Bile acid (BA) homeostasis is vital for various physiological processes, whereas its disruption underlies cholestasis. The farnesoid X receptor (FXR) is a master regulator of BA homeostasis via the ileal fibroblast growth factor (FGF)15/19 endocrine pathway, responding to postprandial or abnormal transintestinal BA flux. However, the de novo paracrine signal mediator of hepatic FXR, which governs the extent of BA synthesis within the liver in non-postprandial or intrahepatic cholestatic conditions, remains unknown. We identified hepatic Fgf4 as a direct FXR target that paracrinally signals to downregulate Cyp7a1 and Cyp8b1. The effect of FXR-FGF4 is mediated by an uncharted intracellular FGF receptor 4 (FGFR4)-LRH-1 signaling node. This liver-centric pathway acts as a first-line checkpoint for intrahepatic and transhepatic BA flux upstream of the peripheral FXR-FGF15/19 pathway, which together constitutes an integral hepatoenteric control mechanism that fine-tunes BA homeostasis, counteracting cholestasis and hepatobiliary damage. Our findings shed light on potential therapeutic strategies for cholestatic diseases.

中文翻译：

---

在胆汁淤积应激下，肝脏 FXR-FGF4 是通过 FGFR4-LRH-1 信号节点实现胆汁酸稳态所必需的


胆汁酸 （BA） 稳态对各种生理过程至关重要，而它的破坏是胆汁淤积的基础。法尼醇 X 受体 （FXR） 是通过回肠成纤维细胞生长因子 （FGF）15/19 内分泌途径的 BA 稳态的主要调节因子，对餐后或异常的经肠 BA 通量做出反应。然而，肝脏 FXR 的新发旁分泌信号介质（在非餐后或肝内胆汁淤积情况下控制肝脏内 BA 合成的程度）仍然未知。我们确定肝脏 Fgf4 是直接的 FXR 靶标，其旁分泌信号下调 Cyp7a1 和 Cyp8b1。FXR-FGF4 的作用是由未知的细胞内 FGF 受体 4 （FGFR4）-LRH-1 信号转导节点介导的。这种以肝脏为中心的通路是外周 FXR-FGF15/19 通路上游肝内和肝跨肝 BA 通量的一线检查点，它们共同构成了一个完整的肝肠控制机制，可微调 BA 稳态，抵消胆汁淤积和肝胆损伤。我们的研究结果揭示了胆汁淤积性疾病的潜在治疗策略。