ATF4 deficiency protects hepatocytes from oxidative stress via inhibiting CYP2E1 expression. Issue 1 (6th November 2013)

• Record Type: Journal Article
• Authors: Wang, Chunxia; Li, Houkai; Meng, Qingshu; Du, Ying; Xiao, Fei; Zhang, Qian; Yu, Junjie; Li, Kai; Chen, Shanghai; Huang, Zhiying; Liu, Bin; Guo, Feifan
• Is Part Of: Journal of cellular and molecular medicine. Volume 18:Issue 1(2014)
• Page Start: 80
• Page End: 90
• Publication Date: 2013-11-06
• Subjects: Cytology; Medicine; Molecular Biology; Cytologie -- Périodiques; Médecine -- Périodiques; Biologie moléculaire -- Périodiques; Cytology -- Periodicals; Medicine -- Periodicals; Molecular biology -- Periodicals; 611.01805
• DOI: 10.1111/jcmm.12166
• Languages: English
• ISSNs: 1582-1838

Abstract

<abstract abstract-type="main" id="jcmm12166-abs-0001"> <title>Abstract</title> <p>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 <italic>via </italic>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 <italic>in vivo</italic> 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.</p> </abstract>