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Hepatic glutamine synthetase augmentation enhances ammonia detoxification.

ABSTRACT: 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.

SUBMITTER: Soria LR

PROVIDER: S-EPMC6684872 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Hepatic glutamine synthetase augmentation enhances ammonia detoxification.

Soria Leandro R LR Nitzahn Matthew M De Angelis Angela A Khoja Suhail S Attanasio Sergio S Annunziata Patrizia P Palmer Donna J DJ Ng Philip P Lipshutz Gerald S GS Brunetti-Pierri Nicola N

Journal of inherited metabolic disease 20190311 6

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 u ...[more]

PMID: 30724386

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Hepatic glutamine synthetase augmentation enhances ammonia detoxification.

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Hepatic glutamine synthetase augmentation enhances ammonia detoxification.

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