C. Croniger et al., ROLE OF THE ISOFORMS OF CCAAT ENHANCER-BINDING PROTEIN IN THE INITIATION OF PHOSPHOENOLPYRUVATE CARBOXYKINASE (GTP) GENE-TRANSCRIPTION AT BIRTH/, The Journal of biological chemistry, 272(42), 1997, pp. 26306-26312
The gene for phosphoenolpyruvate carboxykinase (PEPCK), a target of CC
AAT/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 sho
rtly after birth of hypoglycemia, with no detectable hepatic PEPCK mRN
A 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 bi
rth of hypoglycemia due to a failure to express the gene for PEPCK and
to mobilize hepatic glycogen (phenotype B). Insulin deficiency induce
s C/EBP alpha and PEPCK gene transcription in the livers of 19-day fet
al rats, whereas dibutyryl cyclic AMP (Bt(2)cAMP) increases the expres
sion 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; h
owever, there is no induction of PEPCK mRNA if the cyclic nucleotide i
s injected into C/EBP alpha(-)/(-) mice immediately after delivery. Th
e expression of the gene for C/EBP beta is markedly induced in the liv
ers 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 wi
th 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 mobil
ization of hepatic glycogen, and maintains normal glucose homeostasis
for up to 4 h (duration of the experiment). We conclude that C/EBP alp
ha 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 i
f its concentration is induced to appropriate levels.