Pirozzi, Francesca (2025) Multi-omics insights into long-range and long-term metabolic alterations in Glycogen storage disease type Ia reveal significant alterations in lipid metabolism and an increasing risk of developing insulin resistance over time. [Tesi di dottorato]

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Abstract

Glycogen storage diseases (GSDs), also referred to as Glycogenosis, constitute a group of rare, monogenic disorders resulting from defects in enzymes or transporters involved in the synthesis or breakdown of glycogen. These defects result in the abnormal deposition or type of glycogen in specific tissues. In particular, Glycogen storage disease type Ia (GSDIa) is caused by the inactivating mutations of the G6PC1 gene, which encodes the glucose-6-phosphatase-α (G6Pase-α) enzyme. This plays a pivotal role in maintaining glucose homeostasis by catalyzing the hydrolysis of glucose-6-phosphate (G6P) to glucose and phosphate in the final step of gluconeogenesis and glycogenolysis. As a consequence of G6Pase-α deficiency, which is primarily expressed in the liver, kidney, and to a lesser extent in the intestine, patients with GSDIa accumulate G6P, resulting in the excessive storage of glycogen and fat within the tissues. In particular, the clinical picture of GSDIa encompasses a wide range of biochemical alterations, including hypoglycemia, hyperlipidemia, hyperuricemia, and lactic acidemia, as well as clinical manifestations such as hepatomegaly with hepatic steatosis and kidney disease. If left unmanaged or inadequately managed, these conditions may result in the onset of secondary metabolic disorders, such as insulin resistance and metabolic syndrome, and/or the development of complications, including the formation of hepatic adenomas and carcinoma, as well as chronic kidney disease. At present, despite the increasing exploration of novel therapeutic approaches, including transgene delivery, mRNA therapy, and genome editing, the current treatment strategies for GSDIa remain primarily symptomatic. For patients with GSDIa, adherence to a highly personalized dietary regimen represents the mainstay of treatment and has been demonstrated to enhance prognosis and long-term outcomes in recent decades. Nevertheless, the re-definition of guidelines for the management of patients with GSDIa represents a crucial and imperative point of focus for further research. In order to address the necessity of improving metabolic control and preventing long-term complications in GSDIa, the present PhD thesis project sought to define the long-range and long-term effects of G6Pase-α deficiency. To this end, a detailed study of wide-ranging metabolic alterations was conducted through liquid chromatography-tandem mass spectrometry-based methodologies, with a specific focus on the characterization of the lipidomic, metabolomic, and proteomic profile of serum from patients with GSDIa. Additionally, the investigation delved into the alterations induced by the progression of the disease, both over time and in the presence or absence of the major complication, hepatic cancer. This was accomplished through the characterization of the proteomic and phospho-proteomic profile of liver tissue derived from a GSDIa mouse model. The results of the investigation into long-range effects in patients with GSDIa demonstrated a distinctive serum multi-omics signature, characterized by a marked alteration of lipid metabolism, accompanied by the differential serum abundance of proteins investigated in other liver diseases. These findings underscore the necessity of revising the current guidelines for the management of GSDIa and highlight the pivotal role of the liver in this disease. Indeed, profound alterations in lipid metabolism may serve as a predictor of subsequent complications, such as insulin resistance. In this regard, the results of the investigation in GSDIa mice of long-term effects induced by GSDIa demonstrated that the liver expression profile of proteins involved in the lipid metabolism and insulin signaling pathway is susceptible to alterations over time. Moreover, remodeling of steroid and steroid hormone biosynthesis pathways was observed over time and in the presence of hepatic tumor complications. Furthermore, this dissertation demonstrated that the phosphorylation pattern of liver proteins involved in insulin signaling and steroid metabolism is altered in early-aged GSDIa mice. In view of the novel insights yielded by this study, the integration of data at the multi-omics level may provide crucial and significant support for a redefinition of metabolic control in GSDIa patients, thereby facilitating more effective outcome management of patients with GSDIa.

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