Dehydroabietic acid improves nonalcoholic fatty liver disease through activating the Keap1/Nrf2-ARE signaling pathway to reduce ferroptosis

Abstract

The accumulation of iron-dependent lipid peroxides is one of the important causes of NAFLD. The purpose of this study is to explore the effect of dehydroabietic acid (DA) on ferroptosis in nonalcoholic fatty liver disease (NAFLD) mice and its possible mechanisms. DA improved NAFLD and reduced triglycerides (TG), total cholesterol (TC), and lipid peroxidation level and inhibited ferroptosis in the liver of HFD-induced mice. DA binds with Keap1 to form 3 stable hydrogen bonds at VAL512 and LEU557 and increased nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response elemen (ARE) luciferase activity. DA promoted the expression downstream of Nrf2 such as heme oxygenase-1 (HO-1), glutathione (GSH) and its peroxidase 4 (GPX4), so as to eliminate the accumulation of reactive oxygen species (ROS) and reduce lipid peroxides malondialdehyde (MDA) in the liver. DA inhibited ferroptosis and increased the expression of key genes such as ferroptosis suppressor protein 1 (FSP1) in vitro and vivo. In all, DA may bind with Keap1, activate Nrf2-ARE, induce its target gene expression, inhibit ROS accumulation and lipid peroxidation, and reduce HFD-induced NAFLD.

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Acknowledgements

We would like to acknowledge Caili Zhang, Xianghua Liu, and Ning Sun (TEM Center, Henan University of Chinese Medicine) for their help with transmission electron microscope imaging in this study.

Funding

This work was supported by the Postdoctoral Foundation of China (No. 2018M642761), the Special Research Project of Henan Province on Traditional Chinese Medicine (No. 2018ZYD12), the Key Scientific Research Project Plan of Henan Higher Education Institutions (No. 19A360021), Program for Innovative Research Team (in Science and Technology)  in University of Henan Province (No. 21IRTSTHN026) and Leading Talents Program of Zhongyuan Science and Technology Innovation  (No. 204200510022).

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Data collection: Gai Gao, Erwen Li, and Yong Yuan; data analysis: Yu Fu, Pan Wang, Yonghui Qiao, and Xiaowei Zhang; experimental design: Hui Wang and Zhenqiang Zhang; project design: Zhishen Xie and Jiangyan Xu; data interpretation and manuscript writing: GaiGao and Zhishen Xie; manuscript editing: Christian Hölscher.

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Correspondence to Hui Wang or Zhenqiang Zhang.

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Gao, G., Xie, Z., Li, Ew. et al. Dehydroabietic acid improves nonalcoholic fatty liver disease through activating the Keap1/Nrf2-ARE signaling pathway to reduce ferroptosis. J Nat Med (2021). https://doi.org/10.1007/s11418-021-01491-4

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Keywords

  • Dehydroabietic acid
  • Nonalcoholic fatty liver disease
  • Ferroptosis
  • ROS
  • Nrf2-ARE