Abstract
Cells efficiently adjust their metabolism according to the abundance of nutrients and energy. The ability to switch cellular metabolism between anabolic and catabolic processes is critical for cell growth. Glucose-6 phosphate is the first intermediate of glucose metabolism and plays a central role in the energy metabolism of the liver. It acts as a hub to metabolically connect glycolysis, the pentose phosphate pathway, glycogen synthesis, de novo lipogenesis, and the hexosamine pathway. In this review, we describe the metabolic fate of glucose-6 phosphate in a healthy liver and the metabolic reprogramming occurring in two pathologies characterized by a deregulation of glucose homeostasis, namely type 2 diabetes, which is characterized by fasting hyperglycemia; and glycogen storage disease type I, where patients develop severe hypoglycemia during short fasting periods. In these two conditions, dysfunction of glucose metabolism results in non-alcoholic fatty liver disease, which may possibly lead to the development of hepatic tumors. Moreover, we also emphasize the role of the transcription factor carbohydrate response element-binding protein (ChREBP), known to link glucose and lipid metabolisms. In this regard, comparing these two metabolic diseases is a fruitful approach to better understand the key role of glucose-6 phosphate in liver metabolism in health and disease.
Highlights
The liver plays a crucial role in the maintenance of glucose homeostasis by extracting glucose from the blood and storing it after a meal, and by producing glucose in post-absorptive state
Type 2 diabetes is characterized by an increase in endogenous glucose production (EGP)
In the case of overnutrition, excessive glucose-6 phosphate (G6P) is converted into fatty acids via de novo lipogenesis in the liver
Summary
The liver plays a crucial role in the maintenance of glucose homeostasis by extracting glucose from the blood and storing it after a meal, and by producing glucose in post-absorptive state. G6P cannot cross the cell membrane, preventing the diffusion of free glucose out of the cells Thanks to this phosphorylation step, glucokinase enables hepatocytes to trap glucose. G6P has many possible fates and it represents a central hub for carbohydrate metabolism (Figure 1) After isomerization, it initiates major metabolic pathways, i.e., glycolysis, pentose phosphate pathway (PPP), glycogen synthesis, hexosamine pathway, and glucose production according to the nutritional or hormonal states. G6P in the hepatocytes, which increases all the metabolic pathways downstream of G6P (Figure 2) These two diseases are characterized by an accumulation of ectopic lipids in the liver, which leads to the development of hepatic steatosis and promotes hepatic tumorigenesis over time [5].
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