Abstract
The root of Polygonum multiflorum Thunb (PM) has been used in China to treat a variety of diseases, such as constipation, early graying of the hair and hyperlipemia. Recent evidence shows that PM causes idiosyncratic drug-induced liver injury (IDILI) in humans. In this study, we investigated the molecular basis of PM-induced liver injury in a rat model of IDILI based on a non-hepatotoxic dose of LPS. SD rats were orally administered 3 potentially hepatotoxic compounds of PM: cis-stilbene glucoside (cis-SG, 50 mg/kg), trans-SG (50 mg/kg) or emodin (5 mg/kg), followed by injection of LPS (2.8 mg/kg, iv). Serum and liver histology were evaluated 7 h after LPS injection. Among the 3 compounds tested, cis-SG, but not emodin or trans-SG, induced severe liver injury in rats when combined with LPS. The levels of AST and ALT in plasma and inflammatory cytokines in both plasma and liver tissues were markedly elevated. The liver tissues showed increased injury, hepatocyte apoptosis, and macrophage infiltration, and decreased cell proliferation. Microarray analysis revealed a negative correlation between peroxisome proliferator-activated receptor-γ (PPAR-γ) and LPS/cis-SG-induced liver injury. Immunohistochemical staining and RT-PCR results further confirmed that cis-SG significantly inhibited activation of the PPAR-γ pathway in the liver tissues of LPS/cis-SG-treated rats. Pre-treatment with a PPAR-γ agonist pioglitazone (500 g/kg, ig) reversed LPS/cis-SG-induced liver injury, which was associated with inhibiting the nuclear factor kappa B (NF-κB) pathway. These data demonstrate that cis-stilbene glucoside induces immunological idiosyncratic hepatotoxicity through suppressing PPAR-γ in a rat model of IDILI.
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22 December 2020
A Correction to this paper has been published: https://doi.org/10.1038/s41401-020-00592-2
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (No 81503350 and 81630100), the "Major Drug Discovery" Science and Technology major projects (No 2015ZX09501-004-001-008), the National Public Welfare Industry Subject (No 201507004-04), the Beijing Natural Science Foundation (No 7152142), and the Beijing Nova Program (No xx2016098).
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Supplementary data (DOC 87 kb)
Supplementary Table S1
the differential toxicity of Cis-SG, Trans-SG on the parenchymal hepatic cells (DOC 89 kb)
Supplementary Table S2
Down-expressed genes of Cis-SG vs Trans-SG (DOC 278 kb)
Supplementary Table S3
up- expressed genes of Cis-SG vs Trans-SG (DOC 160 kb)
Supplementary Table S4
The pathway of mRNA differential expression gene (DOC 194 kb)
Supplementary Table S5
The pathway of mRNA differential expression gene of Cis-SG vs Trans-SG (DOC 107 kb)
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Meng, Yk., Li, Cy., Li, Ry. et al. Cis-stilbene glucoside in Polygonum multiflorum induces immunological idiosyncratic hepatotoxicity in LPS-treated rats by suppressing PPAR-γ. Acta Pharmacol Sin 38, 1340–1352 (2017). https://doi.org/10.1038/aps.2017.32
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DOI: https://doi.org/10.1038/aps.2017.32
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