Role of the isoforms of CCAAT/enhancer-binding protein in the initiation of phosphoenolpyruvate carboxykinase (GTP) gene transcription at birth

The gene for phosphoenolpyruvate carboxykinase (PEPCK), a target of CCAAT/enhancer-binding protein-alpha (C/EBP alpha) and -beta (C/EBP beta), begins to be expressed in the liver at birth. Mice homozygous for a deletion in the gene for CEBP alpha (C/EBP alpha(-)/(-) mice) die shortly after birth of hypoglycemia, with no detectable hepatic PEPCK mRNA and negligible hepatic glycogen stores. Half of the mice homozygous for a deletion in the gene for CEBP beta(C/EBP beta(-)/(-) mice) have normal glucose homeostasis (phenotype A), and the other half die at birth of hypoglycemia due to a failure to express the gene for PEPCK and to mobilize hepatic glycogen (phenotype B). Insulin deficiency induces C/EBP alpha and PEPCK gene transcription in the livers of 19-day fetal rats, whereas dibutyryl cyclic AMP (Bt(2)cAMP) increases the expression of the gene for C/EBP beta and causes a transient burst of PEPCK mRNA. Bt(2)cAMP induces PEPCK mRNA in the livers of control animals; however, there is no induction of PEPCK mRNA if the cyclic nucleotide is injected into C/EBP alpha(-)/(-) mice immediately after delivery. The expression of the gene for C/EBP beta is markedly induced in the livers of C/EBP alpha(-)/(-) mice within 2 h after the administration of Bt(2)cAMP. C/EBP beta(-)/(-) mice injected at 20 days of fetal life with Bt(2)cAMP have a normal pattern of induction of hepatic PEPCK mRNA. In C/EBP beta(-)/(-) mice with phenotype B, the administration of Bt(2)cAMP immediately after delivery induces PEPCK mRNA, causes the mobilization of hepatic glycogen, and maintains normal glucose homeostasis for up to 4 h (duration of the experiment). We conclude that C/EBP alpha is required for the cAMP induction of PEPCK gene expression in the liver and that C/EBP beta can compensate for the loss of C/EBP alpha if its concentration is induced to appropriate levels.