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Luteolin-7-diglucuronide, a novel PTP1B inhibitor, ameliorates hepatic stellate cell activation and liver fibrosis in mice

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Liver fibrosis, one of the leading causes of morbidity and mortality worldwide, lacks effective therapy. The activation of hepatic stellate cells (HSCs) is the dominant event in hepatic fibrogenesis. Luteolin-7-diglucuronide (L7DG) is the major flavonoid extracted from Perilla frutescens and Verbena officinalis. Their beneficial effects in the treatment of liver diseases were well documented. In this study we investigated the anti-fibrotic activities of L7DG and the potential mechanisms. We established TGF-β1-activated mouse primary hepatic stellate cells (pHSCs) and human HSC line LX-2 as in vitro liver fibrosis models. Co-treatment with L7DG (5, 20, 50 μM) dose-dependently decreased TGF-β1-induced expression of fibrotic markers collagen 1, α-SMA and fibronectin. In liver fibrosis mouse models induced by CCl4 challenge alone or in combination with HFHC diet, administration of L7DG (40, 150 mg·kg–1·d–1, i.g., for 4 or 8 weeks) dose-dependently attenuated hepatic histopathological injury and collagen accumulation, decreased expression of fibrogenic genes. By conducting target prediction, molecular docking and enzyme activity detection, we identified L7DG as a potent inhibitor of protein tyrosine phosphatase 1B (PTP1B) with an IC50 value of 2.10 µM. Further studies revealed that L7DG inhibited PTP1B activity, up-regulated AMPK phosphorylation and subsequently inhibited HSC activation. This study demonstrates that the phytochemical L7DG may be a potential therapeutic candidate for the treatment of liver fibrosis.

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Fig. 1: L7DG limits TGF-β1 induced LX-2 and primary murine HSC activation.
Fig. 2: PTP1B is the target interaction protein of L7DG.
Fig. 3: L7DG inhibits hepatic stellate cell activation via PTP1B-AMPK signaling pathways.
Fig. 4: L7DG dose-dependently ameliorates liver fibrosis in the CCl4-induced 4-week mouse model.
Fig. 5: L7DG ameliorates liver injury in CCl4-induced 8-week mouse model.
Fig. 6: L7DG attenuates liver injury and fibrosis in high-fat-, high-fructose-combined CCl4-induced mouse model.
Fig. 7: L7DG attuned mice liver fibrosis model via AMPK signaling pathways.
Fig. 8

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Acknowledgements

This article was supported by Shanghai Institute of Materia Medica, Chinese Academy of Sciences (No. CASIMM0120225006-2, SIMM0120232001), Shanghai Municipal Science and Technology Major Project (TM202301H002) and Shanghai Committee of Science and Technology (22ZR1415200).

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  1. These authors contributed equally: Bi-xi Tang, Yong Zhang

Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China

    Bi-xi Tang & Xue-mei Zhang

  2. Stake Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Bi-xi Tang, Yong Zhang, Dan-dan Sun, Qin-yi Liu, Cong Li, Pei-pei Wang, Li-xin Gao, Jia Li & Wei-liang Zhu

  3. University of Chinese Academy of Sciences, 100049, Beijing, China

    Qin-yi Liu & Jia Li

  4. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China

    Jia Li

  5. Lingang Laboratory, Shanghai, 201203, China

    Yi Zang

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Contributions

BXT and DDS performed the biological and pharmacological experiments. YZ purified and identified compounds. CL, PPW and LXG performed molecular experiments. BXT and QYL wrote the original draft. XMZ, JL, WLZ and YZ designed the study and revised the manuscript. All the authors have reviewed the final manuscript.

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Correspondence to Xue-mei Zhang, Jia Li, Wei-liang Zhu or Yi Zang.

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Tang, Bx., Zhang, Y., Sun, Dd. et al. Luteolin-7-diglucuronide, a novel PTP1B inhibitor, ameliorates hepatic stellate cell activation and liver fibrosis in mice. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01351-3

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