The transcription factor CCAAT/enhancer-binding protein beta regulates gluconeogenesis and phosphoenolpyruvate carboxykinase (GTP) gene transcription during diabetes.
CCAAT/enhancer-binding protein (C/EBP) beta and C/EBPalpha are members of the c/ebp gene family and are highly expressed in mammalian liver and adipose tissue. C/EBPalpha is essential for adipogenesis and neonatal gluconeogenesis, as shown by the C/EBPalpha knockout mouse. C/EBPbeta binds to several sequences of the phosphoenolpyruvate carboxykinase (PEPCK) gene promoter with high affinity, and C/EBPbeta protein is increased 200% in the livers of streptozotocin-diabetic mice, concurrent with increased PEPCK mRNA. To elucidate the role of C/EBPbeta in the control of gluconeogenesis during diabetes, we studied the levels of plasma metabolites and hormones related to energy metabolism during diabetes in adult mice heterozygous and homozygous for a null mutation of the gene for C/EBPbeta. We also examined the expression of PEPCK and glucose 6-phosphatase mRNAs and regulation of blood glucose, including the contribution of gluconeogenesis to blood glucose in c/ebpbeta-/- mice. C/EBPbeta was not essential to basal PEPCK mRNA levels. However, C/EBPbeta deletion affected streptozotocin-diabetic response by: (a) delaying hyperglycemia, (b) preventing the increase of plasma free fatty acids, (c) limiting the full induction of PEPCK and glucose 6-phosphatase genes, and (d) preventing the increase in gluconeogenesis rate. Gel supershifts of transcription factor C/EBPalpha, bound to CRE, P3I, and AF-2 sites of the PEPCK promoter, was not increased in diabetic c/ebpbeta-/- mouse liver nuclei, suggesting that C/EBPalpha does not substitute for C/EBPbeta in the diabetic response of liver gene transcription. These results link C/EBPbeta to the metabolic and gene regulatory responses to diabetes and implicate C/EBPbeta as an essential factor underlying glucocorticoid-dependent activation of PEPCK gene transcription in the intact animal.
Arizmendi
C
C
Department of Biochemistry and Molecular Biology, University of Salamanca School of Medicine, Salamanca E-37007, Spain.
Liu
S
S
Croniger
C
C
Poli
V
V
Friedman
J E
JE
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D004247:DNA; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005943:Gluconeogenesis / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics*; D011401:Promoter Regions, Genetic; D013311:Streptozocin; D014158:Transcription, Genetic / Q000502:physiology*
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D013311:Streptozocin; D004247:DNA; D010729:Phosphoenolpyruvate Carboxykinase (GTP)