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Abstract
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.
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.
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1 Telethon Institute of Genetics and Medicine, Pozzuoli, Italy (GRID:grid.410439.b) (ISNI:0000 0004 1758 1171)
2 University Children’s Hospital, Division of Metabolism and Children’s Research Center, Zurich, Switzerland (GRID:grid.412341.1) (ISNI:0000 0001 0726 4330)
3 University of Dundee, School of Life Sciences, Dundee, UK (GRID:grid.8241.f) (ISNI:0000 0004 0397 2876)
4 National Research Council, Institute of Biomolecular Chemistry, Pozzuoli, Italy (GRID:grid.5326.2) (ISNI:0000 0001 1940 4177)
5 David Geffen School of Medicine at UCLA, Molecular Biology Institute, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718)
6 David Geffen School of Medicine at UCLA, Molecular Biology Institute, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); David Geffen School of Medicine at UCLA, Surgery, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718)
7 Universidad Autónoma, Centro de Biología Molecular Severo Ochoa UAM-CSIC, CIBERER, IdiPaz, Madrid, Spain (GRID:grid.5515.4) (ISNI:0000000119578126)
8 Telethon Institute of Genetics and Medicine, Pozzuoli, Italy (GRID:grid.410439.b) (ISNI:0000 0004 1758 1171); Federico II University, Department of Translational Medicine, Naples, Italy (GRID:grid.4691.a) (ISNI:0000 0001 0790 385X); University of Naples Federico II, Scuola Superiore Meridionale (SSM, School of Advanced Studies), Genomics and Experimental Medicine Program, Naples, Italy (GRID:grid.4691.a) (ISNI:0000 0001 0790 385X)