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Functional metabolomics characterizes the contribution of farnesoid X receptor in pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome

  • Toxicogenomics and Omics Technologies
  • Published:
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Abstract

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.

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Data availability

The authors declare that the data supporting the findings of this study are available within the paper. All other data are available from the corresponding author upon reasonable request.

Code availability

Not applicable.

Abbreviations

CA:

Cholic acid

CYP7A1:

Cholesterol 7-alpha-hydroxylase

CYP8B1:

Sterol 12-alpha-hydroxylase

FXR:

Farnesoid X receptor

GCA:

Glycocholic acid

HSOS:

Hepatic sinusoidal obstruction syndrome

HBV:

Hepatitis B virus infections

PBC:

Primary biliary cirrhosis

PA:

Pyrrolizidine alkaloid

PPAs:

Pyrrole-protein adducts

ROC:

Receiver operating characteristic

SHP:

Small heterodimer partner

TCA:

Taurocholic acid

OCA:

Obeticholic acid

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Funding

This work was funded by grants from the National Natural Science Foundation of China (No. 81603384 and 82122074), the Nature Science Foundation of Shanghai (No. 20ZR1473300, 23ZR1463200), Changjiang Scholars Programme of China (No. T2022255), the Shanghai Rising-Star Program (No. 17QA1403600), and the Shanghai Talents Development Foundation (No. 2020099).

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Authors and Affiliations

  1. 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

    Aizhen Xiong, Longhui Lu, Kaiyuan Jiang, Yan Chen, Xunjiang Wang, Qi Liao, Lili Ding, Zhengtao Wang & Li Yang

  2. Shanghai R & D Center for Standardization of Traditional Chinese Medicines, Shanghai, 201210, China

    Aizhen Xiong, Lili Ding, Zhengtao Wang & Li Yang

  3. E-Institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Xiaoning Wang & Ping Liu

  4. Department of Gastroenterology, The Drum Tower Hospital of Nanjing, Affiliated to Nanjing University Medical School, Nanjing, 210008, Jiangsu, China

    Wei Zhang & Yuzheng Zhuge

  5. Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, 91010, USA

    Wendong Huang

  6. Center for Drug of Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, China

    Lujin Li

  7. Department of Obstetrics and Gynecology, and Shanghai Key Laboratory of Gynecologic Oncology Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

    Fan Yang

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  1. Aizhen Xiong
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  2. Longhui Lu
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  5. Yan Chen
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  14. Lili Ding
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  15. Zhengtao Wang
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  16. Li Yang
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Contributions

Aizhen Xiong, Lili Ding, Zhengtao Wang, and Li Yang for study conception and design; Aizhen Xiong, Longhui Lu, Kaiyuan Jiang, Xiaoning Wang, Yan Chen, Wei Zhang, Qi Liao, Fan Yang, Yuzheng Zhuge, and Ping Liu participant screening and collection; Aizhen Xiong, Xiaoning Wang, and Lujin Li for statistical analysis and interpretation of data; Aizhen Xiong and Lili Ding for drafting of the manuscript; Wendong Huang, Fan Yang, Li Yang, and Zhengtao Wang for manuscript review and critical revision; Aizhen Xiong, Lili Ding, Zhengtao Wang, and Li Yang for obtaining funding.

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Correspondence to Aizhen Xiong, Lili Ding, Zhengtao Wang or Li Yang.

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Xiong, A., Lu, L., Jiang, K. et al. Functional metabolomics characterizes the contribution of farnesoid X receptor in pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome. Arch Toxicol (2024). https://doi.org/10.1007/s00204-024-03762-x

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  • DOI: https://doi.org/10.1007/s00204-024-03762-x

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