Mechanisms by Which Metabolic Reprogramming in GSD1 Liver Generates a Favorable Tumorigenic Environment

Abstract

Glycogen storage disease type 1 (GSD1) is an inherited disorder caused by impaired glucose 6-phosphatase activity. This impairment translates into the inhibition of endogenous glucose production and the subsequent accumulation of cellular glucose 6-phosphate. Excess glucose 6-phosphate enhances glycolysis, increases the production of fatty acids, uric acid, and lactate, causes hepatomegaly due to glycogen and lipid accumulation, and finally results in liver tumor development. Although the exact mechanisms of tumorigenesis in patients with GSD1 remain unclear, GSD1 hepatocytes undergo a Warburg-like metabolic switch. The consequent hyperactivation of specific metabolic pathways renders GSD1 hepatocytes susceptible to tumor development, presumably by providing the building blocks and energy required for cell proliferation. In addition to this, enhanced apoptosis in GSD1 may promote mitotic activity and hence result in DNA replication errors, thereby contributing to tumorigenesis. Increased carbohydrate responsive element-binding protein (ChREBP) and mammalian target of rapamycin (mTOR) activity and impaired AMP-activated protein kinase (AMPK) function likely play key roles in these pro-oncogenic processes.

Intracellular lipids are an independent cause of liver injury and chronic kidney disease in non alcoholic fatty liver disease-like context

“…AST and ALT activity, compared to untreated L.G6pc −/− mice ( Figure 6 D). Furthermore, previous studies showed that the metabolic reprogramming occurring in GSDIa livers, as a consequence of the excessive G6P levels, promotes hepatic tumorigenesis [16] , [25] . Recent data have shown a decrease in tumor suppressors in L.G6pc −/− livers (unpublished data), in accordance with the pre-neoplastic status of G6pc −/− hepatocytes [16] .…”

“…Furthermore, previous studies showed that the metabolic reprogramming occurring in GSDIa livers, as a consequence of the excessive G6P levels, promotes hepatic tumorigenesis [16] , [25] . Recent data have shown a decrease in tumor suppressors in L.G6pc −/− livers (unpublished data), in accordance with the pre-neoplastic status of G6pc −/− hepatocytes [16] . Interestingly, tumor suppressors, such as AMP-activated protein kinase (AMPK) and phosphatase and tensin homolog (PTEN), were down-regulated in L.G6pc −/− livers, while fenofibrate restored their expression to the level observed in WT mice ( Figure 6 E).…”

“…GSDIa is a pathology characterized by abnormal glycogen and lipid accumulation, specifically in the liver and kidneys, possibly leading to hepatic tumor development and renal failure with age. The deficiency in G6Pase and the subsequent G6P accumulation in hepatocytes and renal proximal tubules are at the origin of an important metabolic remodeling [16] , [25] , [30] . Indeed, the increased utilization of G6P, a common substrate for both lipid and glycogen synthesis, markedly induces these anabolic pathways in GSDIa.…”

“…G6Pase operates the hydrolysis of glucose-6 phosphate (G6P) in glucose thus allowing liver and kidneys, the main organs responsible for endogenous glucose production, to release glucose in the blood and regulate plasma glucose concentration [15] . The lack of G6Pase induces G6P accumulation in the liver and kidneys, leading to metabolic reprogramming in these organs [16] . The first consequence of G6P increase is abnormal accumulation of glycogen in both organs [11] , [14] , [17] , [18] , which has given its name to the disease.…”

Glucose-6 Phosphate, a Central Hub for Liver Carbohydrate Metabolism

“…All these disturbances contribute to hypertriglyceridemia and hypercholesteridemia observed in diabetes and GSDI. In conclusion, the liver metabolism of diabetes and GSDI is very similar, albeit exacerbated in GSDI, with G6P being at the metabolic crossroad as a main responsible for metabolic reprogramming [39,62].…”