AUTHOR=Fitzpatrick Susan F. , Lambden Simon , Macias David , Puthucheary Zudin , Pietsch Sandra , Mendil Lee , McPhail Mark J. W. , Johnson Randall S. TITLE=2-Hydroxyglutarate Metabolism Is Altered in an in vivo Model of LPS Induced Endotoxemia JOURNAL=Frontiers in Physiology VOLUME=11 YEAR=2020 URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.00147 DOI=10.3389/fphys.2020.00147 ISSN=1664-042X ABSTRACT=

The metabolic response to endotoxemia closely mimics those seen in sepsis. Here, we show that the urinary excretion of the metabolite 2-hydroxyglutarate (2HG) is dramatically suppressed following lipopolysaccharide (LPS) administration in vivo, and in human septic patients. We further show that enhanced activation of the enzymes responsible for 2-HG degradation, D- and L-2-HGDH, underlie this effect. To determine the role of supplementation with 2HG, we carried out co-administration of LPS and 2HG. This co-administration in mice modulates a number of aspects of physiological responses to LPS, and in particular, protects against LPS-induced hypothermia. Our results identify a novel role for 2HG in endotoxemia pathophysiology, and suggest that this metabolite may be a critical diagnostic and therapeutic target for sepsis.