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

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

doi:10.1016/j.cmet.2024.09.008

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

Cell Metab. 2024 Oct 4:S1550-4131(24)00372-3. doi: 10.1016/j.cmet.2024.09.008. Online ahead of print.

Authors

Lintao Song¹, Yushu Hou², Da Xu², Xijia Dai², Jianya Luo², Yi Liu², Zhuobing Huang², Miaomiao Yang², Jie Chen², Yue Hu², Chuchu Chen², Yuli Tang², Zhiheng Rao², Jianjia Ma², Minghua Zheng³, Keqing Shi⁴, Chao Cai⁵, Mingqin Lu⁵, Ruqi Tang⁶, Xiong Ma⁶, Cen Xie⁷, Yongde Luo⁸, Xiaokun Li⁹, Zhifeng Huang¹⁰

Affiliations

¹ Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: lintaosong@wmu.edu.cn.
² Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
³ NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
⁴ Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
⁵ Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
⁶ Division of Gastroenterology and Hepatology, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China.
⁷ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁸ Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
⁹ Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: xiaokunli@wmu.edu.cn.
¹⁰ Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), National Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: hzf@wmu.edu.cn.

PMID: 39393353
DOI: 10.1016/j.cmet.2024.09.008

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.

Keywords: FGF4; FGFR4-LRH-1 pathway; FXR; bile acid homeostasis; cholestasis.