D'Alessio, Alfonso Manuel (2024) Impaired nuclear glycogen metabolism affects liver homeostasis in argininosuccinic aciduria. [Tesi di dottorato]

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Abstract

Urea cycle is the most important biochemical pathway for ammonia detoxification in humans. It takes place in mitochondria and cytoplasm of hepatocytes and incorporates ammonia derived from protein catabolism into urea, which is then eliminated in urine. Deficiencies of any of the enzymes involved in this pathway are responsible for rare inborn errors of metabolism known as urea cycle disorders (UCDs). Nuclear glycogen catabolism supports histone acetylation and reduced nuclear glycogenolysis drives progression of lung cancer through epigenetic changes. We found increased hepatic nuclear glycogen storage in AslNeo/Neo mice, a mouse model of Argininosuccinic Aciduria (ASA), the second most common among UCDs. Notably, nuclear glycogen storage was detected in liver biopsies from ASA patients. Increased nuclear glycogen storage was associated with reduced nuclear abundance of glycogen phosphorylase (PYGL), the first and rate-limiting enzyme of glycogenolysis, suggesting impaired nuclear glycogenolysis. Nuclear glycogen storage was associated to marked decrease in lysine acetylation of several histones and histone 3, lysine 9 (H3K9)-dependent transcriptomic changes in AslNeo/Neo mice. Treatment with a histone deacetylase inhibitor (HDACi) or adeno-associated viral vector (AAV) mediated gene transfer of PYGL in livers of AslNeo/Neo mice improved survival and increased histone acetylation. Liver transcriptomic changes in AslNeo/Neo mice highlighted dysregulation of metabolism, particularly lipid metabolism, including the master regulator of lipogenesis Pparg and the fatty acid receptor Cd36, that were restored in AAV-PYGL injected mice. Interestingly, I found increased nuclear glycogen storage and reduced nuclear PYGL histone acetylation in livers of a diet-induced rat model of metabolic dysfunction-associated fatty liver disease (MAFLD). ASL deficiency in both humans and mice leads to reduced Nitric oxide (NO) synthesis and treatment with NO donors restored nuclear PYGL in livers of AslNeo/Neo mice. In summary, we propose that in ASA livers, impairment of NOdependent nuclear translocation of glycogen metabolizing enzyme results in reduced glycogenolysis, nuclear glycogen storage and histone hypoacetylation that affect expression of lipid metabolism genes. Our findings have implications for the development of improved therapies for liver disease in ASA, but also common diseases such as MAFLD.

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