Chronic ethanol consumption inhibits glucokinase transcriptional activity by Atf3 and triggers metabolic syndrome in vivo

J Biol Chem. 2014 Sep 26;289(39):27065-27079. doi: 10.1074/jbc.M114.585653. Epub 2014 Jul 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Rats
  • Response Elements
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription, Genetic / drug effects*
  • Transcription, Genetic / genetics

Substances

  • ATF3 protein, human
  • Activating Transcription Factor 3
  • Atf3 protein, mouse
  • Atf3 protein, rat
  • Central Nervous System Depressants
  • Homeodomain Proteins
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Ethanol
  • Glucokinase
  • HDAC1 protein, human
  • HDAC2 protein, human
  • Hdac1 protein, mouse
  • Hdac1 protein, rat
  • Hdac2 protein, mouse
  • Hdac2 protein, rat
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Glucose