biostudies-literatureUnknown45(3)Mao XAmino acids, the building blocks of proteins in the cells and tissues, are of fundamental importance for cell survival, maintenance, and proliferation. The liver plays a critical role in amino acid metabolism and detoxication of byproducts such as ammonia. Urea cycle disorders with hyperammonemia remain difficult to treat and eventually necessitate liver transplantation. In this study, ornithine transcarbamylase deficient (Otc^spf-ash ) mouse model was used to test whether knockdown of a key glutamine metabolism enzyme glutaminase 2 (GLS2, gene name: Gls2) or glutamate dehydrogenase 1 (GLUD1, gene name: Glud1) could rescue the hyperammonemia and associated lethality induced by a high protein diet. We found that reduced hepatic expression of Gls2 but not Glud1 by AAV8-mediated delJournal of inherited metabolic disease470-480https://www.ebi.ac.uk/biostudies/studies/S-EPMC9302672biostudies-literatureGlutaminase 2 knockdown reduces hyperammonemia and associated lethality of urea cycle disorder mouse model.PMC9302672Kim SOkamoto HLin AZBurczynski MEHalasz GMurphy AJMao XChen HNa ESleeman MWCheng XfalseGlutaminase 2 knockdown reduces hyperammonemia and associated lethality of urea cycle disorder mouse model.Amino acids, the building blocks of proteins in the cells and tissues, are of fundamental importance for cell survival, maintenance, and proliferation. The liver plays a critical role in amino acid metabolism and detoxication of byproducts such as ammonia. Urea cycle disorders with hyperammonemia remain difficult to treat and eventually necessitate liver transplantation. In this study, ornithine transcarbamylase deficient (Otc^spf-ash ) mouse model was used to test whether knockdown of a key glutamine metabolism enzyme glutaminase 2 (GLS2, gene name: Gls2) or glutamate dehydrogenase 1 (GLUD1, gene name: Glud1) could rescue the hyperammonemia and associated lethality induced by a high protein diet. We found that reduced hepatic expression of Gls2 but not Glud1 by AAV8-mediated del2022-01-01T00:00:00Z2022 May2026-07-14T16:46:45.208Z2025-02-19T03:52:47.363ZS-EPMC93026723498899910.1002/jimd.12474