Wei Shizhang, He Tingting, Zhao Xu, Jing Manyi, Li Haotian, Chen Lisheng, Zheng Ruimao, Zhao Yanling
Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University, Beijing, China.
Department of Pharmacy, Chinese PLA General Hospital, Beijing, China.
Front Pharmacol. 2023 May 22;14:1197847. doi: 10.3389/fphar.2023.1197847. eCollection 2023.
Farnesoid X receptor (FXR) is a key metabolic target of bile acids (BAs) and is also a target for drugs against several liver diseases. However, the contribution of FXR in the pathogenesis of cholestasis is still not fully understood. The purpose of this study is to provide a comprehensive insight into the metabolic properties of FXR-involved cholestasis in mice. In this study, an alpha-naphthylisothiocyanate (ANIT)-induced cholestasis mouse model and FXR mice were established to investigate the effect of FXR on cholestasis. The effect of FXR on liver and ileal pathology was evaluated. Simultaneously, Untargeted metabolomics combined with 16s rRNA gene sequencing analysis was applied to reveal the involvement of FXR in the pathogenesis of cholestasis. The results showed that ANIT (75 mg/kg) induced marked cholestasis in WT and FXR -/- mice. It is noteworthy that FXR mice developed spontaneous cholestasis. Compared with WT mice, significant liver and ileal tissue damage were found. In addition, 16s rRNA gene sequencing analysis revealed gut microbiota dysbiosis in FXR-/- mice and ANIT-induced cholestasis mice. Differential biomarkers associated with the pathogenesis of cholestasis caused by FXR knockout were screened using untargeted metabolomics. Notably, _ _FI9785 has a high correlation with the differential biomarkers associated with the pathogenesis and progression of cholestasis caused by FXR knockout. Our results implied that the disorder of the intestinal flora caused by FXR knockout can also interfere with the metabolism. This study provides novel insights into the FXR-related mechanisms of cholestasis.
法尼酯X受体（FXR）是胆汁酸（BAs）的关键代谢靶点，也是治疗多种肝脏疾病药物的作用靶点。然而，FXR在胆汁淤积发病机制中的作用仍未完全明确。本研究旨在全面深入了解FXR参与的小鼠胆汁淤积的代谢特性。在本研究中，建立了α-萘异硫氰酸酯（ANIT）诱导的胆汁淤积小鼠模型和FXR基因敲除小鼠，以研究FXR对胆汁淤积的影响。评估了FXR对肝脏和回肠病理的影响。同时，应用非靶向代谢组学结合16s rRNA基因测序分析，以揭示FXR在胆汁淤积发病机制中的作用。结果显示，ANIT（75mg/kg）在野生型（WT）小鼠和FXR基因敲除小鼠中均诱导了明显的胆汁淤积。值得注意的是，FXR基因敲除小鼠出现了自发性胆汁淤积。与WT小鼠相比，发现了明显的肝脏和回肠组织损伤。此外，16s rRNA基因测序分析揭示了FXR基因敲除小鼠和ANIT诱导的胆汁淤积小鼠肠道微生物群失调。使用非靶向代谢组学筛选了与FXR基因敲除引起的胆汁淤积发病机制相关的差异生物标志物。值得注意的是，__FI9785与FXR基因敲除引起的胆汁淤积发病机制和进展相关的差异生物标志物高度相关。我们的结果表明，FXR基因敲除引起的肠道菌群紊乱也会干扰代谢。本研究为FXR相关的胆汁淤积机制提供了新的见解。
