title: Activating transcription factor 3 is a target molecule linking hepatic steatosis to impaired glucose homeostasis.
abstract: Non-alcoholic fatty liver disease (NAFLD) contributes to impaired glucose tolerance, leading to type 2 diabetes (T2D); however, the precise mechanisms and target molecules that are involved remain unclear. Activating transcription factor 3 (ATF3) is associated with β-cell dysfunction that is induced by severe stress signals in T2D. We aimed to explore the exact functional role of ATF3 as a mechanistic link between hepatic steatosis and T2D development.
  
  
  
  Zucker diabetic fatty (ZDF) rats were utilized for animal experiments. An in vivo-jetPEI siRNA delivery system against ATF3 was used for loss-of-function experiments. We analyzed the baseline cross-sectional data derived from the biopsy-proven NAFLD registry (n=322). Human sera and liver tissues were obtained from 43 patients with biopsy-proven NAFLD and from seven healthy participants.
  
  
  
  ATF3 was highly expressed in the livers of ZDF rats and in human participants with NAFLD and/or T2D. Insulin resistance and hepatic steatosis were associated with increased ATF3 expression and decreased fatty acid oxidation via mitochondrial dysfunction and were attenuated by in vivo ATF3 silencing. Knockdown of ATF3 also ameliorated glucose intolerance, impaired insulin action, and inflammatory responses in ZDF rats. In patients with NAFLD and/or T2D, a significant positive correlation was observed between hepatic ATF3 expression and surrogate markers of T2D, mitochondrial dysfunction, and macrophage infiltration.
  
  
  
  Increased hepatic ATF3 expression is closely associated with hepatic steatosis and incident T2D; therefore, ATF3 may serve as a potential therapeutic target for NAFLD and hepatic steatosis-induced T2D.
  
  
  
  Hepatic activating transcription factor 3 (ATF3) may play an important role in oxidative stress-mediated hepatic steatosis and the development of type 2 diabetes (T2D) in a Zucker diabetic fatty (ZDF) rat model and in human patients with non-alcoholic fatty liver disease (NAFLD). Therefore, ATF3 may be a useful biomarker for predicting the progression of NAFLD and the development of T2D. Furthermore, given the significant association between hepatic ATF3 expression and both hepatic steatosis and impaired glucose homeostasis, in vivo ATF3 silencing may be a potential central strategy for preventing and managing NAFLD and T2D.
authors.affiliation: Division of Metabolic Disease, #187 Osong Saengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 363-700, Republic of Korea.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Division of Metabolic Disease, #187 Osong Saengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 363-700, Republic of Korea; Department of Anatomy and Cardiology, Chungbuk University, Chungbuk, Republic of Korea.
authors.forename: Keon Jae
authors.initials: KJ
authors.lastname: Park
authors.affiliation: Division of Cardiovascular and Rare Disease, Center for Biomedical Science, #187 Osong Saengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 363-700, Republic of Korea; Division of Structural and Functional Genomics, Center for Genomic Science, National Institute of Health, #187 Osong Saengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 363-700, Republic of Korea.
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Hwang
authors.affiliation: Division of Metabolic Disease, #187 Osong Saengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 363-700, Republic of Korea.
authors.forename: Gyu Hee
authors.initials: GH
authors.lastname: Kim
authors.affiliation: Division of Metabolic Disease, #187 Osong Saengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 363-700, Republic of Korea; Department of Biotechnology, Korea University, Seoul, Republic of Korea.
authors.forename: DaeYeon
authors.initials: D
authors.lastname: Lee
authors.affiliation: Division of Metabolic Disease, #187 Osong Saengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 363-700, Republic of Korea.
authors.forename: Yoo Jeong
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Division of Metabolic Disease, #187 Osong Saengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 363-700, Republic of Korea.
authors.forename: Eun Hyun
authors.initials: EH
authors.lastname: Song
authors.affiliation: Division of Metabolic Disease, #187 Osong Saengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 363-700, Republic of Korea.
authors.forename: Min-Gyu
authors.initials: MG
authors.lastname: Yoo
authors.affiliation: Division of Structural and Functional Genomics, Center for Genomic Science, National Institute of Health, #187 Osong Saengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 363-700, Republic of Korea.
authors.forename: Bong-Jo
authors.initials: BJ
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Young Ho
authors.initials: YH
authors.lastname: Suh
authors.affiliation: Department of Anatomy and Neurobiology, Gyeongsang National University, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Gu Seob
authors.initials: GS
authors.lastname: Roh
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.affiliation: Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea. Electronic address: drwon1@snu.ac.kr.
authors.forename: Won
authors.initials: W
authors.lastname: Kim
authors.affiliation: Division of Metabolic Disease, #187 Osong Saengmyeong2-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 363-700, Republic of Korea. Electronic address: jhkwh@nih.go.kr.
authors.forename: Won-Ho
authors.initials: WH
authors.lastname: Kim
mesh_terms: D051700:Activating Transcription Factor 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism; D005260:Female; D018149:Glucose Intolerance / Q000209:etiology* / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D011446:Prospective Studies; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011924:Rats, Zucker; D015854:Up-Regulation
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C497108:Atf3 protein, rat; D015415:Biomarkers; D034741:RNA, Small Interfering
keywords: Activation transcription factor 3; Human patients; In vivo silencing; Non-alcoholic fatty liver disease; Oxidative stress; Zucker diabetic fatty rat