Baohuoside I inhibits FXR signaling pathway to interfere with bile acid homeostasis via targeting ER α degradation

• Published in: Cell biology and toxicology 2023-08, Vol.39 (4), p.1215-1235
• Main Authors: Zhao, Zhen, Yang, Lu-Lu, Wang, Qiao-Lei, Du, Jin-Fa, Zheng, Zu-Guo, Jiang, Yan, Li, Ping, Li, Hui-Jun
• Format: Article
• Language: English
• Subjects: Bile acids; Bile Acids and Salts - metabolism; Bile Acids and Salts - pharmacology; Binding sites; Biochemistry; Biomedical and Life Sciences; Cell Biology; Chemical and Drug Induced Liver Injury, Chronic - metabolism; Degradation; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens; Gene expression; Gene regulation; Hepatocytes; Hepatotoxicity; Herbal medicine; Homeostasis; Humans; Injuries; Life Sciences; Liver; Original Article; Osteoporosis; Pharmacology/Toxicology; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Cytoplasmic and Nuclear - pharmacology; Signal Transduction
• ISSN: 0742-2091; 1573-6822
• DOI: 10.1007/s10565-022-09737-x

Epimedii folium (EF) is an effective herbal medicine in osteoporosis treatment, but the clinical utilization of EF has been limited due to potential hepatotoxicity. The previous studies identified that baohuoside I (BI), the main active component of EF, was relevant to EF-induced liver injury. However, the mechanisms of BI causing direct injury to hepatocytes remain unclear. Here, we reveal that BI inhibits FXR-mediated signaling pathway via targeting estrogen receptor α (ER α), leading to the accumulation of bile acids (BAs). Targeted bile acid analyses show BI alters the BA composition and distribution, resulting in impaired BA homeostasis. Mechanistically, BI induces FXR-dependent hepatotoxicity at transcriptional level. Additionally, ER α is predicted to bind to the FXR promoter region based on transcription factor binding sites databases and we further demonstrate that ER α positively regulates FXR promoter activity and affects the expression of target genes involved in BA metabolism. Importantly, we discover that ER α and its mediated FXR transcription regulation might be involved in BI-induced liver injury via ligand-dependent ER α degradation. Collectively, our findings indicate that FXR is a newly discovered target gene of ER α mediated BI-induced liver injury, and suggest BI may be responsible for EF-induced liver injury. Graphical abstract