Erythritol synthesis is elevated in response to oxidative stress and regulated by the non-oxidative pentose phosphate pathway in A549 cells

Abstract

BackgroundErythritol is a predictive biomarker of cardiometabolic diseases and is produced from glucose metabolism through the pentose phosphate pathway (PPP). Little is known regarding the regulation of endogenous erythritol synthesis in humans.ObjectiveIn the present study, we investigated the stimuli that promote erythritol synthesis in human lung carcinoma cells and characterized potential points of regulation along the PPP.MethodsHuman A549 lung carcinoma cells were chosen for their known ability to synthesize erythritol. A549 cells were treated with potential substrates for erythritol production, including glucose, fructose, and glycerol. Using siRNA knockdown, we assessed the necessity of enzymes G6PD, TKT, TALDO, and SORD for erythritol synthesis. We also used position-specific 13C-glucose tracers to determine whether the carbons for erythritol synthesis are derived directly from glycolysis or through the oxidative PPP. Finally, we assessed if erythritol synthesis responds to oxidative stress using chemical and genetic models.ResultsIntracellular erythritol was directly associated with media glucose concentration. In addition, siRNA knockdown of TKT or SORD inhibited erythritol synthesis, whereas siG6PD did not. Both chemically induced oxidative stress and constitutive activation of the antioxidant response transcription factor NRF2 elevated intracellular erythritol.ConclusionOur findings indicate that in A549 cells, erythritol synthesis is proportional to flux through the PPP and is regulated by non-oxidative PPP enzymes.

Elevated plasma and urinary erythritol is a biomarker of excess simple carbohydrate intake in mice

“…Overall, however, it appears that the liver is not driving sucrose-induced erythritol synthesis. Elevated kidney erythritol was an expected response based on previous work in human proximal tubule cells in which high glucose media increased intracellular erythritol (14,24). Elevated circulating erythritol is also associated with markers of impaired kidney function (11,25).…”

“…The copyright holder for this preprint this version posted December 4, 2022. ; https://doi.org/10.1101/2022.12.04.519026 doi: bioRxiv preprint cells in which high glucose media increased intracellular erythritol (14,24). Elevated circulating erythritol is also associated with markers of impaired kidney function (11,25).…”

“…The copyright holder for this preprint this version posted December 4, 2022. ; https://doi.org/10.1101/2022.12.04.519026 doi: bioRxiv preprint that has been shown to regulate erythritol synthesis in cultured cells (14). TKT expression was reduced in the kidney of mice fed HFD compared to LFD (Fig.…”

“…The copyright holder for this preprint this version posted December 4, 2022. ; https://doi.org/10.1101/2022.12.04.519026 doi: bioRxiv preprint human cells, erythritol synthesis also exhibits a dose-response to the amount of glucose provided in culture media, suggesting that erythritol may respond to nutrient excess (14).…”

“…The impact of ADH1 expression on erythritol synthesis has not been explored. In human cells, erythritol synthesis also exhibits a dose-response to the amount of glucose provided in culture media, suggesting that erythritol may respond to nutrient excess (14).…”