Hepatic TLR4 signaling in obese NAFLD

Abstract

fatty liver disease occurs frequently in the setting of metabolic syndrome, but the factors leading to nonalcoholic steatohepatitis (NASH) are not fully understood. This study investigated Toll-like receptor 4 (TLR4) signaling in human liver with the goal of delineating whether activation of this pathway segregates those with nonalcoholic fatty liver from those with NASH. Experiments were performed using liver biopsy tissue obtained from class III obese subjects undergoing bariatric surgery, and extended to an immortalized human hepatocyte HepaRG cell line and primary human hepatocytes. The bacterial endotoxin lipopolysaccharide (LPS) and total free fatty acid levels were significantly increased in plasma of NASH patients. TLR4 mRNA levels were significantly increased in subjects with NASH compared with NAFL as was interferon regulatory factor (IRF) 3 in the myeloid differentiation factor 88-independent signaling pathway. In HepaRG cells, nuclear factor-B (NF-B) nuclear translocation and functional activity increased following treatment with the fatty acid, palmitate, and following exposure to LPS compared with hepatocytes stimulated with a lipogenic treatment that induced de novo lipogenesis. Palmitate and LPS induction of NF-B activity was partially attenuated by chemical-or small-interfering RNA-mediated inhibition of TLR4. Expression of TLR4 and its downstream mediators was upregulated with palmitate and LPS. Similar results were observed using primary human hepatocytes from a lean donor. Interestingly, NF-B activity assays showed obese donor hepatocytes were resistant to chemical TLR4 inhibition. In conclusion, TLR4 expression is upregulated in a large cohort of NASH patients, compared with those with NAFL, and this occurs within the setting of increased LPS and fatty acids. nonalcoholic steatohepatitis; palmitate; Toll-like receptor 4; nuclear factor-

Type I interferon responses drive intrahepatic T cells to promote metabolic syndrome

“…Consistent with other recent reports, we identified enhanced hepatic gene expression of key IFN-I regulatory factors, IRF3 and IRF7, during DIO and/or NAFLD, (36, 37). While previous studies used knock-out mice to examine the role of individual IRFs associated with IFN-I pathways and their effects on glucose metabolism (36, 38, 39), we utilized HFD-fed IFNαR1 knock-out mice to broadly eliminate IFN-I and showed that IFN-I responses, as a whole, promote obesity-related IR.…”

Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism

“…59 In addition, TLR4 and IRF3 expression (MyD88 pathway) appear to be upregulated in the liver of patients suffering from NASH versus NAFLD, which is associated with increased lipopolysaccharides (LPS) and fatty acid levels. 60 In accordance with the bile acid profile, we found that specific bacterial genera were different between LKO and WT mice during normal chow diet. Sutterella and Allobaculum were decreased in LKO-CT mice and HFD-fed mice.…”

Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation

“…It has been demonstrated that bacterial LPS enhances hepatic fatty acid synthesis, while inhibiting fatty acid oxidation in liver by reducing FABP gene expression [67]. Thereby, TLR-4 expression upregulation correlated with increased LPS and fatty acids, and associated with induced de novo lipogenesis in NAFLD patients [68]. Thus, TLR-4 plays a critical role in glucose and lipid metabolism and, in turn, free fatty acids have been reported as agonists for TLR-4 [69,70], inducing activation of inflammatory transcription factors as NF-B [69].…”