Yang Yi, Jiao Ling, Huang Yixuan, Shang Hailin, Li Enrui, Chang Hong, Cui Hongyang, Wan Yi
Laboratory for Earth Surface Processes, College of Urban and Environmental Sciences, Peking University, Beijing, China.
College of Environmental Science and Engineering, Beijing Forestry University, Beijing, China.
Environ Health Perspect. 2025 Apr;133(3-4):47005. doi: 10.1289/EHP15435. Epub 2025 Apr 14.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease worldwide, and increasing evidence suggests that exposure to environmental pollutants is associated with the increased incidence of MASLD. The farnesoid X receptor (FXR) plays an important role in the development of MASLD by regulating bile acids (BAs) and lipid metabolism. However, whether FXR-active pollutants are the environmental drivers of MASLD remains unclear.
This study aimed to determine whether FXR-active pollutants exist in the environment and evaluate their ability to trigger MASLD development in mice.
An FXR protein affinity pull-down assay and nontargeted mass spectrometry (MS) analysis were used to identify environmental FXR ligands in sewage sludge. A homogeneous time-resolved fluorescence coactivator recruitment assay and cell-based dual-luciferase reporter assay were used to determine the FXR activities of the identified pollutants. Targeted analysis of BAs, MS imaging, lipidomic analysis, 16S rRNA sequencing, and quantitative polymerase chain reaction were conducted to assess the ability of FXR-active pollutants to induce metabolic disorders of BAs and lipids and to contribute to MASLD development in C57BL/6N mice.
We identified 19 compounds in the sewage sludge that had FXR-antagonistic activity, and triphenyl phosphate (TPHP) was the FXR antagonist with the highest efficacy. Mice exposed to either 10 or TPHP for 30 d had higher levels of conjugated primary BAs in enterohepatic circulation, and the BA pool showed FXR antagonistic activities. The exposed mice also had greater lipogenesis (more Oil Red O staining and high triglyceride levels) in liver.
Nineteen FXR-antagonistic pollutants were identified in sewage sludge. FXR inhibition by the strongest antagonist TPHP may have a role in promoting MASLD development in mice by inducing a positive feedback loop between the FXR and BAs. https://doi.org/10.1289/EHP15435.
代谢功能障碍相关脂肪性肝病（MASLD）是全球最常见的肝脏疾病，越来越多的证据表明，接触环境污染物与MASLD发病率增加有关。法尼醇X受体（FXR）通过调节胆汁酸（BAs）和脂质代谢在MASLD的发展中起重要作用。然而，具有FXR活性的污染物是否是MASLD的环境驱动因素仍不清楚。
本研究旨在确定环境中是否存在具有FXR活性的污染物，并评估其在小鼠中引发MASLD发展的能力。
采用FXR蛋白亲和下拉试验和非靶向质谱（MS）分析来鉴定污水污泥中的环境FXR配体。采用均相时间分辨荧光共激活剂募集试验和基于细胞的双荧光素酶报告基因试验来测定所鉴定污染物的FXR活性。对BAs进行靶向分析、MS成像、脂质组学分析、16S rRNA测序和定量聚合酶链反应，以评估具有FXR活性的污染物诱导BAs和脂质代谢紊乱以及促进C57BL/6N小鼠发生MASLD的能力。
我们在污水污泥中鉴定出19种具有FXR拮抗活性的化合物，其中磷酸三苯酯（TPHP）是效力最高的FXR拮抗剂。暴露于10或TPHP 30天的小鼠肝肠循环中结合型初级BAs水平较高，且BA池表现出FXR拮抗活性。暴露的小鼠肝脏中脂肪生成也更多（油红O染色更多且甘油三酯水平较高）。
在污水污泥中鉴定出19种FXR拮抗污染物。最强拮抗剂TPHP对FXR的抑制作用可能通过诱导FXR和BAs之间的正反馈回路在促进小鼠MASLD发展中起作用。https://doi.org/10.1289/EHP15435
