Xu Zhiyue, Xu Shu, Liu Xiaoming, Cheng Lan, Liu Xinghuang, Xie Xiaotian, Zhou Dan, Wang Dongke, Chen Jie, Deng Xiaoling, Zhang Lei, He Ruohang, Li Ying, Cheng Mengmeng, Yang Ling, Hou Xiaohua, Bai Tao
Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Int J Biol Sci. 2025 Jan 1;21(2):745-757. doi: 10.7150/ijbs.102906. eCollection 2025.
PIEZO1 has been found to play a vital role in regulating intestinal epithelial cells (IEC) function and maintaining intestinal barrier in recent years. Therefore, IEC PIEZO1 might exert a significant impact on liver metabolism through the gut-liver axis, but there is no research on this topic currently. Classic high-fat diet (HFD) model and mice with IEC-specific deficiency of PIEZO1 ( ) were used to explore the problem. IEC PIEZO1 deletion significantly alleviated liver steatosis, without change on glucose tolerance and energy expenditure. Fibroblast growth factor 15/19 (FGF15/19) was downregulated in IEC and portal vein of mice, which was associated with phenotypic change. After supplementary of exogenous FGF19, the effect of improving liver steatosis brought by PIEZO1 deletion was blocked. Notably, PIEZO1 depletion-induced FGF15 reduction was not dependent on classic bile acids (BAs) - farnesoid X receptor (FXR) pathway, but attributed to impaired retinol metabolism and lower content of retinoic acid (RA). Subsequently, addition of RA but not retinol benefited inducing FGF15 production in ileal organoid from mice. Altogether, IEC PIEZO1 represents a promising target for therapy of hepatic steatosis via the gut-liver axis.
近年来发现，PIEZO1在调节肠上皮细胞（IEC）功能和维持肠道屏障方面发挥着至关重要的作用。因此，IEC中的PIEZO1可能通过肠-肝轴对肝脏代谢产生重大影响，但目前尚无关于该主题的研究。本研究采用经典高脂饮食（HFD）模型和IEC特异性缺失PIEZO1的小鼠来探究这一问题。IEC中PIEZO1的缺失显著减轻了肝脏脂肪变性，而对葡萄糖耐量和能量消耗无影响。在PIEZO1缺失小鼠的IEC和门静脉中，成纤维细胞生长因子15/19（FGF15/19）表达下调，这与表型变化有关。补充外源性FGF19后，PIEZO1缺失所带来的改善肝脏脂肪变性的作用被阻断。值得注意的是，PIEZO1缺失诱导的FGF15减少并不依赖于经典胆汁酸（BAs）-法尼醇X受体（FXR）途径，而是归因于视黄醇代谢受损和视黄酸（RA）含量降低。随后，添加RA而非视黄醇有助于诱导PIEZO1缺失小鼠回肠类器官中FGF15的产生。总之，IEC中的PIEZO1是通过肠-肝轴治疗肝脂肪变性的一个有前景的靶点。
