Metabolic response of mice to a postnatal ablation of CCAAT/enhancer-binding protein α
Metabolic response of mice to a postnatal ablation of CCAAT/enhancer-binding protein α
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DOI：
10.1074/jbc.m503486200
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发表时间：
2005-11-18
影响因子：
4.8
通讯作者：
Hanson, RW
中科院分区：
文献类型：
--
作者：
Yang, JQ;Croniger, CM;Hanson, RW
虽然CCAAT/增强子结合蛋白α（C/EBP α）在围产期启动或维持几个代谢过程是必不可少的，但出生后发育过程中C/EBP α完全消融的后果尚未研究。我们已经建立了一个条件性基因敲除模型，其中给予poly（I：C）导致小鼠肝脏、脾脏、白色和棕色脂肪组织、胰腺、肺和肾脏中c/ebp α（C/EBP α（Delta/-）小鼠）几乎完全缺失。在注射poly（I：C）后第4天，C/EBP α本身在肝脏中完全消融。在注射后的前15天内，表型没有明显变化。小鼠保持正常的空腹血糖水平，并对链脲佐菌素的致糖尿病作用作出反应。从第16天开始，小鼠出现食欲减退，表现出严重的体重减轻，在白色但不是棕色脂肪组织中损失甘油三酯，变得低血糖和低胰岛素血症，耗尽它们的肝糖原，并出现脂肪肝。他们还表现出血浆游离脂肪酸、甘油三酯和胆固醇水平降低，以及C/EBP δ、过氧化物酶体增殖物激活受体α、固醇调节元件结合蛋白1、羟甲基戊二酰辅酶A还原酶和载脂蛋白的肝脏mRNA发生显著变化。虽然磷酸烯醇式丙酮酸羧激酶和葡萄糖-6-磷酸酶的胞质异构体的肝脏mRNA的基础水平降低，这些酶的基因的转录是由C/EBP α（Delta/-）小鼠的二丁酰环AMP诱导。动物在注射poly（I：C）后约1个月死亡。这些研究结果表明，C/EBP α是必不可少的生存动物在出生后的生活，其消融导致明显的双相变化的代谢过程。
Although CCAAT/enhancer-binding protein alpha (C/EBP alpha) is essential for initiating or sustaining several metabolic processes during the perinatal period, the consequences of total ablation of C/EBP alpha during postnatal development have not been investigated. We have created a conditional knock-out model in which the administration of poly(I:C) caused a virtually total deletion of c/ebp alpha(C/EBP alpha(Delta/-) mice) in the liver, spleen, white and brown adipose tissues, pancreas, lung, and kidney of the mice. C/EBP alpha itself was completely ablated in the liver by day 4 after the injection of poly(I:C). There was no noticeable change in phenotype during the first 15 days after the injection. The mice maintained a normal level of fasting blood glucose and responded to the diabetogenic action of streptozotocin. From day 16 onward, the mice developed hypophagia, exhibited severe weight loss, lost triglyceride in white but not brown adipose tissue, became hypoglycemic and hypoinsulinemic, depleted their hepatic glycogen, and developed fatty liver. They also exhibited lowered plasma levels of free fatty acid, triglyceride, and cholesterol, as well as marked changes in hepatic mRNA for C/EBP delta, peroxisome proliferator-activated receptor alpha, sterol regulatory element-binding protein 1, hydroxymethylglutaryl-coenzyme A reductase, and apolipoproteins. Although basal levels of hepatic mRNA for the cytosolic isoform of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase were reduced, transcription of the genes for these enzymes was inducible by dibutyryl cyclic AMP in C/EBP alpha(Delta/-) mice. The animals died about 1 month after the injection of poly(I:C). These findings demonstrate that C/EBP alpha is essential for the survival of animals during postnatal life and that its ablation leads to distinct biphasic change in metabolic processes.