Eritoran Attenuates Hepatic Inflammation and Fibrosis in Mice with Chronic Liver Injury.
Yun-Cheng HsiehKuei-Chuan LeePei-Shan WuTeh-Ia HuoYi-Hsiang HuangMing-Chih HouHan-Chieh LinPublished in: Cells (2021)
Toll-like receptor 4 (TLR4) signaling plays a key role in liver inflammation and fibrosis. The therapeutic effects of eritoran, a TLR4 antagonist, in mice with chronic liver injury remained unclear. C57BL/6 mice were fed a fast-food diet (FFD) or treated with carbon tetrachloride (CCl4) to induce chronic liver injury. Eritoran (10 mg/kg) or a vehicle was randomly intraperitoneally administered to the FFD-fed mice and the CCl4-injured mice. Primary mouse liver cells were cultured with lipopolysaccharide (LPS) or eritoran. In both FFD and CCl4 mouse models, eritoran significantly reduced serum ALT levels and decreased hepatic inflammatory cell infiltration without altering hepatic steatosis. Additionally, eritoran attenuated liver fibrosis by decreasing hepatic stellate cells (HSCs) activation and the abundance of α-smooth muscle actin and transforming growth factor-β1. Hepatic TLR4 downstream signaling including MyD88 expression, NF-κB p65 nuclear translocation, p38 and JNK phosphorylation were successfully inhibited by eritoran. In the in vitro study, LPS-induced nuclear translocation of NF-κB in primary HSCs and Kupffer cells was significantly suppressed by eritoran. In conclusion, eritoran attenuated hepatic inflammation and fibrosis by inhibition of the TLR4 signaling pathway in mice with chronic liver injury. Eritoran may serve as a potential drug for chronic liver disease.
Keyphrases
- liver injury
- drug induced
- toll like receptor
- inflammatory response
- lps induced
- induced apoptosis
- signaling pathway
- nuclear factor
- oxidative stress
- high fat diet induced
- liver fibrosis
- immune response
- transforming growth factor
- cell cycle arrest
- pi k akt
- epithelial mesenchymal transition
- adverse drug
- stem cells
- cell death
- insulin resistance
- poor prognosis
- emergency department
- cell proliferation
- single cell
- adipose tissue
- skeletal muscle
- physical activity
- type diabetes
- binding protein
- human health
- weight loss
- anti inflammatory