Quercetin attenuates the activation of hepatic stellate cells and liver fibrosis in mice through modulation of HMGB1-TLR2/4-NF-κB signaling pathways.
This study aimed to investigate the effects of quercetin on liver fibrogenesis in mice and to elucidate the underlying molecular mechanisms. Mice were administered with carbon tetrachloride (CCl4) for eight weeks to induce liver fibrosis and concomitantly orally treated with quercetin (50mgkg-1day-1). Here, we demonstrated that quercetin dramatically ameliorated liver injury, inflammation, and hepatic fibrogenesis induced by CCl4. Quercetin also inhibited the activation of hepatic stellate cells (HSC) in vivo and in vitro, as evaluated by α-smooth muscle actin (α-SMA) expression, which is a specific marker of HSC activation. Moreover, reduced fibrosis was associated with decreased high-mobility group box 1 (HMGB1), toll like receptor (TLR) 2 and TLR4 genes, and protein expression. Quercetin also inhibited the cytoplasmic translocation of HMGB1 in hepatocytes of fibrotic livers. Further investigation demonstrated that quercetin treatment significantly attenuated CCl4-induced nuclear translocation of the nuclear factor-κB (NF-κB) p65 and inhibited degradation of IκBα (an inhibitor of NF-κB) expression in the liver compared with vehicle-treated fibrotic mice. Considered together, our data indicate that quercetin has hepatoprotective and anti-fibrotic effects in animal models of liver fibrosis, the mechanism of which may be involved in modulating the HMGB1-TLR2/4-NF-κB signaling pathways.
Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai Institute of Liver Diseases, Shanghai, China; Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: li.xi@zs-hospital.sh.cn.
Xi
X
Li
Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai Institute of Liver Diseases, Shanghai, China. Electronic address: jin.qianwen@zs-hospital.sh.cn.
Qianwen
Q
Jin
Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai Institute of Liver Diseases, Shanghai, China. Electronic address: yao.qunyan@zs-hospital.sh.cn.
Qunyan
Q
Yao
Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai Institute of Liver Diseases, Shanghai, China. Electronic address: xu.beili@zs-hospital.sh.cn.
Beili
B
Xu
Laboratory Animal Center, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: li.zheng1@zs-hospital.sh.cn.
Zheng
Z
Li
Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai Institute of Liver Diseases, Shanghai, China. Electronic address: tu.chuantao@zs-hospital.sh.cn.
Chuantao
C
Tu
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000187:drug effects*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology*; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D016328:NF-kappa B; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D011794:Quercetin; D002251:Carbon Tetrachloride
Hepatic stellate cells; High-mobility group box 1; Liver fibrosis; Nuclear factor kappa-B; Quercetin; Toll like receptors