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Bile Duct Ligation in Mice: Induction of Inflammatory Liver Injury and Fibrosis by Obstructive Cholestasis
Published on: February 10, 2015
Notoginsenoside R1 alleviates cholestatic liver fibrosis through modulation of the intestinal FXR-FGF15 axis and bile
Min Yang1, Qiaolian Ma1, Bairong Yang2
1Yunnan Key Laboratory of Sustainable Utilization of Panax notoginseng Resources, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China; Center for Translational Research in Clinical Medicine, Medical School, Kunming University of Science and Technology, Kunming 650500, China.
Abstract:
Cholestatic liver fibrosis is a progressive liver disease characterized by disrupted bile acid homeostasis, persistent inflammation, and excessive extracellular matrix deposition, for which effective pharmacological therapies remain limited. Although Notoginsenoside R1 (NG-R1), a major bioactive saponin from Panax notoginseng, exhibits anti-fibrotic activity in experimental liver injury, its disease-specific mechanism in cholestatic liver fibrosis remains unclear. Here, C57BL/6 mice subjected to bile duct ligation (BDL) were treated with NG-R1 for 14 days. NG-R1 significantly improved liver function, alleviated hepatic and intestinal injury, suppressed inflammatory responses, and attenuated liver fibrosis. Mechanistically, NG-R1 restored intestinal FXR-FGF15 endocrine signaling by enhancing ileal FXR expression and increasing circulating FGF15 levels, thereby contributing to improved gut-liver bile acid homeostasis. Consistent with these changes, hepatic CYP7A1 expression was reduced, bile acid transporters were coordinately regulated (upregulation of BSEP and OSTα/β and downregulation of NTCP), and hepatic bile acid accumulation was decreased. In Caco-2 cells, NG-R1 increased the expression of FXR, FGF19, Occludin, and ZO-1, whereas these effects were partially abolished by the FXR antagonist guggulsterone, supporting direct activation of intestinal FXR signaling. NG-R1 also partially corrected BDL-induced gut microbial dysbiosis. Collectively, these findings suggest that modulation of the intestinal FXR-FGF15 endocrine axis and restoration of gut-liver bile acid homeostasis contribute to the protective effects of NG-R1 against cholestatic liver fibrosis, providing a mechanistic basis for its therapeutic potential.
Insights
Notoginsenoside R1 (NG-R1) treats cholestatic liver fibrosis by restoring gut-liver bile acid balance via the intestinal FXR-FGF15 pathway. This reduces inflammation and fibrosis, offering therapeutic potential.
Area of Science:
- Hepatology
- Pharmacology
- Gastroenterology
Background:
- Cholestatic liver fibrosis lacks effective treatments and involves bile acid disruption.
- Notoginsenoside R1 (NG-R1) shows anti-fibrotic effects, but its mechanism in cholestasis is unknown.
Purpose of the Study:
- To investigate the therapeutic mechanism of NG-R1 in cholestatic liver fibrosis.
Main Methods:
- Mice underwent bile duct ligation (BDL) and received NG-R1 treatment.
- Liver function, injury, inflammation, and fibrosis were assessed.
- Intestinal FXR-FGF15 signaling, bile acid homeostasis, and gut microbiota were analyzed.
Main Results:
- NG-R1 improved liver function, reduced hepatic and intestinal injury, and attenuated fibrosis.
- NG-R1 restored intestinal FXR-FGF15 signaling, enhancing gut-liver bile acid homeostasis.
- NG-R1 modulated bile acid transporters, decreased hepatic bile acid accumulation, and corrected gut dysbiosis.
Conclusions:
- NG-R1 protects against cholestatic liver fibrosis by modulating the intestinal FXR-FGF15 axis.
- Restoration of gut-liver bile acid homeostasis is a key mechanism for NG-R1's protective effects.
- NG-R1 demonstrates therapeutic potential for cholestatic liver fibrosis.
