The inflammatory accumulation of lipids and ROS in human Nrf1α-deficient hepatoma cells is ameliorated by 2-bromopalmitate
The inflammatory accumulation of lipids and ROS in human Nrf1α-deficient hepatoma cells is ameliorated by 2-bromopalmitate
复制标题
2-bromopalmitate 可改善人 Nrf1α 缺陷型肝癌细胞中脂质和 ROS 的炎症积累
DOI：
10.1101/2021.09.29.462358
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Yiguo Zhang
中科院分区：
文献类型：
--
作者：
Ze Zheng;Meng Wang;Shaofan Hu;Rongzhen Deng;Jing Feng;Yiguo Zhang
由于Nrf 1和Nrf 2是调节脂质代谢途径所必需的，因此它们的失调也被证明与癌症发展中的不可控炎症病理学密切相关。然而，Nrf 1和Nrf 2之间的相互作用在调节脂质代谢，特别是在肝癌细胞中的作用尚不清楚。在此，我们通过比较分析Nrf 1 α-/-和/或Nrf 2-/-细胞系中脂质代谢相关基因相对于野生型对照的变化，进一步探讨了其独特调节脂质代谢的分子机制。结果表明，Nrf 1的缺失导致脂质代谢紊乱，JNK-Nrf 2-AP 1信号上调了其脂质合成途径，而核受体PPAR-PGC 1信号下调了其脂质分解途径，导致脂质严重积聚并沉积在脂滴中。相比之下，敲除Nrf 2引起脂质合成和摄取能力的降低。这表明Nrf 1和Nrf 2在细胞脂质代谢调节谱和相关病理反应中具有显著差异。进一步的实验揭示了Nrf 1 α-/-细胞中的脂质沉积是通过激活PI 3 K-AKT-mTOR途径上调CD 36导致的，从而诱导炎症反应。用2-溴棕榈酸酯（2BP）处理Nrf 1 α-/-细胞后，脂滴的产生显著减少，同时CD 36和关键的炎性细胞因子基本消失。2BP可显著改善Nrf 1 α-/--导致的脂质和ROS的炎症积聚。总的来说，这项研究提供了一种通过精确靶向Nrf 1、Nrf 2或两者来预防和治疗癌症的潜在策略。
Since Nrf1 and Nrf2 are essential for regulating the lipid metabolism pathways, their dysregulation was also shown to be critically involved in the non-controllable inflammatory pathology into cancer development. However, it is unknown that the interaction between Nrf1 and Nrf2 in the regulation of lipid metabolism, especially in hepatoma cells. Here, we have further explored the molecular mechanisms underlying their distinct regulation of lipid metabolism, by comparative analysis of 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 Nrf1 leads to disordered lipid metabolism; its lipid synthesis pathway was up-regulated by JNK-Nrf2-AP1 signaling, while its lipid decomposition pathway was down-regulated by the nuclear receptor PPAR-PGC1 signaling, 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 regulatory profiles and relevant pathological responses. Further experiments unraveled that lipid deposition in Nrf1α-/- cells was resulted from CD36 upregulation by activating the PI3K-AKT-mTOR pathway, leading to induction of the inflammatory response. Following treatment of Nrf1α-/- cells with 2-bromopaImitate (2BP), it enabled the yield of lipid droplets to be strikingly alleviated, as companied by substantial abolishment of CD36 and critical inflammatory cytokines. Such Nrf1α-/--led inflammatory accumulation of lipids and ROS was significantly ameliorated by 2BP. Overall, this study provides a potential strategy for cancer prevention and treatment by precision targeting of Nrf1, Nrf2, or both.