2-Hydroxyglutarate Metabolism Is Altered in an in vivo Model of LPS Induced Endotoxemia
Fitzpatrick, Susan F.
McPhail, Mark J. W.
Johnson, Randall S.
Frontiers in Physiology
Frontiers Media S.A.
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Fitzpatrick, S. F., Lambden, S., Macias, D., Puthucheary, Z., Pietsch, S., Mendil, L., McPhail, M. J. W., & et al. (2020). 2-Hydroxyglutarate Metabolism Is Altered in an in vivo Model of LPS Induced Endotoxemia. Frontiers in Physiology, 11 https://doi.org/10.3389/fphys.2020.00147
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.
Physiology, 2-hydroxyglutarate, endotoxemia, sepsis, hypothermia, 2-hydroxygluterate dehydrogenase, iNOS
External DOI: https://doi.org/10.3389/fphys.2020.00147
This record's URL: https://www.repository.cam.ac.uk/handle/1810/303540
Attribution 4.0 International (CC BY 4.0)
Licence URL: https://creativecommons.org/licenses/by/4.0/