Abstract
We combined 1H NMR metabolomics with functional and molecular biochemical assays to describe the metabolic changes elicited by vitamin D in HEK293T, an embryonic proliferative cell line adapted to high-glucose concentrations. Activation of the polyol pathway, was the most important consequence of cell exposure to high glucose concentration, resembling cells exposed to hyperglycemia. Vitamin D induced alterations in HEK293T cells metabolism, including a decrease in sorbitol, glycine, glutamate, guanine. Vitamin D modulated glycolysis by increasing phosphoglycerate mutase and decreasing enolase activities, changing carbon fate without changing glucose consumption, lactate export and Krebs cycle. The decrease in sorbitol intracellular concentration seems to be related to vitamin D regulated redox homeostasis and protection against oxidative stress, and helped maintaining the high proliferative phenotype, supported by the decrease in glycine and guanine and orotate concentration and increase in choline and phosphocholine concentration. The decrease in orotate and guanine indicated an increased biosynthesis of purine and pyrimidines. Vitamin D elicited metabolic alteration without changing cellular proliferation and mitochondrial respiration, but reclaiming reductive power. Our study may contribute to the understanding of the metabolic mechanism of vitamin D upon exposure to hyperglycemia, suggesting a role of protection against oxidative stress.
Highlights
One of the most important genes up-regulated by vitamin D is the thioredoxin interacting protein (TXNIP), initially named as vitamin D up-regulated protein-1, VDUP-114
We combined 1H Nuclear Magnetic Resonance (NMR) metabolomics with functional and molecular biochemical assays to describe the metabolic changes elicited by vitamin D in HEK293T, an embryonic proliferative cell line adapted to high-glucose concentrations
We are interested in the metabolic mechanisms in the presence of high-glucose concentrations and the way cells deal with oxidative stress
Summary
One of the most important genes up-regulated by vitamin D is the thioredoxin interacting protein (TXNIP), initially named as vitamin D up-regulated protein-1, VDUP-114. TXNIP binds to thioredoxin (TRX)[16], linking the intermediary and primary metabolism, the redox regulation and cell cycle[17,18,19]. TXNIP competes with apoptosis signal-regulating kinase 1, ASK1, for binding to TRX. TXNIP, such as observed in diabetes mellitus type 2, leads to the displacement of TRX from binding to ASK1, promoting the activation of apoptosis[20, 21]. Since vitamin D is a major regulator of TXNIP, one conceivable suggestion is that vitamin D is an important regulator of cellular and redox metabolism. We combined 1H Nuclear Magnetic Resonance (NMR) metabolomics with functional and molecular biochemical assays to describe the metabolic changes elicited by vitamin D in HEK293T, an embryonic proliferative cell line adapted to high-glucose concentrations. Vitamin D treatment reprogrammed the metabolism of these cells by decreasing the polyols pathway and by channeling glucose carbons to the maintenance of the cell’s reductive power and the cell proliferative phenotype, possibly protecting them from the oxidative stress promoted by high glucose concentration
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