1. Dehydroabietic acid improves nonalcoholic fatty liver disease through activating the Keap1/Nrf2-ARE signaling pathway to reduce ferroptosis
- Author
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Xu Jiangyan, Wang Pan, Qiao Yonghui, Gao Gai, Wang Hui, Xie Zhishen, Yuan Yong, Christian Hölscher, Er-Wen Li, Yu Fu, Zhenqiang Zhang, and Xiaowei Zhang
- Subjects
Male ,NF-E2-Related Factor 2 ,Pharmacology ,GPX4 ,01 natural sciences ,Lipid peroxidation ,Mice ,chemistry.chemical_compound ,Non-alcoholic Fatty Liver Disease ,Malondialdehyde ,Nonalcoholic fatty liver disease ,medicine ,Animals ,Ferroptosis ,Humans ,S100 Calcium-Binding Protein A4 ,Luciferase ,Triglycerides ,Kelch-Like ECH-Associated Protein 1 ,biology ,010405 organic chemistry ,Membrane Proteins ,Glutathione ,Phospholipid Hydroperoxide Glutathione Peroxidase ,medicine.disease ,KEAP1 ,Antioxidant Response Elements ,0104 chemical sciences ,Mice, Inbred C57BL ,010404 medicinal & biomolecular chemistry ,Cholesterol ,HEK293 Cells ,chemistry ,Abietanes ,biology.protein ,Molecular Medicine ,Lipid Peroxidation ,Signal transduction ,Reactive Oxygen Species ,Heme Oxygenase-1 ,Signal Transduction ,Peroxidase - 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.
- Published
- 2021