Blood Pressure; Case-Control Studies; China; Diabetes Mellitus, Type 2; Female; Humans; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Osteoprotegerin; Ultrasonography

To investigate the correlation of serum osteoprotegerin (OPG) with the progression of nonalcoholic fatty liver disease (NAFLD) and the noninvasive prediction and diagnosis of nonalcoholic steatohepatitis (NASH).. A total of 136 patients with NAFLD were enrolled, and their tissue samples for liver biopsy and serum samples obtained at 1 week after liver biopsy were collected; 83 healthy subjects without the symptoms of fatty liver disease proved by ultrasound examination were enrolled as controls. The physiological indicators including height, body weight, and waist circumference were measured, and body mass index was calculated. The biochemical parameters including alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ALT, alkaline phosphatase, gamma-glutamyl transferase, total cholesterol, triglyceride (TG), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were measured. Double-antibody sandwich enzyme-linked immunosorbent assay was used to determine the serum level of OPG. The rank sum test, chi-square test, t-test, one-way analysis of variance, Spearman correlation analysis, least significant difference test, and receiver operating characteristic (ROC) curve were applied for statistical analysis of various data.. Serum OPG level was correlated with AST and TG (P < 0.05), and was highly correlated with hepatocyte fatty degeneration, ballooning degeneration, intralobular inflammation, portal inflammation, and fibrosis degree (P < 0.01). With the increasing NAFLD activity score (NAS), serum OPG level decreased, and there was a highly negative correlation between them (r = -0.928, P < 0.01). Serum OPG level was significantly lower in NASH patients than non-NASH patients. The area under the ROC curve of serum OPG level was 0.963, and according to the Youden index, its optimal sensitivity and specificity were 96.1% and 97.4%, respectively, at an optimal cut-off value of 242.96 ng/L, which suggested a high diagnostic power.. In NASH patients, serum OPG level decreases significantly. Serum OPG level can be used as an independent predictive factor to evaluate NASH and its severity, as well as a noninvasive diagnostic index for NASH.

Topics: Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Biopsy; Body Mass Index; Case-Control Studies; Cholesterol; Disease Progression; Enzyme-Linked Immunosorbent Assay; Fibrosis; gamma-Glutamyltransferase; Humans; Inflammation; Liver; Non-alcoholic Fatty Liver Disease; Osteoprotegerin; ROC Curve; Triglycerides

Nonalcoholic fatty liver disease is the most common cause of liver dysfunction in Western countries and an independent risk factor for atherosclerotic heart disease. Appropriate noninvasive parameters are lacking for optimal risk stratification of cardiovascular disease in these patients. We evaluated several recently discovered noninvasive parameters for atherosclerosis in patients with nonalcoholic fatty liver disease: epicardial fat thickness, aortic flow propagation velocity, and osteoprotegerin level.. Forty-one patients (27 men and 14 women; mean age, 37.9±8.9 years) with nonalcoholic fatty liver disease and 37 control subjects (17 men and 20 women; mean age, 34.5±8.6 years) were enrolled in this observational case-control study. Patients with nonalcoholic fatty liver disease diagnosed at a gastroenterology outpatient clinic were included. Patients with cardiac pathology other than hypertension were excluded. Epicardial fat thickness and aortic flow propagation velocity were measured by echocardiography. The serum concentration of osteoprotegerin was measured using a commercial enzyme-linked immunosorbent assay kit.. Nonalcoholic fatty liver disease patients exhibited a significantly lower aortic flow propagation velocity (155.17±30.00 vs. 179.00±18.14 cm/s, p=0.000) and significantly higher epicardial fat thickness (0.51±0.25 vs. 0.29±0.09 cm, p=0.000) than control subjects. Osteoprotegerin levels were higher, but not significant, in patients with nonalcoholic fatty liver disease (28.0±13.0 vs. 25.2±10.8 pg/mL, p=0.244). Binary logistic regression analysis showed that aortic flow propagation velocity (OR, -0.973; 95% CI, 0.947-0.999) and waist circumference (OR, -1.191; 95% CI, 1.088-1.303) were independent predictors of nonalcoholic fatty liver disease.. In this study, epicardial fat thickness and osteoprotegerin level were higher and aortic flow propagation velocity was lower in patients with nonalcoholic fatty liver disease. Early detection of abnormal epicardial fat thickness and aortic flow propagation velocity may warrant a search for undetected cardiovascular disease in patients with nonalcoholic fatty liver disease.

Topics: Adipose Tissue; Adult; Atherosclerosis; Blood Flow Velocity; Case-Control Studies; Female; Humans; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Osteoprotegerin; Pericardium; Risk Factors

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in hepatocytes. The role of SENP3 in lipid metabolism, particularly NAFLD, is unclear. Our results showed that hepatic SENP3 was up-regulated in NAFLD patients and an animal model in vivo and after loading hepatocytes with free fatty acids (FFA) in vitro. Intracellular lipid accumulation was determined in SENP3 silenced or overexpressed hepatocytes with/without FFA in vitro. Confirming a role for SENP3, gene silencing was associated in vitro with amelioration of lipid accumulation and overexpression with enhancement of lipid accumulation. SENP3 related genes in NAFLD were determined in vitro using RNA-Seq. Eleven unique genes closely associated with lipid metabolism were generated using bioinformatics. Three selected genes (apoe, a2m and tnfrsf11b) were verified in vitro, showing apoe, a2m and tnfrsf11b were regulated by SENP3 with FFA stimulation. Intrahepatic and circulating APOE, A2M and TNFRSF11B were elevated in NAFLD compared with controls. These data demonstrate the important role of SENP3 in lipid metabolism during the development of NAFLD via downstream genes, which may be useful information in the development of NAFLD. The precise role of SENP3 in NAFLD will be investigated using liver-specific conditional knockout mice in future studies.

Topics: alpha-Macroglobulins; Animals; Apolipoproteins E; Case-Control Studies; Cell Line; Cysteine Endopeptidases; Hepatocytes; Humans; Lipid Metabolism; Liver; Male; Non-alcoholic Fatty Liver Disease; Osteoprotegerin; Rats, Sprague-Dawley

This study was designed to evaluate carotid intima media thickness (CIMT) and serum osteoprotegerin (OPG) levels in nonalcoholic fatty liver disease (NAFLD) in comparison to healthy controls and to investigate factors predicting the CIMT increase.. A total of 60 outpatients [median (min-max) age 44.5 (24.0-65.0) years, 63.3% were females] diagnosed with NAFLD via ultrasonography performed during their admission to our hospital for any reason and 30 control subjects [median (min-max) age 39.5 (24.0-57.0) years, 73.3% were females] with normal liver echogenicity in ultrasonography were included in this study. Data on demographic characteristics, anthropometric measurements, biochemical and hematological tests, CIMT measurement, serum levels for OPG, and predictive factors for the CIMT increase were collected.. Median (min-max) CIMT [0.60 (0.40-1.10) vs. 0.50 (0.30-0.60), P<0.001) and OPG (pg/mL) [65.0 (18.1-272.8) vs. 32.0 (10.1-82.3), P<0.001] levels were significantly higher in NAFLD patients compared to controls, while there was a significant positive correlation between CIMT and serum OPG (r=0.42, P<0.001). Mean CIMT value was determined to increase significantly by 0.001 cm (P=0.001) for each 1 pg/mL of increase in OPG levels, by 0.103 cm (P<0.001) in case of concomitant NAFLD (P<0.001), and by 0.006 cm (P<0.001) for each 1 pg/mL of increase in urea levels.. Our findings indicate higher levels of serum OPG and CIMT in patients with NAFLD compared to controls along with a positive correlation between serum OPG and CIMT levels. High levels of serum OPG, presence of NAFLD, and high levels of serum urea seem to be the independent risk factors predictive for the CIMT increase.

Topics: Adult; Aged; Anthropometry; Carotid Intima-Media Thickness; Case-Control Studies; Female; Humans; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Osteoprotegerin; Outpatients; Predictive Value of Tests; Risk Factors; Urea

Although liver biopsy remains the best diagnostic standard for nonalcoholic steatohepatitis (NASH), non-invasive tests are eagerly awaited. In this study, we sought to develop a support vector machine (SVM) algorithm to discriminate with high accuracy between subjects with NASH and controls using a blood-based biomarker panel.. A total of 17 biomarkers were measured by commercially available enzyme-linked immunosorbent assays in 136 serum samples from patients with biopsy-proven NASH (n = 60) and subjects with normal ALT and no evidence of fatty liver on ultrasound (n = 76). The database was randomly divided (1:1 fashion) into a discovery set for classification training and in a validation set of the chosen biomarkers in blinded samples. Multivariate analysis was performed by means of SVM.. After the identification of a group of three most discriminative biomarkers (osteoprotegerin, fibroblast growth factor 21, and M30) in the discovery set, the application of SVM to the validation test resulted in a 92.5% sensitivity and 84.1% specificity for distinguishing subjects with NASH from controls.. A targeted biomarker profiling combined with a SVM-based pattern identification approach may allow the identification of patients with NASH with clinically relevant accuracy and validity.

Topics: Biomarkers; Body Mass Index; Cohort Studies; Enzyme-Linked Immunosorbent Assay; Fatty Liver; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Male; Middle Aged; Multivariate Analysis; Non-alcoholic Fatty Liver Disease; Osteoprotegerin; Sensitivity and Specificity