Glycine N-methyltransferase-/- mice develop chronic hepatitis and glycogen storage disease in the liver
Glycine N-methyltransferase-/- mice develop chronic hepatitis and glycogen storage disease in the liver
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DOI：
10.1002/hep.21863
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发表时间：
2007-11-01
期刊：
影响因子：
13.5
通讯作者：
Chen, Yi-Ming Arthur
中科院分区：
文献类型：
--
作者：
Liu, Shih-Ping;Li, Ying-Shiuan;Chen, Yi-Ming Arthur
甘氨酸N-甲基转移酶（GNMT）通过调节DNA甲基化和与环境致癌物相互作用影响遗传稳定性。为了建立Gnmt敲除小鼠模型，分离了2个含有小鼠Gnmt基因组的λ噬菌体克隆。在11周龄时，Gnmt（-/-）小鼠具有肝肿大、高甲硫氨酸血症以及显著更高水平的血清丙氨酸转氨酶和肝S-腺苷甲硫氨酸。这种表型模拟患有先天性GNMT缺陷的患者。对一碳代谢途径中10个基因的实时聚合酶链反应分析显示，Gnmt（-/-）小鼠中5，10-亚甲基四氢叶酸还原酶、S-腺苷高半胱氨酸水解酶（Ahcy）和甲酰亚胺转移酶环脱氨酶（Ftcd）显著下调。该报告表明，GNMT调节Ftcd和Ahcy基因的表达。病理学检查结果显示，Gnmt（-/-）小鼠肝糖原累积病（GSD）发生率为57.1%（8/14）。在雄性Gnmt（-/-）肝脏中观察到局灶性坏死，而在雌性Gnmt（-/-）肝脏的中间区发现退行性变化。此外，在Gnmt（-/-）小鼠中观察到低血糖、血清胆固醇升高以及白色血细胞、中性粒细胞和单核细胞数量显著降低。实时聚合酶链反应分析参与胚胎发生途径的基因显示，以下基因在Gnmt（-/-）小鼠中显著下调：果糖1，6-二磷酸酶、磷酸烯醇丙酮酸羧激酶和葡萄糖-6-磷酸转运蛋白。结论：由于Gnmt（-/-）小鼠表型模仿GNMT缺陷患者的表型，并与GSD Ib患者共享几个特征，我们建议，它们是有用的先天性GNMT缺陷的发病机制和GNMT在GSD和肝脏肿瘤发生中的作用的研究。
Glycine N-methyltransferase (GNMT) affects genetic stability by regulating DNA methylation and interacting with environmental carcinogens. To establish a Gnmt knockout mouse model, 2 lambda phage clones containing a mouse Gnmt genome were isolated. At I I weeks of age, the Gnmt(-/-) mice had hepatomegaly, hypermethioninemia, and significantly higher levels of both serum alanine aminotransferase and hepatic S-adenosylmethionine. Such phenotypes mimic patients with congenital GNMT deficiencies. A real-time polymerase chain reaction analysis of 10 genes in the one-carbon metabolism pathway revealed that 5,10-methylenetetrahydrofolate reductase, S-adenosylhomocysteine hydrolase (Ahcy), and formiminotransferase cyclodeaminase (Ftcd) were significantly down-regulated in Gnmt(-/-) mice. This report demonstrates that GNMT regulates the expression of both Ftcd and Ahcy genes. Results from pathological examinations indicated that 57.1% (8 of 14) of the Gnmt(-/-) mice had glycogen storage disease (GSD) in their livers. Focal necrosis was observed in male Gnmt(-/-) livers, whereas degenerative changes were found in the intermediate zones of female Gnmt(-/-) livers. In addition, hypoglycemia, increased serum cholesterol, and significantly lower numbers of white blood cells, neutrophils, and monocytes were observed in the Gnmt(-/-) mice. A real-time polymerase chain reaction analysis of genes involved in the gluconeogenesis pathways revealed that the following genes were significantly down-regulated in Gnmt(-/-) mice: fructose 1,6-bisphosphatase, phosphoenolpyruvate carboxykinase, and glucose-6-phosphate transporter. Conclusion: Because Gnmt(-/-) mice phenotypes mimic those of patients with GNMT deficiencies and share several characteristics with GSD Ib patients, we suggest that they are useful for studies of the pathogenesis of congenital GNMT deficiencies and the role of GNMT in GSD and liver tumorigenesis.