Disruption of the Ugt1 locus in mice resembles human Crigler-Najjar type I disease
Disruption of the Ugt1 locus in mice resembles human Crigler-Najjar type I disease
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DOI：
10.1074/jbc.m709244200
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发表时间：
2008-03-21
影响因子：
4.8
通讯作者：
Tukey, Robert H.
中科院分区：
文献类型：
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作者：
Nguyen, Nghia;Bonzo, Jessica A.;Tukey, Robert H.
由人类UGT 1基因座编码的9种UDP-葡萄糖醛酸基转移酶（UGT）是大多数药物以及内源性物质（如胆汁酸、脂肪酸、类固醇、激素、神经递质和胆红素）代谢的关键酶。患有Crigler-Najjar I型疾病的人的严重非结合型高胆红素血症由UGT 1A 1基因的病变引起，并且通常是致命的。为了检查Ugt 1基因座在小鼠中的生理重要性，通过中断外显子4使该基因座无功能以产生Ugt 1（-/-）小鼠。由于UGT 1A 1在人体中负责100%的结合胆红素，因此新生Ugt 1（-/-）小鼠的血清非结合胆红素水平比Ugt 1（+/-）或野生型小鼠高40 - 60倍。Ugt 1（-/-）小鼠中极端未结合胆红素的结果（与Crigler-Najjar 1型疾病患者中观察到的诱导水平相当）在出生后2周内对新生Ugt 1（-/-）小鼠具有致死性。8小时后，皮肤颜色出现极端黄疸。新生Ugt 1（-/-）小鼠未检测到UGT 1A特异性RNA，这对应于肝微粒体中完全不存在UGT 1A蛋白。在Ugt 1（-/-）小鼠中可确定归因于Ugt 1基因座的保守葡萄糖醛酸化活性，因为UGT 2依赖性葡萄糖醛酸化活性不受影响。值得注意的是，肝脏中UGT 1A功能的丧失导致细胞代谢的显著改变，如通过基因表达的变化所研究的。因此，Ugt 1（-/-）小鼠中UGT 1A功能的丧失导致代谢综合征，可作为进一步研究与非结合胆红素相关的毒性以及该疾病对人类的影响的模型。
The 9 UDP-glucuronosyltranferases (UGTs) encoded by the UGT1 locus in humans are key enzymes in the metabolism of most drugs as well as endogenous substances such as bile acids, fatty acids, steroids, hormones, neurotransmitters, and bilirubin. Severe unconjugated hyperbilirubinemia in humans that suffer from Crigler-Najjar type I disease results from lesions in the UGT1A1 gene and is often fatal. To examine the physiological importance of the Ugt1 locus in mice, this locus was rendered non-functional by interrupting exon 4 to create Ugt1(-/-) mice. Because UGT1A1 in humans is responsible for 100% of the conjugated bilirubin, it followed that newborn Ugt1(-/-) mice developed serum levels of unconjugated bilirubin that were 40 - 60 times higher than Ugt1(+/-) or wild-type mice. The result of extreme unconjugated bilirubin in Ugt1(-/-) mice, comparable to the induced levels noted in patients with Crigler-Najjar type 1 disease, is fatal in neonatal Ugt1(-/-) mice within 2 weeks following birth. The extreme jaundice is present as a phenotype in skin color after 8 h. Neonatal Ugt1(-/-) mice exhibit no detectable UGT1A-specific RNA, which corresponds to a complete absence of UGT1A proteins in liver microsomes. Conserved glucuronidation activity attributed to the Ugt1 locus can be defined in Ugt1(-/-) mice, because UGT2-dependent glucuronidation activity is unaffected. Remarkably, the loss of UGT1A functionality in liver results in significant alterations in cellular metabolism as investigated through changes in gene expression. Thus, the loss of UGT1A function in Ugt1(-/-) mice leads to a metabolic syndrome that can serve as a model to further investigate the toxicities associated with unconjugated bilirubin and the impact of this disease in humans.