The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, China.
Shanghai R & D Center for Standardization of Traditional Chinese Medicines, Shanghai, 201210, China.
Arch Toxicol. 2024 Aug;98(8):2557-2576. doi: 10.1007/s00204-024-03762-x. Epub 2024 May 4.
Consumption of herbal products containing pyrrolizidine alkaloids (PAs) is one of the major causes for hepatic sinusoidal obstruction syndrome (HSOS), a deadly liver disease. However, the crucial metabolic variation and biomarkers which can reflect these changes remain amphibious and thus to result in a lack of effective prevention, diagnosis and treatments against this disease. The aim of the study was to determine the impact of HSOS caused by PA exposure, and to translate metabolomics-derived biomarkers to the mechanism. In present study, cholic acid species (namely, cholic acid, taurine conjugated-cholic acid, and glycine conjugated-cholic acid) were identified as the candidate biomarkers (area under the ROC curve 0.968 [95% CI 0.908-0.994], sensitivity 83.87%, specificity 96.55%) for PA-HSOS using two independent cohorts of patients with PA-HSOS. The increased primary bile acid biosynthesis and decreased liver expression of farnesoid X receptor (FXR, which is known to inhibit bile acid biosynthesis in hepatocytes) were highlighted in PA-HSOS patients. Furtherly, a murine PA-HSOS model induced by senecionine (50 mg/kg, p.o.), a hepatotoxic PA, showed increased biosynthesis of cholic acid species via inhibition of hepatic FXR-SHP singling and treatment with the FXR agonist obeticholic acid restored the cholic acid species to the normal levels and protected mice from senecionine-induced HSOS. This work elucidates that increased levels of cholic acid species can serve as diagnostic biomarkers in PA-HSOS and targeting FXR may represent a therapeutic strategy for treating PA-HSOS in clinics.
食用含有吡咯里西啶生物碱（PA）的草药产品是肝窦阻塞综合征（HSOS）的主要原因之一，这是一种致命的肝脏疾病。然而，能够反映这些变化的关键代谢变化和生物标志物仍然是不确定的，因此导致缺乏有效的预防、诊断和治疗这种疾病的方法。本研究的目的是确定 PA 暴露引起的 HSOS 的影响，并将代谢组学衍生的生物标志物转化为机制。在本研究中，胆酸种类（即胆酸、牛磺酸结合胆酸和甘氨酸结合胆酸）被确定为 PA-HSOS 的候选生物标志物（ROC 曲线下面积 0.968 [95%CI 0.908-0.994]，灵敏度 83.87%，特异性 96.55%），使用两个独立的 PA-HSOS 患者队列。在 PA-HSOS 患者中，发现初级胆汁酸生物合成增加，肝脏法尼醇 X 受体（FXR）表达降低，FXR 已知可抑制肝细胞中的胆汁酸生物合成。此外，用 senecionine（50mg/kg，po）诱导的 PA-HSOS 小鼠模型显示，通过抑制肝 FXR-SHP 信号，胆酸种类的生物合成增加，用 FXR 激动剂 obeticholic acid 治疗可将胆酸种类恢复到正常水平，并可保护小鼠免受 senecionine 诱导的 HSOS。这项工作阐明了胆酸种类水平的升高可以作为 PA-HSOS 的诊断生物标志物，靶向 FXR 可能代表治疗 PA-HSOS 的临床治疗策略。
