Role of serum toll-like receptors 2 and 4 in non-alcoholic steatohepatitis and liver fibrosis.
Cengiz Mustafa,Ozenirler Seren,Elbeg Sehri
Journal of gastroenterology and hepatology
BACKGROUND AND AIM:Non-alcoholic fatty liver disease is a common cause of chronic liver disease, including non-alcoholic steatohepatitis (NASH). Our aim was to investigate whether serum toll-like receptors 2 and 4 (TLR2 and TLR4) levels are correlated with NASH and able to predict liver fibrosis, as well as to compare these markers with other non-invasive fibrosis scores (aspartate aminotransferase [AST] to alanine aminotransferase ratio, AST to platelet ratio index, fibrosis index, fibrosis 4, and fibrosis cirrhosis index). METHODS:Serum samples were obtained from consecutive biopsy proven NASH patients and healthy controls. Serum TLR2 and TLR4 were measured using ELISA. Stage of fibrosis was evaluated using the Brunt Criteria. The different non-invasive fibrosis scores were compared using areas under the curve. RESULTS:Fifty-seven patients with NASH and 57 healthy individuals were enrolled in the study. Serum TLR2 levels were not significantly different between the healthy controls and NASH patients. The medians were 3.88 ng/mL ± 0.29 versus 3.81 ng/mL ± 0.32, respectively (P = 0.587). In comparing the levels of TLR4 between groups, the medians were 1.05 ng/mL ± 0.13 versus 1.46 ng/mL ± 0.27, respectively (P < 0.001). In NASH patients, the levels of serum TLR4 increased with the stage of fibrosis: TLR4 medians were F0:1.01, F1:1.46, F2:2.14, F3:3.74, F4:5.83 (P < 0.001). TLR4 produced AUCs for ≥ F1, ≥ F2, and ≥ F3 of 0.862, 0.810, and 0.905, respectively (P < 0.001). TLR4 levels were more predictive than other non-invasive fibrosis scores in liver fibrosis. CONCLUSION:Serum TLR4 levels but not TLR2 were elevated in NASH patients in comparison with healthy controls. And in NASH patients, serum TLR4 levels both correlated with and were able to predict liver fibrosis.
Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease.
Miura Kouichi,Ohnishi Hirohide
World journal of gastroenterology
Emerging data have shown a close association between compositional changes in gut microbiota and the development of nonalcoholic fatty liver disease (NAFLD). The change in gut microbiota may alter nutritional absorption and storage. In addition, gut microbiota are a source of Toll-like receptor (TLR) ligands, and their compositional change can also increase the amount of TLR ligands delivered to the liver. TLR ligands can stimulate liver cells to produce proinflammatory cytokines. Therefore, the gut-liver axis has attracted much interest, particularly regarding the pathogenesis of NAFLD. The abundance of the major gut microbiota, including Firmicutes and Bacteroidetes, has been considered a potential underlying mechanism of obesity and NAFLD, but the role of these microbiota in NAFLD remains unknown. Several reports have demonstrated that certain gut microbiota are associated with the development of obesity and NAFLD. For instance, a decrease in Akkermansia muciniphila causes a thinner intestinal mucus layer and promotes gut permeability, which allows the leakage of bacterial components. Interventions to increase Akkermansia muciniphila improve the metabolic parameters in obesity and NAFLD. In children, the levels of Escherichia were significantly increased in nonalcoholic steatohepatitis (NASH) compared with those in obese control. Escherichia can produce ethanol, which promotes gut permeability. Thus, normalization of gut microbiota using probiotics or prebiotics is a promising treatment option for NAFLD. In addition, TLR signaling in the liver is activated, and its downstream molecules, such as proinflammatory cytokines, are increased in NAFLD. To data, TLR2, TLR4, TLR5, and TLR9 have been shown to be associated with the pathogenesis of NAFLD. Therefore, gut microbiota and TLRs are targets for NAFLD treatment.
Key genes associated with non-alcoholic fatty liver disease and acute myocardial infarction.
Dai Weiran,Sun Yue,Jiang Zhiyuan,Du Kuan,Xia Ning,Zhong Guoqiang
Medical science monitor : international medical journal of experimental and clinical research
BACKGROUND With the increasing research on non-alcoholic fatty liver (NAFLD) and acute myocardial infarction (AMI), many evidences show a tight correlation between NAFLD and AMI, however the underlying pathophysiology is still not clear. This study was to identify the potential hub genes and pathways related to these two diseases via bioinformatic method. MATERIAL AND METHODS Gene Expression Omnibus (GEO) dataset GSE63067 of NAFLD patients and normal controls was downloaded from GEO database. The GSE60993 and GSE66360 datasets for AMI patients and healthy controls were also obtained. Differential expression genes (DEGs) of NAFLD and AMI datasets, accompanied with common genes between them were achieved. Further GO and KEGG enrichment analysis for common genes were performed. RESULTS To obtain the pathogenesis associated with both NAFLD and AMI, protein-protein interaction (PPI) network was constructed and the top ten hub genes (TLR2, LILRB2, CXCL1, FPR1, TLR4, TYROBP, MMP9, FCER1G, CLEC4D and CCR2) were selected with CONCLUSIONS The results of this study suggesting some novel genes may play an important role in the occurrence and progression NAFLD and AMI. But more experimental researches and clinical trials need to verify.
Increased Expression Profile and Functionality of TLR6 in Peripheral Blood Mononuclear Cells and Hepatocytes of Morbidly Obese Patients with Non-Alcoholic Fatty Liver Disease.
Arias-Loste María Teresa,Iruzubieta Paula,Puente Ángela,Ramos David,Santa Cruz Carolina,Estébanez Ángel,Llerena Susana,Alonso-Martín Carmen,San Segundo David,Álvarez Lorena,López Useros Antonio,Fábrega Emilio,López-Hoyos Marcos,Crespo Javier
International journal of molecular sciences
Current evidence suggests that gut dysbiosis drives obesity and non-alcoholic fatty liver disease (NAFLD) pathogenesis. Toll-like receptor 2 (TLR2) and TLR6 specifically recognize components of Gram-positive bacteria. Despite the potential implications of TLR2 in NAFLD pathogenesis, the role of TLR6 has not been addressed. Our aim is to study a potential role of TLR6 in obesity-related NAFLD. Forty morbidly obese patients undergoing bariatric surgery were prospectively studied. Cell surface expression of TLR2 and TLR6 was assessed on peripheral blood mononuclear cells (PBMCs) by flow cytometry. Freshly isolated monocytes were cultured with specific TLR2/TLR6 agonists and intracellular production of cytokines was determined by flow-cytometry. In liver biopsies, the expression of TLR2 and TLR6 was analyzed by immunohistochemistry and cytokine gene expression using RT-qPCR. TLR6 expression in PBMCs from non-alcoholic steatohepatitis (NASH) patients was significantly higher when compared to those from simple steatosis. The production of pro-inflammatory cytokines in response to TLR2/TLR6 stimulation was also significantly higher in patients with lobular inflammation. Hepatocyte expression of TLR6 but not that of TLR2 was increased in NAFLD patients compared to normal liver histology. Deregulated expression and activity of peripheral TLR6 in morbidly obese patients can mirror the liver inflammatory events that are well known drivers of obesity-related NASH pathogenesis. Moreover, TLR6 is also significantly overexpressed in the hepatocytes of NAFLD patients compared to their normal counterparts. Thus, deregulated TLR6 expression may potentiate TLR2-mediated liver inflammation in NAFLD pathogenesis, and also serve as a potential peripheral biomarker of obesity-related NASH.