thymosin-beta(4) and Non-alcoholic-Fatty-Liver-Disease

Thymosin beta 4 (Tβ4) can improve the liver fibrosis and reduce inflammation, while the role of Tβ4 in non-alcoholic fatty liver disease (NAFLD) whether mediated by ferroptosis remains unclear. A rat model of NAFLD was established on a high-fat diet (HFD), and rats were assigned ferroptosis inducer erastin and inhibitor Ferrostatin 1 (Fer-1). Subsequently, histopathology of the liver and the expression of ferroptosis-related genes in rat liver were detected. The steatosis of LO2 cells was induced by palmitic acid (PA) to reproduce the results of the rat experiment. The small interfering RNA (siRNA) was used to interfere with GPX4 expression to explore the influence on Tβ4 function. Tβ4 improved the inflammation, biochemical and lipid metabolism indexes, increased the antioxidant level, and inhibited abnormal accumulation of intracellular reactive oxygen species in HFD-induced NAFLD rats. Also, Tβ4 improved PA-induced LO2 damage and inhibited apoptosis of PA-induced LO2 cells. Both in vivo and in vitro, Tβ4 regulated expression of genes associated with ferroptosis, and Fer-1 treatment exaggerated the above effects of Tβ4, while erastin attenuated the protective effect of Tβ4. Moreover, siRNA GPX4 attenuated the protective effect of Tβ4 on the rat liver and on the mitochondrial membrane integrity of LO2 cells. Interfered expression of GPX4 with siRNA also regulated the expression of Bcl-2, Bax, Caspase-3 and SOD1, which attenuated therapeutic effect of Tβ4 on rat liver and LO2 cells. This study revealed that Tβ4 protects hepatocytes by inhibiting the GPX4-mediated ferroptosis pathway, which provides a new strategy and target for the treatment of NAFLD.

Topics: Animals; Ferroptosis; Non-alcoholic Fatty Liver Disease; Rats; Thymosin; Up-Regulation

non-alcoholic fatty liver disease (NAFLD) is the most common type of chronic liver injury worldwide. Some studies have shown that thymosin beta4 (Tβ4) is closely related to liver diseases. Nevertheless, only a few published studies have reported the relationship between Tβ4 and NAFLD. The purpose of this study was to evaluate the levels of Tβ4 in patients with NAFLD compared with controls and to validate their relationship in a larger cohort.. a total of 76 NAFLD patients and 130 healthy controls were included in the study. Serum levels of Tβ4, IL-6 and adiponectin were determined by ELISA. Serum glucose, insulin and lipids, as well as liver function were measured. Multivariate statistical analyses were performed via logistic regression modelling to determine the predictors with a significant relevance to NAFLD. The association between serum Tβ4 and study variables was tested using correlation coefficients calculations.. serum Tβ4 content was 3.20 ± 0.98 mg/l in NAFLD patients (n = 76) and 5.53 ± 1.24 mg/l in healthy controls (n = 130); the difference between the two groups was statistically significant (p = 0.000). Multivariate logistic regression analysis identified Tβ4 (OR = 0.343, 95% CI 0.240-0.491, p < 0.001), LDL (OR = 1.019, 95% CI 1.007-1.030, p = 0.001), ALT (OR = 1.021, 95% CI 1.001-1.041, p = 0.040) and IL-6 (OR = 1.443, 95% CI 1.079-1.929, p = 0.013) as independent predictors of NAFLD diagnosis. Serum Tβ4 levels had a significant negative correlation with total cholesterol, TG, AST, GGT and IL-6 (p < 0.05 for all) and the correlation coefficient values were -0.163, -0.253, -0.143, -0.245 and -0.155, respectively. Serum Tβ4 levels were positively correlated with serum adiponectin levels, with a correlation coefficient value of 0.143.. serum Tβ4 may play a defensive role in the development of NAFLD. Further studies are needed to confirm the role of Tβ4 in NAFLD.

Topics: Adiponectin; Alanine Transaminase; Aspartate Aminotransferases; Blood Glucose; Case-Control Studies; Female; gamma-Glutamyltransferase; Humans; Insulin; Interleukin-6; Lipids; Logistic Models; Male; Microfilament Proteins; Middle Aged; Non-alcoholic Fatty Liver Disease; Thymosin

The aim of the study was to determine whether serum thymosin beta4 (Tβ4) can be a useful noninvasive biomarker to differentiate between nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver (NAFL).. The study included 24 NAFL patients and 21 NASH patients. The levels of Tβ4, 8-hydroxydeoxyguanosine acid (8-OhdG), liver function parameters, blood lipid, and glucose were detected in the venous blood of all patients. The NAFLD histological activity score (NAS) was examined in biopsy specimens from all patients. Statistical analysis was performed in order to find differences between the two abovementioned groups. In addition, receiver operator characteristic (ROC) analyses for alanine aminotransferase (ALT) and Tβ4 levels were performed in NAFL and NASH patients and the cut-off value was determined. Associations between the variables were tested using correlation coefficient calculations. Statistical significance was set at a p value of < 0.05.. Serum Tβ4 content was 5.12 ± 1.87 mg/l in the NAFL group and 2.98 ± 1.35 mg/l in the NASH group (p < 0.001). Serum Tβ4 content and NAS, histological features of hepatic steatosis, lobular inflammation and ballooning, ALT, glucose and 8-OhdG levels were negatively correlated (p < 0.05 for all) in the NASH group. The correlation coefficient values were -0.530, -0.562, -0.574, -0.438, -0.446, -0.426 and -0.563, respectively. On the basis of ROC analysis, the best predictive Tβ4 cut-off value for detecting NASH was 3.94 mg/l (85.7% sensitivity and 79.2% specificity, which were higher than those of ALT).. Serum Tβ4 level can be used as a biomarker for the diagnosis of NASH and was negatively correlated with the oxidation state of the liver.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aspartate Aminotransferases; Biomarkers; Deoxyguanosine; Diagnosis, Differential; Female; Humans; Liver; Liver Function Tests; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Thymosin

The aim of the study was to detect the expression level of thymosin β4 (Tβ4) in serum and tissues of patients with chronic hepatitis B (CHB) combined nonalcoholic fatty liver disease (NAFLD). The effects of Tβ4 in hepatic steatosis, chronic inflammation, and fibrosis development in CHB combined NAFLD patients were also discussed. The study included 46 patients in the case group with CHB and NAFLD and 42 patients in the control group with CHB. ELISA was applied to detect serum Tβ4 and TNF-α level. Furthermore, the correlation analysis of Tβ4 levels with biochemical index, pathological index, and TNF-α level was performed. The Tβ4 immunohistochemical levels of different inflammation fibrosis levels were compared, and the correlation analysis with TNF expression was performed. The Tβ4 levels in patients with CHB combined NAFLD showed no statistical difference when compared to the control group. In patients with CHB combined NAFLD group, the Tβ4 level had no correlation with ALT, AST, TG, FGP, hepatitis B virus (HBV)-DNA levels, and fat grading, but had negative correlation with inflammation score and fibrosis score (P <0.01). The immunohistochemical results of hepatic tissues showed that the expression intensity of severe inflammation fibrosis group had statistical significance compared with that of slight group, and the Tβ4 expression both in serum and in liver tissue negatively correlated with TNF-α expression. Tβ4 could be involved in the regulation of chronic inflammation and fibrosis and plays a defense role in the disease progression of CHB combined NAFLD patients.

Topics: Adult; Female; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Thymosin; Tumor Necrosis Factor-alpha