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

中文翻译：

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保火苷 I 抑制 FXR 信号通路，通过靶向 ER α 降解干扰胆汁酸稳态

淫羊藿（EF）是治疗骨质疏松症的有效草药，但由于潜在的肝毒性，其临床应用受到限制。前期研究发现EF的主要活性成分保活苷I（BI）与EF引起的肝损伤有关。然而，BI对肝细胞造成直接损伤的机制仍不清楚。在此，我们发现 BI 通过靶向雌激素受体 α (ER α) 抑制 FXR 介导的信号通路，导致胆汁酸 (BA) 的积累。靶向胆汁酸分析显示，BI 改变了 BA 的组成和分布，导致 BA 稳态受损。从机制上讲，BI 在转录水平上诱导 FXR 依赖性肝毒性。此外，根据转录因子结合位点数据库，预计 ER α 会与 FXR 启动子区域结合，我们进一步证明 ER α 正向调节 FXR 启动子活性并影响 BA 代谢相关靶基因的表达。重要的是，我们发现 ER α 及其介导的 FXR 转录调控可能通过配体依赖性 ER α 降解参与 BI 诱导的肝损伤。总的来说，我们的研究结果表明 FXR 是新发现的 ER α 介导的 BI 诱导的肝损伤的靶基因，并表明 BI 可能是 EF 诱导的肝损伤的原因。

图形概要