title: Chronic ethanol consumption inhibits glucokinase transcriptional activity by Atf3 and triggers metabolic syndrome in vivo.
abstract: Chronic ethanol consumption induces pancreatic β-cell dysfunction through glucokinase (Gck) nitration and down-regulation, leading to impaired glucose tolerance and insulin resistance, but the underlying mechanism remains largely unknown. Here, we demonstrate that Gck gene expression and promoter activity in pancreatic β-cells were suppressed by chronic ethanol exposure in vivo and in vitro, whereas expression of activating transcription factor 3 (Atf3) and its binding to the putative Atf/Creb site (from -287 to -158 bp) on the Gck promoter were up-regulated. Furthermore, in vitro ethanol-induced Atf3 inhibited the positive effect of Pdx-1 on Gck transcriptional regulation, enhanced recruitment of Hdac1/2 and histone H3 deacetylation, and subsequently augmented the interaction of Hdac1/Pdx-1 on the Gck promoter, which were diminished by Atf3 siRNA. In vivo Atf3-silencing reversed ethanol-mediated Gck down-regulation and β-cell dysfunction, followed by the amelioration of impaired glucose tolerance and insulin resistance. Together, we identified that ethanol-induced Atf3 fosters β-cell dysfunction via Gck down-regulation and that its loss ameliorates metabolic syndrome and could be a potential therapeutic target in treating type 2 diabetes. The Atf3 gene is associated with the induction of type 2 diabetes and alcohol consumption-induced metabolic impairment and thus may be the major negative regulator for glucose homeostasis.
authors: Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea.
authors: Ji Yeon
authors: JY
authors: Kim
authors: Division of Structural and Functional Genomics, Center for Genomic Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea.
authors: Joo-Yeon
authors: JY
authors: Hwang
authors: Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea; Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
authors: Dae Yeon
authors: DY
authors: Lee
authors: Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea.
authors: Eun Hyun
authors: EH
authors: Song
authors: Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea; Division of Cardiology, Department of Internal Medicine, Chungbuk National University School of Medicine, Cheongju 361-763, Korea, and.
authors: Keon Jae
authors: KJ
authors: Park
authors: Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea.
authors: Gyu Hee
authors: GH
authors: Kim
authors: Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea.
authors: Eun Ae
authors: EA
authors: Jeong
authors: Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea.
authors: Yoo Jeong
authors: YJ
authors: Lee
authors: Division of Structural and Functional Genomics, Center for Genomic Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea.
authors: Min Jin
authors: MJ
authors: Go
authors: Departments of Psychiatry and College of Medicine, Catholic University, Bucheon 420-743, Korea.
authors: Dae Jin
authors: DJ
authors: Kim
authors: Departments of Endocrinology, College of Medicine, Catholic University, Bucheon 420-743, Korea.
authors: Seong Su
authors: SS
authors: Lee
authors: Division of Structural and Functional Genomics, Center for Genomic Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea.
authors: Bong-Jo
authors: BJ
authors: Kim
authors: Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea.
authors: Jihyun
authors: J
authors: Song
authors: Department of Anatomy and Neurobiology, Institute of Health Sciences, Gyeongsang National University, Jinju, Gyeongnam 660-751, Korea.
authors: Gu Seob
authors: GS
authors: Roh
authors: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892.
authors: Bin
authors: B
authors: Gao
authors: Division of Metabolic Disease, Center for Biomedical Science, National Institutes of Health, Osong-eup, Cheongwon-gun, Chungbuk 363-951, Korea. Electronic address: jhkwh@nih.go.kr.
authors: Won-Ho
authors: WH
authors: Kim
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000428:Alcohol Drinking / Q000009:adverse effects / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002492:Central Nervous System Depressants / Q000009:adverse effects* / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D000431:Ethanol / Q000009:adverse effects* / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D005941:Glucokinase / Q000096:biosynthesis* / Q000235:genetics; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D051379:Mice; D051381:Rats; D020218:Response Elements; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; C497108:Atf3 protein, rat; D002492:Central Nervous System Depressants; D018398:Homeodomain Proteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D000431:Ethanol; D005941:Glucokinase; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; C484389:Hdac1 protein, mouse; C515890:Hdac1 protein, rat; C533424:Hdac2 protein, mouse; C533426:Hdac2 protein, rat; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D005947:Glucose
keywords: Gene Expression; Gene Therapy; Glucokinase; Metabolic Disease; Pancreatic Islet; Type 2 Diabetes