Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-32904-x
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Funding
- Fondazione Telethon Italy
- MIUR (PRIN2017)
- Swiss National Science Foundation [320030_176088]
- US National Institutes of Health [R21NS091654, R01NS100979]
- Spanish Ministry of Science and Innovation [PID2019-105344RB-I00/AEI/10.13039/501100011033]
- Wellcome Trust Investigator Award [110061]
- Swiss National Science Foundation (SNF) [320030_176088] Funding Source: Swiss National Science Foundation (SNF)
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Hyperammonemia, a life-threatening condition, occurs in liver diseases affecting ureagenesis. This study demonstrates that increased liver UDP-GlcNAc during hyperammonemia leads to O-GlcNAcylation of CPS1, enhancing ureagenesis and ammonia detoxification. The authors also find that pharmacological increase of protein O-GlcNAcylation reduces hyperammonemia in mouse models of liver disease. These findings suggest that hepatic O-GlcNAcylation of CPS1 could be a novel target for therapy of hyperammonemia in both genetic and acquired liver diseases.
Hyperammonemia occurs in liver diseases affecting ureagenesis, and is life-threatening. Here, the authors show that liver UDP-GlcNAc is increased during hyperammonemia, leading to O-GlcNAcylation of the rate-limiting ureagenesis enzyme CPS1, that enhanced ureagenesis and ammonia detoxification. They also showed that pharmacological increase of protein O-GlcNAcylation reduces hyperammonemia in mouse models of liver disease. Life-threatening hyperammonemia occurs in both inherited and acquired liver diseases affecting ureagenesis, the main pathway for detoxification of neurotoxic ammonia in mammals. Protein O-GlcNAcylation is a reversible and nutrient-sensitive post-translational modification using as substrate UDP-GlcNAc, the end-product of hexosamine biosynthesis pathway. Here we show that increased liver UDP-GlcNAc during hyperammonemia increases protein O-GlcNAcylation and enhances ureagenesis. Mechanistically, O-GlcNAcylation on specific threonine residues increased the catalytic efficiency for ammonia of carbamoyl phosphate synthetase 1 (CPS1), the rate-limiting enzyme in ureagenesis. Pharmacological inhibition of O-GlcNAcase, the enzyme removing O-GlcNAc from proteins, resulted in clinically relevant reductions of systemic ammonia in both genetic (hypomorphic mouse model of propionic acidemia) and acquired (thioacetamide-induced acute liver failure) mouse models of liver diseases. In conclusion, by fine-tuned control of ammonia entry into ureagenesis, hepatic O-GlcNAcylation of CPS1 increases ammonia detoxification and is a novel target for therapy of hyperammonemia in both genetic and acquired diseases.
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