Ascorbate as a substrate for glycolysis or gluconeogenesis: evidence for an interorgan ascorbate cycle

Area of Science:

• Biochemistry
• Cell Biology
• Metabolic pathways

Background:

• Ascorbate (vitamin C) is essential but not synthesized by humans and some animals due to absent gulonolactone oxidase.
• Understanding ascorbate catabolism is crucial for comprehending its metabolic fate and potential therapeutic applications.

Purpose of the Study:

• To investigate ascorbate catabolism in cells lacking endogenous synthesis.
• To explore the metabolic pathways involved in ascorbate breakdown and its connection to glucose metabolism.

Main Methods:

• Studied ascorbate and dehydroascorbate metabolism in human (HepG2, MCF7, erythrocytes) and murine cells.
• Utilized menadione (oxidative agent) and oxythiamine (transketolase inhibitor) to probe metabolic pathways.
• Measured glucose production and lactate formation as indicators of metabolic flux.

Main Results:

• HepG2 cells showed high glucose production with ascorbate/dehydroascorbate, indicating gluconeogenesis.
• Human erythrocytes, MCF7 cells, and murine blood cells converted ascorbate/dehydroascorbate to lactate, suggesting a glycolytic route.
• Menadione stimulated dehydroascorbate metabolism, while oxythiamine inhibited it in lactate-producing cells.

Conclusions:

• Ascorbate catabolism via the pentose phosphate pathway can integrate with glycolytic/gluconeogenic pathways.
• A potential interorgan ascorbate cycle exists, with peripheral cells utilizing an ascorbate-lactate route for catabolism.
• Exogenous ascorbate catabolism is demonstrable in human cells, highlighting its metabolic relevance.