温州医科大学黄志锋等研究人员合作发现，肝脏FXR-FGF4通过FGFR4-LRH-1信号节点在胆汁淤积应激下维持胆汁酸稳态。该研究于2024年10月10日在线发表于国际一流学术期刊《细胞—代谢》。

研究人员表示，胆汁酸（BA）稳态对多种生理过程至关重要，而其紊乱是胆汁淤积的根源。法尼醇X受体（FXR）通过回肠成纤维细胞生长因子（FGF）15/19内分泌通路调控BA稳态，以应对餐后或异常肠道胆汁酸通量。然而，非餐后或肝内胆汁淤积条件下，肝脏内FXR调控的胆汁酸合成范围的旁分泌信号介质仍未知。

研究人员发现肝脏Fgf4是FXR的直接靶基因，旁分泌信号通过下调Cyp7a1和Cyp8b1来实现其作用。FXR-FGF4的效果由一个未知的细胞内FGF受体4（FGFR4）-LRH-1信号节点介导。该以肝脏为中心的途径作为肝内和跨肝胆汁酸通量的第一道检查点，位于外周FXR-FGF15/19通路的上游。两者共同构成了精细调节BA稳态的肝肠控制机制，对抗胆汁淤积和肝胆损伤。

该研究为胆汁淤积性疾病的潜在治疗策略提供了新见解。

附：英文原文

Title: Hepatic FXR-FGF4 is required for bile acid homeostasis via an FGFR4-LRH-1 signal node under cholestatic stress

Author: Lintao Song, Yushu Hou, Da Xu, Xijia Dai, Jianya Luo, Yi Liu, Zhuobing Huang, Miaomiao Yang, Jie Chen, Yue Hu, Chuchu Chen, Yuli Tang, Zhiheng Rao, Jianjia Ma, Minghua Zheng, Keqing Shi, Chao Cai, Mingqin Lu, Ruqi Tang, Xiong Ma, Cen Xie, Yongde Luo, Xiaokun Li, Zhifeng Huang

Issue&Volume: 2024-10-10

Abstract: 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.

DOI: 10.1016/j.cmet.2024.09.008

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00372-3