非胆汁酸法尼醇 X 受体激动剂曲匹凡可通过调节肠-肝轴有力抑制胆汁淤积性肝损伤和纤维化。
A nonbile acid farnesoid X receptor agonist tropifexor potently inhibits cholestatic liver injury and fibrosis by modulating the gut-liver axis.
机构信息
Division of Pediatric Gastroenterology and Nutrition, Xin Hua hosiptal, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Pediatric Surgery, Xin Hua hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
出版信息
Liver Int. 2021 Sep;41(9):2117-2131. doi: 10.1111/liv.14906. Epub 2021 May 18.
BACKGROUND & AIMS: Tropifexor (TXR) is a novel nonbile acid that acts as an agonist of farnesoid X receptor (FXR). TXR is currently in Phase 2 trials for the treatment of non-alcoholic steatohepatitis (NASH). Herein, we report the impact of TXR on in a piglet model in which cholestatic liver damage and fibrosis where induced by bile duct ligation (BDL).
METHODS
The piglets received BDL and TXR for 2 wk. Hepatic, portal and colonic bile acid and amino acid profiles and gut microbiome were analysed. Portal fibroblast growth factor (FGF) 19 levels were measured using an enzyme-linked immunosorbent assay (ELISA).
RESULTS
We first showed that bile acid metabolism and signalling are dysfunctional in patients with biliary atresia. Next, we observed that TXR potently suppresses BDL-induced liver injury, fibrosis and ductular reaction in piglets. Within the ileum, TXR enhances FGF19 expression and subsequently increases portal FGF19 levels. In the liver, TXR promotes the expression of small heterodimer partner (SHP) and inhibits cholesterol 7α-hydroxylase (CYP7A1). Additionally, TXR increases the abundance of bile acid-biotransforming bacteria in the distal ileum and alters the composition of amino acids in the colon. Lastly, TXR ameliorates intestinal barrier injury in piglets subjected to BDL.
CONCLUSION
TXR potently ameliorated cholestatic liver injury and fibrosis by modulating the gut-liver axis in piglets. It supports the clinical evaluation of TXR as a therapeutic strategy for cholestatic liver diseases, such as biliary atresia.
背景与目的
Tropifexor（TXR）是一种新型非胆酸类药物，作为法尼醇 X 受体（FXR）激动剂发挥作用。TXR 目前正在进行治疗非酒精性脂肪性肝炎（NASH）的 2 期临床试验。在此，我们报告了 TXR 对胆总管结扎（BDL）诱导的胆汁淤积性肝损伤和纤维化的仔猪模型的影响。
方法
仔猪接受 BDL 和 TXR 治疗 2 周。分析肝、门脉和结肠胆汁酸和氨基酸谱以及肠道微生物组。使用酶联免疫吸附测定（ELISA）测量门脉成纤维细胞生长因子（FGF）19 水平。
结果
我们首先表明胆汁酸代谢和信号转导在胆道闭锁患者中存在功能障碍。接下来，我们观察到 TXR 可有效抑制仔猪 BDL 诱导的肝损伤、纤维化和胆管反应。在回肠中，TXR 增强 FGF19 的表达，随后增加门脉 FGF19 水平。在肝脏中，TXR 促进小异二聚体伴侣（SHP）的表达并抑制胆固醇 7α-羟化酶（CYP7A1）。此外，TXR 增加了回肠远端胆汁酸转化细菌的丰度，并改变了结肠中氨基酸的组成。最后，TXR 改善了 BDL 仔猪的肠道屏障损伤。
结论
TXR 通过调节仔猪的肠-肝轴，强力改善胆汁淤积性肝损伤和纤维化。它支持将 TXR 作为胆汁淤积性肝病（如胆道闭锁）的治疗策略进行临床评估。
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