Yong Zhang, Zibao Huang, Zhi Zhou, Ning Ma, Ruiqi Wang, Mimi Chen, Xiaowen He, Lin Dong, Zhixuan Xia, Qiang Liu, Weiying Lu, Xiaopo Zhang
Department of Pharmacology, Hainan Medical University, Haikou, China.
Key Laboratory of Tropical Translational Medicine of the Ministry of Education, Hainan Key Laboratory for Research and Development of Tropical Herbs, School of Pharmaceutical Science, Hainan Medical University, Haikou, China.
Front Pharmacol. 2022 Jul 5;13:909280. doi: 10.3389/fphar.2022.909280. eCollection 2022.
Metabolic-associated fatty liver disease (MAFLD) is becoming more common due to lifestyle changes. A long-term high-fat and high-glucose diet induces glycolipid metabolism disorders in the liver, which results in the development of MAFLD. To date, there is no specific clinically useful therapeutics for this disease. Natural products or synthetic compounds were screened and investigated to find effective agents for treating MAFLD. In this study, nootkatone (Nok), a natural sesquiterpene ketone isolated from fructus, was explored for its potential to treat MAFLD, and underlying mechanisms were studied. Our results show that Nok dramatically ameliorated the disordered lipid and glucose metabolism in MAFLD mice, decreased fat accumulation in hepatic tissue, and improved liver injury. Inflammation, metabolic disorder, and oxidative stress were ameliorated in liver tissue based on RNA-seq transcriptome comparison between a Nok-treated group and an MAFLD model group. Furthermore, Nok significantly activated AMPK activity and inhibited MAPK activity especially the p38 and JNK signaling pathways, based on western blot analysis. The pharmaceutical effects and potential signaling pathways impacted by Nok were also investigated in L02 cells. Nok significantly promoted the consumption of glucose and decreased the deposition of triglycerides . The p-AMPKα level was notably upregulated by Nok, indicating dramatic AMPK activation. In addition, Nok decreased the levels of p-ERK1/2, p-p38, and p-JNK. Nok also inhibited the activation of MAPK signaling and, thus, alleviated MAFLD development. Our results suggest that Nok may be useful in treating MAFLD. Nok may ameliorate MAFLD by regulating glycolipid metabolism disorders by activating AMPK and inhibiting MAPK activity. Collectively, this study suggests that Nok is an effective compound for the treatment of MAFLD.
由于生活方式的改变，代谢相关脂肪性肝病（MAFLD）正变得越来越普遍。长期高脂高糖饮食会诱发肝脏中的糖脂代谢紊乱，从而导致MAFLD的发生。迄今为止，针对这种疾病尚无特定的临床有效治疗方法。人们筛选并研究了天然产物或合成化合物，以寻找治疗MAFLD的有效药物。在本研究中，探索了从果实中分离出的天然倍半萜酮诺卡酮（Nok）治疗MAFLD的潜力，并研究了其潜在机制。我们的结果表明，Nok显著改善了MAFLD小鼠紊乱的脂质和葡萄糖代谢，减少了肝组织中的脂肪堆积，并改善了肝损伤。基于Nok治疗组和MAFLD模型组之间的RNA测序转录组比较，肝组织中的炎症、代谢紊乱和氧化应激得到了改善。此外，基于蛋白质免疫印迹分析，Nok显著激活了AMPK活性并抑制了MAPK活性，尤其是p38和JNK信号通路。还在L02细胞中研究了Nok的药理作用和潜在信号通路。Nok显著促进了葡萄糖的消耗并减少了甘油三酯的沉积。Nok显著上调了p-AMPKα水平，表明AMPK被显著激活。此外，Nok降低了p-ERK1/2、p-p38和p-JNK的水平。Nok还抑制了MAPK信号的激活，从而减轻了MAFLD的发展。我们的结果表明，Nok可能对治疗MAFLD有用。Nok可能通过激活AMPK和抑制MAPK活性来调节糖脂代谢紊乱，从而改善MAFLD。总体而言，本研究表明Nok是治疗MAFLD的有效化合物。
