Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China.
Oxid Med Cell Longev. 2022 Feb 18;2022:5180242. doi: 10.1155/2022/5180242. eCollection 2022.
Nonalcoholic fatty liver disease (NAFLD), characterized with oxidative stress and hepatic steatosis, is a serious threat to human health. As a specific activator of nuclear factor E2-related factor 2 (Nrf2), the 4-octyl itaconate (4-OI) has the beneficial effects in antioxidant and anti-inflammation; however, whether 4-OI can alleviate hepatic steatosis and its mechanism is still unknown. The present study was aimed at investigating the protective effects of 4-OI on free fat acid- (FFA-) induced lipid metabolism disorder and its potential molecular mechanism in hepatocytes. The results showed that 4-OI treatment markedly alleviated FFA-induced oxidative stress and excessive lipid accumulation in hepatocytes. Mechanistically, 4-OI significantly suppressed the overproduction of reactive oxygen species (ROS) through activation of Nrf2; the downregulation of ROS level induced a downregulation of AMP-dependent protein kinase (AMPK) phosphorylation level which finally ameliorated excessive lipid accumulation in FFA-stimulated hepatocytes. In general, our data demonstrated that 4-OI relieves the oxidative stress and lipid metabolism disorder in FFA-stimulated hepatocytes; and these beneficial effects were achieved by activating the Nrf2-AMPK signaling pathway. These data not only expand the new biological function of 4-OI but also provide a theoretical basis for 4-OI to protect against lipid metabolism disorders and related diseases, such as NAFLD.
非酒精性脂肪性肝病（NAFLD）的特征为氧化应激和肝脂肪变性，严重威胁着人类健康。4-辛基衣康酸（4-OI）作为核因子 E2 相关因子 2（Nrf2）的特异性激活剂，具有抗氧化和抗炎作用；然而，4-OI 是否能缓解肝脂肪变性及其机制尚不清楚。本研究旨在探讨 4-OI 对游离脂肪酸（FFA）诱导的脂质代谢紊乱的保护作用及其在肝细胞中的潜在分子机制。结果表明，4-OI 处理可显著减轻 FFA 诱导的肝细胞氧化应激和脂质蓄积过度。机制上，4-OI 通过激活 Nrf2 显著抑制活性氧（ROS）的过度产生；ROS 水平的下调诱导 AMP 依赖的蛋白激酶（AMPK）磷酸化水平下调，最终改善 FFA 刺激的肝细胞中过量的脂质蓄积。总的来说，我们的数据表明，4-OI 缓解了 FFA 刺激的肝细胞中的氧化应激和脂质代谢紊乱；这些有益作用是通过激活 Nrf2-AMPK 信号通路实现的。这些数据不仅扩展了 4-OI 的新生物学功能，也为 4-OI 预防脂质代谢紊乱和相关疾病（如非酒精性脂肪性肝病）提供了理论依据。
