ATF3 mediates inhibitory effects of ethanol on hepatic gluconeogenesis.
Increases in circulating glucagon during fasting maintain glucose balance by stimulating hepatic gluconeogenesis. Acute ethanol intoxication promotes fasting hypoglycemia through an increase in hepatic NADH, which inhibits hepatic gluconeogenesis by reducing the conversion of lactate to pyruvate. Here we show that acute ethanol exposure also lowers fasting blood glucose concentrations by inhibiting the CREB-mediated activation of the gluconeogenic program in response to glucagon. Ethanol exposure blocked the recruitment of CREB and its coactivator CRTC2 to gluconeogenic promoters by up-regulating ATF3, a transcriptional repressor that also binds to cAMP-responsive elements and thereby down-regulates gluconeogenic genes. Targeted disruption of ATF3 decreased the effects of ethanol in fasted mice and in cultured hepatocytes. These results illustrate how the induction of transcription factors with overlapping specificity can lead to cross-coupling between stress and hormone-sensitive pathways.
Clayton Foundation Laboratories for Peptide Biology and.
Wen-Wei
WW
Tsai
Clayton Foundation Laboratories for Peptide Biology and.
Shigenobu
S
Matsumura
Clayton Foundation Laboratories for Peptide Biology and.
Weiyi
W
Liu
Clayton Foundation Laboratories for Peptide Biology and.
Naomi G
NG
Phillips
Clayton Foundation Laboratories for Peptide Biology and.
Tim
T
Sonntag
Clayton Foundation Laboratories for Peptide Biology and.
Ergeng
E
Hao
Laboratory of Neuronal Structure and Function, The Salk Institute for Biological Studies, La Jolla, CA 92037; and.
Soon
S
Lee
Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, OH 43210.
Tsonwin
T
Hai
Clayton Foundation Laboratories for Peptide Biology and montminy@salk.edu.
Marc
M
Montminy
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D005215:Fasting / Q000378:metabolism; D005943:Gluconeogenesis / Q000187:drug effects* / Q000235:genetics; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009249:NADP / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D002492:Central Nervous System Depressants; C492004:Creb1 protein, mouse; C504923:Crtc2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors; D000431:Ethanol; D009249:NADP; D005947:Glucose
ATF3; CREB; cAMP; glucagon; gluconeogenesis