Chronic Ethanol Consumption Inhibits Glucokinase Transcriptional Activity by Atf3 and Triggers Metabolic Syndrome in Vivo

• Published in: The Journal of biological chemistry 2014-09, Vol.289 (39), p.27065-27079
• Main Authors: Kim, Ji Yeon, Hwang, Joo-Yeon, Lee, Dae Yeon, Song, Eun Hyun, Park, Keon Jae, Kim, Gyu Hee, Jeong, Eun Ae, Lee, Yoo Jeong, Go, Min Jin, Kim, Dae Jin, Lee, Seong Su, Kim, Bong-Jo, Song, Jihyun, Roh, Gu Seob, Gao, Bin, Kim, Won-Ho
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 3 - genetics; Activating Transcription Factor 3 - metabolism; Alcohol Drinking - adverse effects; Alcohol Drinking - genetics; Alcohol Drinking - metabolism; Animals; Cell Line; Central Nervous System Depressants - adverse effects; Central Nervous System Depressants - pharmacology; Diabetes Mellitus, Type 2 - chemically induced; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Ethanol - adverse effects; Ethanol - pharmacology; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - genetics; Glucokinase - biosynthesis; Glucokinase - genetics; Glucose - genetics; Glucose - metabolism; Histone Deacetylase 1 - genetics; Histone Deacetylase 1 - metabolism; Histone Deacetylase 2 - genetics; Histone Deacetylase 2 - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Insulin-Secreting Cells - metabolism; Male; Metabolic Syndrome - etiology; Metabolic Syndrome - genetics; Metabolic Syndrome - metabolism; Mice; Molecular Bases of Disease; Rats; Response Elements; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription, Genetic - drug effects; Transcription, Genetic - genetics
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.585653

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.