The roles of ATF3 in liver dysfunction and the regulation of phosphoenolpyruvate carboxykinase gene expression.
Activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element-binding protein family of transcription factors, is a transcriptional repressor, and the expression of its corresponding gene, ATF3, is induced by many stress signals. In this report, we demonstrate that transgenic mice expressing ATF3 in the liver had symptoms of liver dysfunction such as high levels of serum bilirubin, alkaline phosphatase, alanine transaminase, aspartate transaminase, and bile acids. In addition, these mice had physiological responses consistent with hypoglycemia including a low insulin:glucagon ratio in the serum and reduced adipose tissue mass. Electrophoretic mobility shift assays indicated that ATF3 bound to the ATF/cAMP-responsvie element site derived from the promoter of the gene encoding the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK). Furthermore, transient transfection assays indicated that ATF3 repressed the activity of the PEPCK promoter. Taken together, our results are consistent with the model that the expression of ATF3 in the liver results in defects in glucose homeostasis by repressing gluconeogenesis. Because ATF3 is a stress-inducible gene, these mice may provide a model to investigate the molecular mechanisms of some stress-associated liver diseases.
Allen-Jennings
Amy E
AE
Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210, USA.
Hartman
Matthew G
MG
Kociba
Gary J
GJ
Hai
Tsonwin
T
D051700:Activating Transcription Factor 3; D000818:Animals; D000831:Animals, Newborn; D001663:Bilirubin / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006003:Glycogen / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology*; D014162:Transfection
D051700:Activating Transcription Factor 3; D014157:Transcription Factors; D006003:Glycogen; D015500:Chloramphenicol O-Acetyltransferase; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D001663:Bilirubin