Abstract
Cholestasis is a liver disease characterized by the accumulation of toxic bile salts, bilirubin, and cholesterol, resulting in hepatocellular damage. Recent findings have revealed several key steps of cholestasis liver injury including the toxicity of bile acids and accumulation of proinflammatory mediator. In this study, we investigated the protective effect of bicyclol in cholestasis caused by bile duct ligation (BDL), as well as relevant mechanisms. Bicyclol attenuated liver damage in BDL mice by increasing the levels of hydrophilic bile acid such as α-MCA and β-MCA, regulating bile acid-related pathways and improving histopathological indexes. High-mobility group box 1 (HMGB1) is an extracellular damage-associated molecular pattern molecule which can be used as biomarkers of cells and host defense. Bicyclol treatment decreased extracellular release of HMGB1. In addition, HMGB1 is also involved in regulating autophagy in response to oxidative stress. Bicyclol promoted the lipidation of LC3 (microtubule-associated protein 1 light chain 3)-Ⅱ to activate autophagy. The nuclear factor, E2-related factor 2 (Nrf2) and its antioxidant downstream genes were also activated. Our results indicate that bicyclol is a promising therapeutic strategy for cholestasis by regulating the bile acids and autophagy-mediated HMGB1/p62/Nrf2 pathway.
Highlights
Cholestasis is a pathological condition caused by obstruction or cessation of bile flow resulting in intrahepatic cholestasis and accompanied by cell injury, inflammatory infiltration, cell apoptosis, liver fibrosis, and even cirrhosis (Yokoda and Carey, 2019)
The serum aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), GGT, TBA, and total cholesterol (TC) levels increased in bile duct ligation (BDL) compared with the sham group (Figures 1A–F)
The results showed that NADPH: quinone oxidoreductase 1 (Nqo1) and heme oxygenase-1 (Hmox1) were upregulated in BDL and BDL + Bicyclol groups compared with the Sham group (Figures 6B,C)
Summary
Cholestasis is a pathological condition caused by obstruction or cessation of bile flow resulting in intrahepatic cholestasis and accompanied by cell injury, inflammatory infiltration, cell apoptosis, liver fibrosis, and even cirrhosis (Yokoda and Carey, 2019). The main drug treatment for chronic cholestatic liver injury is ursodeoxycholic acid (UDCA). A previous study found that primary bile acids conjugated with glycine or taurine were significantly increased in serum of patients with cholestasis liver injury (Woolbright et al, 2015). The conjugated groups affected the hydrophobicity of bile acids, where unconjugated was the most hydrophobic and glycine conjugated was more hydrophobic than taurine or sulphate conjugated (Ashby et al, 2018). The toxicity of BAs during obstructive cholestatic liver injury likely occurs because of biliary BAs leakage. Previous studies proved that biliary BAs at 0.5x dose resulted in significant hepatocyte necrosis (Woolbright et al, 2015)
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call