title: Liver-specific Gene Inactivation of the Transcription Factor ATF4 Alleviates Alcoholic Liver Steatosis in Mice.
abstract: Although numerous biological functions of the activating transcription factor 4 (ATF4) have been identified, a direct effect of ATF4 on alcoholic liver steatosis has not been described previously. The aim of our current study is to investigate the role of ATF4 in alcoholic liver steatosis and elucidate the underlying mechanisms. Here, we showed that the expression of ATF4 is induced by ethanol in hepatocytes in vitro and in vivo, and liver-specific ATF4 knock-out mice are resistant to ethanol-induced liver steatosis, associated with stimulated hepatic AMP-activated protein kinase (AMPK) activity. Furthermore, adenovirus-mediated AMPK knockdown significantly reversed the suppressive effects of ATF4 deficiency on ethanol-induced liver steatosis in mice. In addition, ethanol-fed ATF4 knock-out mice exhibit AMPK-dependent inhibition of fatty acid synthase and stimulation of carnitine palmitoyltransferase 1 (CPT1) in the liver. Moreover, hepatic Tribbles homolog 3 (TRB3) expression was stimulated by ethanol in an ATF4-dependent manner, and adenovirus-mediated TRB3 knockdown blocked ATF4-dependent ethanol-induced AMPK inhibition and triglyceride accumulation in AML-12 cells. Finally, TRB3 directly interacted with AMPK to suppress its phosphorylation. Taken together, these results identify the ATF4-TRB3-AMPK axis as a novel pathway responsible for ethanol-induced liver steatosis.
authors.affiliation: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, the Graduate School of the Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.affiliation: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, the Graduate School of the Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, the Graduate School of the Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Yu
authors.affiliation: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, the Graduate School of the Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Xia
authors.affiliation: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, the Graduate School of the Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, the Graduate School of the Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Guo
authors.affiliation: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, the Graduate School of the Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Deng
authors.affiliation: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, the Graduate School of the Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
authors.forename: Shanghai
authors.initials: S
authors.lastname: Chen
authors.affiliation: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, the Graduate School of the Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China wangcx@sibs.ac.cn.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Wang
authors.affiliation: From the Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, the Graduate School of the Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China ffguo@sibs.ac.cn.
authors.forename: Feifan
authors.initials: F
authors.lastname: Guo
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D000431:Ethanol / Q000009:adverse effects / Q000494:pharmacology; D005235:Fatty Liver, Alcoholic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D015398:Signal Transduction; D014280:Triglycerides / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C081452:Atf4 protein, mouse; D018797:Cell Cycle Proteins; C474830:TRB3 protein, mouse; D014280:Triglycerides; D051701:Activating Transcription Factor 4; D000431:Ethanol; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated kinase (AMPK); ATF4; Alcoholic liver steatosis; CPT1; TRB3; fatty acid synthase (FAS); lipid; liver injury; liver metabolism