Abstract
Cholestasis is a major cause of a series of bile flow malfunction-related liver diseases. Pregnane X receptor (PXR) is a key regulator in endo- and xeno-biotics metabolism, which has been considered as a promising therapeutic target for cholestasis. In this study we conducted human PXR (hPXR) agonistic screening using dual-luciferase reporter gene assays, which led to discovering a series of potent hPXR agonists from a small Euphorbiaceae diterpenoid library, containing 35 structurally diverse diterpenoids with eight different skeleton types. The most active compound 6, a lathyrane diterpenoid (5/11/3 ring system), dose-dependently activated hPXR with a high selectivity, and significantly upregulated the expression of hPXR downstream genes CYP3A4 and UGT1A1. In LCA-induced cholestasis mouse model, administration of compound 6 (50 mg· kg−1. d−1, ip) for 7 days significantly suppressed liver necrosis and decreased serum levels of AST, ALT, Tbili, ALP, and TBA, ameliorating LCA-induced cholestatic liver injury. We further revealed that compound 6 exerted its anti-cholestatic efficacy via activation of PXR pathway, accelerating the detoxification of toxic BAs and promoting liver regeneration. These results suggest that lathyrane diterpenoids may serve as a promising scaffold for future development of anti-cholestasis drugs.
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Acknowledgements
This work was supported by National Natural Science Foundation of China (nos. 82025034, 81973392, 81973195, and 82104020), the Shenzhen Science and Technology Program (no. KQTD20190929174023858), the National Key Research and Development Program (Grant: 2017YFE0109900), the Fundamental Research Funds for the Central Universities (no. 20ykjc04), the Guangdong Provincial Key Laboratory of Construction Foundation (no. 2017B030314030), the China Postdoctoral Science Foundation (no. 2020M683138), the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (no. 2017BT01Y093), the 111 project (no. B16047), the Key Laboratory Foundation of Guangdong Province (no. 2017B030314030), the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01Y093).
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DH, YYZ, RMW, SY, and HCB participated in research design. DH, YYZ, RMW, FYY, and XY performed experiments. DH, YYZ, RMW, WL, XLY, GHT, SY, and HCB wrote or revised the paper.
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Huang, D., Zhao, Yy., Wang, Rm. et al. Natural product-based screening led to the discovery of a novel PXR agonist with anti-cholestasis activity. Acta Pharmacol Sin 43, 2139–2146 (2022). https://doi.org/10.1038/s41401-021-00793-3
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DOI: https://doi.org/10.1038/s41401-021-00793-3
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