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.
Keywords:
Gene Expression; Gene Therapy; Glucokinase; Metabolic Disease; Pancreatic Islet; Type 2 Diabetes.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 3 / genetics
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Activating Transcription Factor 3 / metabolism*
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Alcohol Drinking* / adverse effects
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Alcohol Drinking* / genetics
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Alcohol Drinking* / metabolism
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Animals
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Cell Line
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Central Nervous System Depressants / adverse effects*
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Central Nervous System Depressants / pharmacology
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Diabetes Mellitus, Type 2 / chemically induced
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Diabetes Mellitus, Type 2 / genetics
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Diabetes Mellitus, Type 2 / metabolism
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Ethanol / adverse effects*
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Ethanol / pharmacology
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Enzymologic / genetics
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Glucokinase / biosynthesis*
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Glucokinase / genetics
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Glucose / genetics
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Glucose / metabolism
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Histone Deacetylase 1 / genetics
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Histone Deacetylase 1 / metabolism
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Histone Deacetylase 2 / genetics
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Histone Deacetylase 2 / metabolism
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Insulin-Secreting Cells / metabolism
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Male
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Metabolic Syndrome* / etiology
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Metabolic Syndrome* / genetics
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Metabolic Syndrome* / metabolism
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Mice
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Rats
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Response Elements
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription, Genetic / drug effects*
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Transcription, Genetic / genetics
Substances
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ATF3 protein, human
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Activating Transcription Factor 3
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Atf3 protein, mouse
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Atf3 protein, rat
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Central Nervous System Depressants
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Homeodomain Proteins
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Trans-Activators
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pancreatic and duodenal homeobox 1 protein
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Ethanol
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Glucokinase
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HDAC1 protein, human
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HDAC2 protein, human
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Hdac1 protein, mouse
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Hdac1 protein, rat
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Hdac2 protein, mouse
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Hdac2 protein, rat
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Histone Deacetylase 1
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Histone Deacetylase 2
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Glucose