2-Hydroxyglutarate Metabolism Is Altered in an in vivo Model of LPS Induced Endotoxemia
Susan F. Fitzpatrick, Simon Lambden, David Macías, Zudin Puthucheary, Sandra Pietsch, Lee Mendil, Mark McPhail, Randall S. Johnson
Abstract
The metabolic response to endotoxemia is closely mimics those seen in sepsis. Here, we show that the urinary excretion of the metabolite 2-hydroxyglutarate (2HG) is dramatically suppressed following 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.