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.
Highlights
Chronic ethanol consumption induces pancreatic -cell dysfunction and metabolic syndrome
We provide evidence that ethanol-induced activating transcription factor 3 (Atf3) suppresses Gck gene expression through direct interaction with the Atf/Creb-binding site (Ϫ185/Ϫ174) of the Gck promoter
This study demonstrates a functional role of Atf3 as a major upstream regulator that negatively regulates Gck transcriptional activity in ethanol-fed mice, based on the following observations. (i) The reduction of Gck transcriptional activity by ethanol was potentiated by Atf3, which was inhibited by Atf3 depletion. (ii) Two putative Atf3-binding sites that are essential for the inhibitory responsiveness by Atf3 were identified between Ϫ185 and Ϫ174 bp of the Gck promoter. (iii) Atf3 binds to the pancreatic duodenal homeobox-1 (Pdx-1)-binding sites between Ϫ102 and Ϫ92 of the
Summary
Chronic ethanol consumption induces pancreatic -cell dysfunction and metabolic syndrome. Chronic ethanol consumption induces pancreatic -cell dysfunction through glucokinase (Gck) nitration and downregulation, leading to impaired glucose tolerance and insulin resistance, but the underlying mechanism remains largely unknown. In vivo Atf3-silencing reversed ethanol-mediated Gck down-regulation and -cell dysfunction, followed by the amelioration of impaired glucose tolerance and insulin resistance. We identified that ethanol-induced Atf fosters -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. Chronic ethanol consumption is well established as an independent risk factor for type 2 diabetes (T2D) and has been suggested to cause increased adiposity, impaired glucose homeostasis, and insulin resistance (1, 2).
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have