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J Biol Chem, Vol. 274, Issue 19, 13033-13040, May 7, 1999
The Transcription Factor CCAAT/Enhancer-binding Protein Regulates Gluconeogenesis and Phosphoenolpyruvate Carboxykinase (GTP)
Gene Transcription during Diabetes
Carmen
Arizmendi ,
Sha
Liu§,
Colleen
Croniger¶,
Valeria
Poli**, and
Jacob E.
Friedman§
From the Departments of § Nutrition and
¶ Biochemistry, Case Western Reserve University School of
Medicine, Cleveland, Ohio 44106-4935, the Department of
Biochemistry and Molecular Biology, University of Salamanca School of
Medicine, Salamanca E-37007, Spain, and the ** Department of
Biochemistry, University of Dundee, Dundee, Scotland, United
Kingdom
CCAAT/enhancer-binding protein
(C/EBP) and C/EBP are members of the c/ebp gene
family and are highly expressed in mammalian liver and adipose tissue.
C/EBP is essential for adipogenesis and neonatal gluconeogenesis, as
shown by the C/EBP knockout mouse. C/EBP binds to several
sequences of the phosphoenolpyruvate carboxykinase (PEPCK) gene
promoter with high affinity, and C/EBP protein is increased 200% in
the livers of streptozotocin-diabetic mice, concurrent with increased
PEPCK mRNA. To elucidate the role of C/EBP 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/EBP . 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/ebp / mice. C/EBP was not essential
to basal PEPCK mRNA levels. However, C/EBP 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/EBP , bound to CRE, P3I, and AF-2 sites of the PEPCK
promoter, was not increased in diabetic
c/ebp / mouse liver nuclei, suggesting
that C/EBP does not substitute for C/EBP in the diabetic response
of liver gene transcription. These results link C/EBP to the
metabolic and gene regulatory responses to diabetes and implicate
C/EBP as an essential factor underlying
glucocorticoid-dependent activation of PEPCK gene
transcription in the intact animal.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 1999 by the American Society for Biochemistry and Molecular Biology.
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