Disentangling Organ‐Specific Roles of Farnesoid X Receptor in Bile Acid and Glucolipid Metabolism

作者：Tingting Li, Chenyang Fu, Zhongzheng Tang, Changkun Li, Duanyi Hua, Bei Liu, Zheying Tao, Jie Yang, Li Zhang, Tingting Cheng, Shujie Wang, Guang Ning, Yanyun Gu · 发表于：Liver International · 年份：2025 · DOI：10.1111/liv.70027 · 被引用次数：10 · 研究领域：Drug Transport and Resistance Mechanisms、Gut microbiota and health、Liver Disease Diagnosis and Treatment

BACKGROUND AND AIMS: The farnesoid X receptor (FXR) is an attractive pharmaceutical target for metabolic dysfunction-associated steatotic liver disease (MASLD). However, its tissue-specific roles in energy metabolism remain controversial, hindering the development of effective therapies. To address this, new approaches are required. METHODS: A novel mouse model was developed to facilitate the re-expression of endogenous FXR in specific tissues on a global FXR-null background. Liver-specific and gut-specific FXR re-expression models were generated. Mice were subjected to a high-fat diet (HFD) for 12 weeks, after which metabolic indices, bile acid (BA) profiles, and gut microbiota composition were analysed. Antibiotic treatment was used to mimic germ-free conditions. RESULTS: The resistance of FXR-null mice to MASLD and most HFD-induced metabolic disorders, including increased body weight, adiposity, hepatic triglyceride (TG) accumulation, and hyperglycemia, was reversed by liver, but not gut, FXR re-expression. Gut FXR re-expression restored the increased intestinal TG absorption in FXR-null mice by limiting 12OH BA synthesis and inhibiting intestinal microsomal triglyceride transfer protein (MTTP). Moreover, gut FXR activity was essential for gut microbiota-driven promotion of diet-induced obesity (DIO) and MASLD. CONCLUSIONS: Our study overcomes the limitations of traditional tissue-specific knockout models, providing a more comprehensive understanding of FXR's complex roles...