The transcription factor CCAAT/enhancer-binding protein β regulates gluconeogenesis and phosphoenolpyruvate carboxykinase (GTP) gene transcription during diabetes
The transcription factor CCAAT/enhancer-binding protein β regulates gluconeogenesis and phosphoenolpyruvate carboxykinase (GTP) gene transcription during diabetes
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DOI：
10.1074/jbc.274.19.13033
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发表时间：
1999-05-07
影响因子：
4.8
通讯作者：
Friedman, JE
中科院分区：
文献类型：
--
作者：
Arizmendi, C;Liu, S;Friedman, JE
CCAAT/增强子结合蛋白（C/EBP）β和C/EBP α是c/ebp基因家族的成员，在哺乳动物肝脏和脂肪组织中高度表达。如C/EBP α基因敲除小鼠所示，C/EBP α对脂肪形成和新生儿胚胎形成至关重要。C/EBP β以高亲和力与磷酸烯醇丙酮酸羧激酶（PEPCK）基因启动子的几个序列结合，在链脲佐菌素糖尿病小鼠的肝脏中，C/EBP β蛋白增加200%，同时增加PEPCK mRNA。为了阐明C/EBP β在控制糖尿病过程中的代谢中的作用，我们研究了C/EBP β基因无效突变的杂合和纯合成年小鼠在糖尿病过程中与能量代谢相关的血浆代谢物和激素水平。我们还检测了PEPCK和葡萄糖6-磷酸酶mRNA的表达以及血糖的调节，包括c/ebp β（-/-）小鼠中造血对血糖的贡献。C/EBP β对基础PEPCK mRNA水平不是必需的。然而，C/EBP β缺失通过以下方式影响链脲佐菌素-糖尿病反应：（a）延迟高血糖，（B）防止血浆游离脂肪酸增加，（c）限制PEPCK和葡萄糖6-磷酸酶基因的完全诱导，以及（d）防止血管生成率增加。与PEPCK启动子的CRE、P3 I和AF-2位点结合的转录因子C/EBP α的凝胶超位移在糖尿病c/ebp β（-/-）小鼠肝细胞核中没有增加，表明C/EBP α在糖尿病肝基因转录反应中不能取代C/EBP β。这些结果将C/EBP β与糖尿病的代谢和基因调控反应联系起来，并暗示C/EBP β是完整动物中糖皮质激素依赖性PEPCK基因转录激活的基本因子。
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.