S -Nitrosylation of glycogen phosphorylase regulates nuclear glycogenolysis and is impaired in metabolic liver disorders

Nuclear glycogen storage has been known for nearly 100 years. However, its role in diseases remains unclear. Here, we found nuclear glycogen storage in livers of mice and humans with argininosuccinic aciduria (ASA), an inborn error of metabolism. Nuclear glycogenolysis sustains histone acetylation and liver homeostasis. We show that hepatic nuclear glycogenolysis is regulated by nitric oxide (NO)–dependent control of the nuclear abundance of liver glycogen phosphorylase (PYGL), an enzyme involved in glycogen breakdown that translocates from the cytosol to the nucleus. In vivo, NO supplementation restored the nuclear content of PYGL by promoting its S -nitrosylation at cysteine-446 and its nuclear translocation. Next, we found that nuclear import of PYGL is mediated by HNRNPF, a regulator of RNA maturation that shuttles between the nucleus and cytosol, thus linking control of gene expression to RNA metabolism. Similar changes were detected in both rodent and human livers with metabolic dysfunction-associated steatotic liver disease (MASLD), a global health concern with limited therapies, that shares with ASA a decrease in NO synthesis. In conclusion, our findings reveal a mechanism underlying reduced glycogenolysis and hepatic nuclear glycogen storage disorders, a new group of metabolic disorders.