Hyperphenylalaninemia and impaired glucose tolerance in mice lacking the bifunctional DCoH gene
Hyperphenylalaninemia and impaired glucose tolerance in mice lacking the bifunctional DCoH gene
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DOI：
10.1074/jbc.m201983200
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发表时间：
2002-08-09
影响因子：
4.8
通讯作者：
Crabtree, GR
中科院分区：
文献类型：
--
作者：
Bayle, JH;Randazzo, F;Crabtree, GR
双功能蛋白DCoH（HNF 1的二聚辅因子）在中间代谢中起酶的作用，并作为转录激活因子HNF 1家族的结合伴侣。HNF1蛋白指导肝脏、肾脏、胰腺和肠道中多种基因的表达，对葡萄糖稳态的调节至关重要。HNF1a基因突变是人类年轻人成熟型糖尿病（MODY3）的基础。DCoH作为HNF 1的辅因子，稳定二聚体HNF 1复合物。DCoH还催化四氢生物蝶呤的再循环，四氢生物蝶呤是芳香族氨基酸羟化酶的辅因子。为了检查DCoH的作用，创建了鼠DCoH基因的靶向缺失等位基因。缺乏DCoH的小鼠是可行的和可生育的，但显示高苯丙氨酸血症和白内障形成的倾向。令人惊讶的是，DCoH基因敲除小鼠中的HNF1功能仅轻微受损，与糖尿病HNF1 α基因敲除小鼠相比，小鼠具有轻度葡萄糖不耐受性。DCoH的功能，因为它涉及到HNF 1的活动似乎是部分补充了一个新发现的同源物，DCoH2。
The bifunctional protein DCoH (Dimerizing Cofactor for HNF1) acts as an enzyme in intermediary metabolism and as a binding partner of the HNF1 family of transcriptional activators. HNF1 proteins direct the expression of a variety of genes in the liver, kidney, pancreas, and gut and are critical to the regulation of glucose homeostasis. Mutations of the HNF1 a gene underlie maturity onset diabetes of the young (MODY3) in humans. DCoH acts as a cofactor for HNF1 that stabilizes the dimeric HNF1 complex. DCoH also catalyzes the recycling of tetrahydrobiopterin, a cofactor of aromatic amino acid hydroxylases. To examine the roles of DCoH, a targeted deletion allele of the murine DCoH gene was created. Mice lacking DCoH are viable and fertile but display hyperphenylalaninemia and a predisposition to cataract formation. Surprisingly, HNF1 function in DCoH null mice is only slightly impaired, and mice are mildly glucose-intolerant in contrast to HNF1alpha null mice, which are diabetic. DCoH function as it pertains to HNF1 activity appears to be partially complemented by a newly identified homolog, DCoH2.