ATF4 deficiency protects hepatocytes from oxidative stress via inhibiting CYP2E1 expression

Journal of Cellular and Molecular Medicine

Chunxia Wang¹  Houkai Li¹  Qingshu Meng¹  Ying Du¹  Fei Xiao¹  Qian Zhang¹  Junjie Yu¹  Kai Li¹  Shanghai Chen¹  Zhiying Huang¹  Bin Liu¹ 

[1] 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

关键词: ATF4;    primary hepatocytes;    CYP2E1;    oxidative stress;    ROS;    TG accumulation;   

DOI  :  10.1111/jcmm.12166

来源: Wiley

【 摘 要 】

Abstract

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.

【 授权许可】

CC BY   
© 2013 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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