Bicyclol Alleviates Signs of BDL-Induced Cholestasis by Regulating Bile Acids and Autophagy-Mediated HMGB1/p62/Nrf2 Pathway

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.

Detrimental Role of CXCR3 in α-Naphthylisothiocyanate- and Triptolide-Induced Cholestatic Liver Injury

“…The concentrations of free BAs α-MCA and β-MCA were not altered in WT mice but markedly increased in CXCR3-deficient mice (Figures C and S1B). α-MCA and β-MCA are hydrophilic BAs, and upregulation of their levels promotes BA excretion, thereby reducing the accumulation and damage from toxic BAs . Triptolide administration also significantly increased the hepatic concentrations of HDCA, CDCA, and DCA in WT mice, whereas their concentrations were downregulated in CXCR3 –/– mice compared to WT mice (Figures C and S1B).…”

“…α-MCA and β-MCA are hydrophilic BAs, and upregulation of their levels promotes BA excretion, thereby reducing the accumulation and damage from toxic BAs. 28 Triptolide administration also significantly increased the hepatic concentrations of HDCA, CDCA, and DCA in WT mice, whereas their concentrations were downregulated in CXCR3 −/− mice compared to WT mice (Figures 4C and S1B). Therefore, triptolide-induced dysregulated hepatic BAs were restored by CXCR3 deficiency with varying degrees and CXCR3 was involved in the perturbation of BA homeostasis induced by triptolide.…”

Bicyclol attenuates high fat diet-induced non-alcoholic fatty liver disease/non-alcoholic steatohepatitis through modulating multiple pathways in mice

“…Pharmacological studies displayed that bicyclol had obvious protective effects against hepatocyte injury caused by tetracycline, alcoholic and non-alcoholic fatty liver associated with cell apoptosis, endoplasmic reticulum (ER), and oxidative stress (Yao et al, 2016;Jia et al, 2022). Not only that, bicyclol intervention attenuated hepatocyte injury by moderating bile acid-mediated pathways (α-MCA/β-MCA) and regulating autophagy-related pathways (HMGB1/p62/Nrf2) (Zhao J et al, 2021;Zhao et al, 2022). Extensive pharmacological properties highlight the potential of bicyclol as a therapeutic agent of NAFLD.…”

Bacteroides uniformis regulates TH17 cell differentiation and alleviates chronic colitis by producing alpha-muricholic acid

“…Nevertheless, host enzyme may be involved in this process. In addition, bicyclol reduces liver injury in mice by increasing the levels of α-MCA, regulating bile acid metabolism and improving histopathological parameters 44 . However, it is unknown whether α-MCA can alleviate in ammation through TH17 cells.…”