Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, The Graduate School of the Chinese Academy of Sciences, Shanghai, China.
J Cell Mol Med. 2014 Jan;18(1):80-90. doi: 10.1111/jcmm.12166. Epub 2013 Nov 6.
Activating transcription factor (ATF) 4 is involved in the regulation of oxidative stress in fibroblasts and neurons. The role of ATF4 in hepatocytes, however, is unknown. The aim of this study was to investigate the role of ATF4 in hepatocytes in oxidative stress under a high-fat diet (HFD). Here, we showed that palmitate-stimulated reactive oxygen species (ROS) production and triglyceride (TG) accumulation is blocked by ATF4 deficiency in primary hepatocytes. Consistently, HFD-induced oxidative stress, TG accumulation and expression of cytochrome P450, family 2, subfamily, polypeptide 1 (CYP2E1) are also blocked by knocking down ATF4 expression in the mouse liver. This suggests that ATF4 might regulate oxidative stress via CYP2E1 under an HFD. In addition, we observed that expression of CYP2E1 is indirectly regulated by ATF4 in a cAMP-responsive element binding protein (CREB)-dependent manner, which can directly activate the CYP2E1 promoter activity. Notably, ATF4-stimulated ROS production is inhibited in vivo by treatment with diallyl sulphide, a selective CYP2E1 inhibitor. Finally, we showed that ATF4 expression in the liver is responsible for the protective effects against HFD-induced CYP2E1 expression, oxidative stress, and TG accumulation. Taken together, these observations suggest that ATF4 is a novel regulator of oxidative stress as well as accumulation of TG in response to HFD.
激活转录因子 4（ATF4）参与调节成纤维细胞和神经元中的氧化应激。然而，ATF4 在肝细胞中的作用尚不清楚。本研究旨在研究在高脂肪饮食（HFD）下 ATF4 在肝细胞中对氧化应激的作用。在这里，我们表明棕榈酸刺激的活性氧（ROS）产生和甘油三酯（TG）积累被原代肝细胞中 ATF4 缺乏所阻断。一致地，HFD 诱导的氧化应激、TG 积累和细胞色素 P450，家族 2，亚家族，多肽 1（CYP2E1）的表达也被敲低小鼠肝脏中的 ATF4 表达所阻断。这表明 ATF4 可能通过 CYP2E1 在 HFD 下调节氧化应激。此外，我们观察到 CYP2E1 的表达是通过 ATF4 以 cAMP 反应元件结合蛋白（CREB）依赖性的方式间接调节的，它可以直接激活 CYP2E1 启动子活性。值得注意的是，用二烯丙基硫醚处理可抑制体内 ATF4 刺激的 ROS 产生，二烯丙基硫醚是一种选择性 CYP2E1 抑制剂。最后，我们表明肝脏中的 ATF4 表达负责对 HFD 诱导的 CYP2E1 表达、氧化应激和 TG 积累的保护作用。综上所述，这些观察结果表明 ATF4 是一种新型的氧化应激以及对 HFD 反应的 TG 积累的调节剂。
