Loss of Nrf1 rather than Nrf2 leads to inflammatory accumulation of lipids and reactive oxygen species (ROS) in human hepatoma cells, which is alleviated by 2-bromopalmitate

作者：Rongzhen Deng, Ze Zheng, Shaofan Hu, Meng Wang, Jing Feng, Peter Mattjus, Zhengwen Zhang, Yiguo Zhang · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2021 · DOI：10.1101/2021.09.29.462358 · 被引用次数：3 · 研究领域：Lipid metabolism and biosynthesis、Genomics, phytochemicals, and oxidative stress、Peroxisome Proliferator-Activated Receptors

Abstract Since Nrf1 and Nrf2 are essential for regulating the lipid metabolism pathways, their dysregulation has thus been shown to be critically involved in the non-controllable inflammatory transformation into cancer. Herein, we have explored the molecular mechanisms underlying their distinct regulation of lipid metabolism, by comparatively analyzing the changes in those lipid metabolism-related genes in Nrf1α –/– and/or Nrf2 –/– cell lines relative to wild-type controls. The results revealed that loss of Nrf1α leads to lipid metabolism disorders. That is, its lipid synthesis pathway was up-regulated by the JNK-Nrf2-AP1 signaling, while its lipid decomposition pathway was down-regulated by the nuclear receptor PPAR-PGC1 signaling, thereby resulting in severe accumulation of lipids as deposited in lipid droplets. By contrast, knockout of Nrf2 gave rise to decreases in lipid synthesis and uptake capacity. These demonstrate that Nrf1 and Nrf2 contribute to significant differences in the cellular lipid metabolism profiles and relevant pathological responses. Further experimental evidence unraveled that lipid deposition in Nrf1α –/– cells resulted from CD36 up-regulation by activating the PI3K-AKT-mTOR pathway, leading to abnormal activation of the inflammatory response. This was also accompanied by a series of adverse consequences, e.g., accumulation of reactive oxygen species (ROS) in Nrf1α –/– cells. Interestingly, treatment of Nrf1α –/– cells with 2-bromopalmitate (2BP) enab...