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Salvianolic acid B suppresses hepatic fibrosis by inhibiting ceramide glucosyltransferase in hepatic stellate cells

Acta Pharmacologica Sinica volume 44, pages 1191–1205 (2023)Cite this article

Abstract

UDP-glucose ceramide glucosyltransferase (UGCG) is the first key enzyme in glycosphingolipid (GSL) metabolism that produces glucosylceramide (GlcCer). Increased UGCG synthesis is associated with cell proliferation, invasion and multidrug resistance in human cancers. In this study we investigated the role of UGCG in the pathogenesis of hepatic fibrosis. We first found that UGCG was over-expressed in fibrotic livers and activated hepatic stellate cells (HSCs). In human HSC-LX2 cells, inhibition of UGCG with PDMP or knockdown of UGCG suppressed the expression of the biomarkers of HSC activation (α-SMA and collagen I). Furthermore, pretreatment with PDMP (40 μM) impaired lysosomal homeostasis and blocked the process of autophagy, leading to activation of retinoic acid signaling pathway and accumulation of lipid droplets. After exploring the structure and key catalytic residues of UGCG in the activation of HSCs, we conducted virtual screening, molecular interaction and molecular docking experiments, and demonstrated salvianolic acid B (SAB) from the traditional Chinese medicine Salvia miltiorrhiza as an UGCG inhibitor with an IC50 value of 159 μM. In CCl4-induced mouse liver fibrosis, intraperitoneal administration of SAB (30 mg · kg−1 · d−1, for 4 weeks) significantly alleviated hepatic fibrogenesis by inhibiting the activation of HSCs and collagen deposition. In addition, SAB displayed better anti-inflammatory effects in CCl4-induced liver fibrosis. These results suggest that UGCG may represent a therapeutic target for liver fibrosis; SAB could act as an inhibitor of UGCG, which is expected to be a candidate drug for the treatment of liver fibrosis.

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Fig. 1: The expression of UGCG is up-regulated in hepatic diseases, especially hepatic fibrosis.
Fig. 2: The inhibition of UGCG suppresses the activation of HSCs in vitro.
Fig. 3: The inhibition of UGCG blocks autophagy flow.
Fig. 4: The inhibition of UGCG impairs lysosomal homeostasis and promotes lipid droplet accumulation.
Fig. 5: Study on protein structure and activity of UGCG.
Fig. 6: Screening of potential inhibitors from traditional Chinese medicine for UGCG.
Fig. 7: Salvianolic acid B targets UGCG.
Fig. 8: The inhibition of UGCG ameliorates CCl4-induced hepatic fibrogenesis.
Fig. 9: Effects of PDMP and SAB on liver injury and inflammation.

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Acknowledgements

We are truly grateful to the oncomine, GEO and alphafold working groups for generously sharing their data. This work was supported by the National Natural Science Foundation of China (Grant No. 81930114), Key-Area Research and Development Program of Guangdong Province (Grant No. 2020B1111100004), the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong-Hong Kong-Macau Joint Laboratory, Grant No. 2020B1212030006).

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  1. These authors contributed equally: Zi-bo Li, Lin Jiang

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  1. Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Zi-bo Li, Lin Jiang, Jia-dong Ni, Yuan-hang Xu, Shao-gui Wang, Zhong-qiu Liu & Cai-yan Wang

  2. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Fang Liu & Wen-ming Liu

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Contributions

ZBL and LJ performed the experiments; SGW, ZQL, and CYW designed the project and revised the paper; ZBL, LJ, JDN, YHX, FL, WML performed the informatics analysis and experiments; ZBL and CYW wrote the paper. All authors read and approved the final paper.

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Correspondence to Shao-gui Wang, Zhong-qiu Liu or Cai-yan Wang.

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Li, Zb., Jiang, L., Ni, Jd. et al. Salvianolic acid B suppresses hepatic fibrosis by inhibiting ceramide glucosyltransferase in hepatic stellate cells. Acta Pharmacol Sin 44, 1191–1205 (2023). https://doi.org/10.1038/s41401-022-01044-9

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