Regulation of Erythritol Metabolism, a Biomarker of Cardiometabolic Disease

Abstract

Abstract Objectives Serum erythritol is a predictive biomarker of chronic disease development and complications. In cohort studies, elevated serum erythritol at baseline was predictive of central adiposity gain, T2DM, and cardiovascular disease development up to 20 years later. Erythritol is a polyol that has been well characterized as a non-nutritive sweetener. Erythritol was recently discovered to be synthesized endogenously in humans from glucose through the pentose phosphate pathway (PPP). The regulation of erythritol synthesis in mammals, however, is not characterized. The purpose of this study was to assess stimuli that modulate intracellular erythritol levels and the distribution of erythritol in key metabolic tissues. Methods First, we fed 8-week-old C57BL/6J mice a defined diet (AIN93G) for two weeks, after which plasma and tissue erythritol were measured by GC-MS. To further evaluate the cellular regulation of erythritol synthesis, we used A549 cells for their high PPP activity. Using siRNA, we knocked down SORD (a potential erythritol-synthesizing enzyme) and glucose-6-phosphate dehydrogenase (G6PD) under normal (5 mM) and high (25 mM) glucose conditions and measured intracellular erythritol. We also exposed A549’s to hydrogen peroxide to assess if erythritol synthesis is elevated by oxidative stress, an additional stimulator of the PPP. Results Plasma erythritol ranged from 0.44 uM to 0.73 uM in young, healthy mice. Erythritol differed significantly based on tissue type (p < 0.0001). The liver and kidney had the highest relative erythritol, followed by quadriceps, whereas white adipose tissue contained the least erythritol. SORD knockdown significantly reduced erythritol synthesis under high glucose, but not normal glucose conditions (p < 0.01). Knockdown of G6PD did not impact erythritol synthesis at either glucose concentration. Finally, treatment with hydrogen peroxide significantly increased intracellular erythritol (p < 0.0001). Conclusions In conclusion, erythritol is present in mouse plasma, SORD-expressing tissues, and human cells. Erythritol was elevated by high glucose and oxidative stress–two key factors in the pathogenesis of cardiometabolic diseases. Together, these data suggest that erythritol synthesis occurs parallel to elevated PPP flux in response to metabolic stressors. Funding Sources N/A