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.

危及生命的高氨血症发生在影响尿素生成的遗传性和获得性肝病中，尿素生成是哺乳动物神经毒性氨解毒的主要途径。蛋白 O-GlcNAc 酰化是一种可逆且营养敏感的翻译后修饰，使用己糖胺生物合成途径的终产物 UDP-GlcNAc 作为底物。在这里，我们发现，高氨血症期间肝脏 UDP-GlcNAc 的增加会增加蛋白质 O-GlcNAc 化并增强尿素生成。从机制上讲，特定苏氨酸残基上的 O-GlcNA 酰化提高了氨基甲酰磷酸合成酶 1 (CPS1)（尿素合成中的限速酶）对氨的催化效率。 O-GlcNAcase（一种从蛋白质中去除 O-GlcNAc 的酶）的药理学抑制作用，可导致遗传性（丙酸血症的亚效性小鼠模型）和获得性（硫代乙酰胺诱导的急性肝衰竭）小鼠肝病模型中全身氨的临床相关减少。总之，通过微调控制氨进入尿素合成，CPS1 的肝脏 O-GlcNAc 酰化可增加氨解毒，是治疗遗传性疾病和获得性疾病中高氨血症的新靶点。