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.

Graphic abstract

中文翻译：

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脱氢松香酸通过激活Keap1 / Nrf2-ARE信号通路来减少肥大症，从而改善非酒精性脂肪肝疾病

摘要

铁依赖性脂质过氧化物的积累是NAFLD的重要原因之一。这项研究的目的是探讨脱氢松香酸（DA）对非酒精性脂肪肝疾病（NAFLD）小鼠肥大症的作用及其可能的机制。DA改善了NAFLD，并降低了HFD诱导的小鼠肝脏中的甘油三酸酯（TG），总胆固醇（TC）和脂质过氧化水平，并抑制了肥大症。DA与Keap1结合，在VAL512和LEU557处形成3个稳定的氢键，并增加核因子红系2相关因子2（Nrf2）-抗氧化反应元件（ARE）荧光素酶的活性。DA促进Nrf2下游的表达，例如血红素加氧酶-1（HO-1），谷胱甘肽（GSH）及其过氧化物酶4（GPX4），以消除肝脏中的活性氧（ROS）的积累并减少脂质过氧化物丙二醛（MDA）。DA可以在体外和体内抑制肥大症并增加关键基因的表达，例如肥大症抑制蛋白1（FSP1）。总之，DA可能与Keap1结合，激活Nrf2-ARE，诱导其靶基因表达，抑制ROS积累和脂质过氧化，并降低HFD诱导的NAFLD。

图形摘要