作者
Lintao Song,Yushu Hou,Da Xu,Xijia Dai,Jianya Luo,Yi Liu,Zhiming Huang,Miaomiao Yang,Jie Chen,Yongmei Hu,Chen Chuchu,Yuli Tang,Zhiheng Rao,Jianjia Ma,Ming‐Hua Zheng,Keqing Shi,Chao Cai,Mingqin Lu,Ruqi Tang,Xiong Ma,Cen Xie,Yongde Luo,Xiaokun Li,Zhifeng Huang
摘要
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.