The transcription factor CCAAT/enhancer-binding protein β regulates gluconeogenesis and phosphoenolpyruvate carboxykinase (GTP) gene transcription during diabetes

被引:71
|
作者
Arizmendi, C
Liu, S
Croniger, C
Poli, V
Friedman, JE
机构
[1] Case Western Reserve Univ, Dept Nutr, Sch Med, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Dept Biochem, Sch Med, Cleveland, OH 44106 USA
[3] Univ Salamanca, Sch Med, Dept Biochem & Mol Biol, E-37007 Salamanca, Spain
[4] Univ Dundee, Dept Biochem, Dundee DD1 4HN, Scotland
关键词
D O I
10.1074/jbc.274.19.13033
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
CCAAT/enhancer-binding protein (C/EBP) beta and C/EBP alpha are members of the c/ebp gene family and are highly expressed in mammalian liver and adipose tissue. C/EBP alpha is essential for adipogenesis and neonatal gluconeogenesis, as shown by the C/EBP alpha knockout mouse. C/EBP beta binds to several sequences of the phosphoenolpyruvate carboxykinase (PEPCK) gene promoter with high affinity, and C/EBP beta protein is increased 200% in the livers of streptozotocin-diabetic mice, concurrent with increased PEPCK mRNA. To elucidate the role of C/EBP beta 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 beta. 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 beta(-/-) mice. C/EBP beta was not essential to basal PEPCK mRNA levels. However, C/EBP beta 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 alpha, bound to CRE, P3I, and AF-2 sites of the PEPCK promoter, was not increased in diabetic c/ebp beta(-/-) mouse liver nuclei, suggesting that C/EBP alpha does not substitute for C/EBP beta in the diabetic response of liver gene transcription. These results ling C/EBP beta to the metabolic and gene regulatory responses to diabetes and implicate C/EBP beta as an essential factor underlying glucocorticoid-dependent activation of PEPCK gene transcription in the intact animal.
引用
收藏
页码:13033 / 13040
页数:8
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