title: ATF4 deficiency protects hepatocytes from oxidative stress via inhibiting CYP2E1 expression.
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.
authors.affiliation: 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.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Wang
authors.forename: Houkai
authors.initials: H
authors.lastname: Li
authors.forename: Qingshu
authors.initials: Q
authors.lastname: Meng
authors.forename: Ying
authors.initials: Y
authors.lastname: Du
authors.forename: Fei
authors.initials: F
authors.lastname: Xiao
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Junjie
authors.initials: J
authors.lastname: Yu
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.forename: Shanghai
authors.initials: S
authors.lastname: Chen
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Huang
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Feifan
authors.initials: F
authors.lastname: Guo
mesh_terms: D051701:Activating Transcription Factor 4 / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D004794:Enzyme Repression; D057809:HEK293 Cells; D022781:Hepatocytes / Q000201:enzymology*; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D010168:Palmitates / Q000633:toxicity; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: C081452:Atf4 protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D010168:Palmitates; D017382:Reactive Oxygen Species; D014280:Triglycerides; D051701:Activating Transcription Factor 4; D019392:Cytochrome P-450 CYP2E1
keywords: ATF4; CYP2E1; ROS; TG accumulation; oxidative stress; primary hepatocytes