Hepatic glutamine synthetase augmentation enhances ammonia detoxification
Hepatic glutamine synthetase augmentation enhances ammonia detoxification
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DOI：
10.1002/jimd.12070
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发表时间：
2019-11-01
影响因子：
4.2
通讯作者：
Brunetti-Pierri, Nicola
中科院分区：
文献类型：
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作者：
Soria, Leandro R.;Nitzahn, Matthew;Brunetti-Pierri, Nicola
尿素循环和谷氨酰胺合成酶（GS）是废水脱氮的两条主要途径，它们的缺乏会导致高氨血症。在这里，我们研究了肝脏特异性GS过表达治疗高氨血症的疗效。为了实现肝脏GS过表达，我们产生了辅助依赖性腺病毒（HDAd）载体，在肝脏特异性表达盒（HDAd-GS）的控制下表达鼠GS。与注射表达无关报告基因（HDAd-甲胎蛋白）的对照载体的小鼠相比，肝GS增加的野生型小鼠在腹膜内注射氯化铵后显示血氨水平降低和血谷氨酰胺伴随增加，而血尿素不受影响。此外，注射HDAd-GS降低了基线时的血氨水平，并在氨激发后在氨甲酰磷酸合成酶1（Cps 1）条件性肝缺陷小鼠模型中保护急性高氨血症，Cps 1是尿素生成的初始和限速步骤。总之，我们发现肝GS的上调减少了野生型和Cps 1缺陷小鼠的高氨血症，从而证实了GS在氨解毒中的关键作用。这些结果表明，肝脏GS增强治疗有可能治疗原发性和继发性高氨血症。
The urea cycle and glutamine synthetase (GS) are the two main pathways for waste nitrogen removal and their deficiency results in hyperammonemia. Here, we investigated the efficacy of liver-specific GS overexpression for therapy of hyperammonemia. To achieve hepatic GS overexpression, we generated a helper-dependent adenoviral (HDAd) vector expressing the murine GS under the control of a liver-specific expression cassette (HDAd-GS). Compared to mice injected with a control vector expressing an unrelated reporter gene (HDAd-alpha-fetoprotein), wild-type mice with increased hepatic GS showed reduced blood ammonia levels and a concomitant increase of blood glutamine after intraperitoneal injections of ammonium chloride, whereas blood urea was unaffected. Moreover, injection of HDAd-GS reduced blood ammonia levels at baseline and protected against acute hyperammonemia following ammonia challenge in a mouse model with conditional hepatic deficiency of carbamoyl phosphate synthetase 1 (Cps1), the initial and rate-limiting step of ureagenesis. In summary, we found that upregulation of hepatic GS reduced hyperammonemia in wild-type and Cps1-deficient mice, thus confirming a key role of GS in ammonia detoxification. These results suggest that hepatic GS augmentation therapy has potential for treatment of both primary and secondary forms of hyperammonemia.