Hypoglycemia-associated hyperammonemia caused by impaired expression of ornithine cycle enzyme genes in C/EBPα knockout mice
Hypoglycemia-associated hyperammonemia caused by impaired expression of ornithine cycle enzyme genes in C/EBPα knockout mice
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DOI：
10.1074/jbc.273.42.27505
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发表时间：
1998-10-16
影响因子：
4.8
通讯作者：
Takiguchi, M
中科院分区：
文献类型：
--
作者：
Kimura, T;Christoffels, VM;Takiguchi, M
由氨基酸代谢产生的氨通过肝脏中的鸟氨酸循环转化为尿素而解毒，而氨基酸的碳骨架则通过产酸酶转化为葡萄糖。鸟氨酸循环酶的几个基因的启动子和增强子序列与CCAAT/增强子结合蛋白（C/EBP）转录因子家族的成员相互作用。小鼠中C/EBP α基因的破坏导致与致血糖酶表达受损相关的低血糖。在这里，我们研究了C/EBP α缺陷小鼠肝脏中鸟氨酸循环酶基因的表达。在C/EBP α缺陷小鼠中，循环中五种酶的第一、第三、第四和第五种酶的mRNA水平降低。第一、第二、第四和第五种酶的蛋白质水平也降低。原位杂交分析显示，酶mRNA在门静脉周围区域正常分布，但在C/EBP α缺陷小鼠中分布混乱，小叶中部区域mRNA水平相对较高。突变小鼠的血氨浓度比野生型小鼠高几倍。因此，C/EBP α对于通过鸟氨酸循环酶的氨解毒以及对于代谢和尿素合成的协调至关重要。
Ammonia produced by amino acid metabolism is detoxified through conversion into urea by the ornithine cycle in the Liver, whereas carbon skeletons of amino acids are converted to glucose by gluconeogenic enzymes. Promoter and enhancer sequences of several genes for ornithine cycle enzymes interact with members of the CCAAT/enhancer-binding protein (C/EBP) transcription factor family. Disruption of the C/EBP alpha gene in mice causes hypoglycemia associated with the impaired expression of gluconeogenic enzymes. Here we examined the expression of ornithine cycle enzyme genes in the livers of C/EBP alpha-deficient mice. mRNA levels for the first, third, fourth, and fifth enzymes of five enzymes in the cycle were decreased in C/EBP alpha-deficient mice. Protein levels for the first, second, fourth, and fifth enzymes were also decreased. In situ hybridization analysis revealed that the enzyme mRNAs were distributed normally in the periportal region but were disordered in C/EBP alpha-deficient mice with relatively higher mRNA levels in the midlobular region. Blood ammonia concentrations in the mutant mice were severalfold higher than in wild-type mice. Thus, C/EBP alpha is crucial for ammonia detoxification by ornithine cycle enzymes and for coordination of gluconeogenesis and urea synthesis.