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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.

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