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2-Hydroxyglutarate Metabolism Is Altered in an in vivo Model of LPS Induced Endotoxemia

Published version
Peer-reviewed

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Authors

Fitzpatrick, Susan F. 
Lambden, Simon 
Macias, David 
Puthucheary, Zudin 
Pietsch, Sandra 

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.

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Keywords

Physiology, 2-hydroxyglutarate, endotoxemia, sepsis, hypothermia, 2-hydroxygluterate dehydrogenase, iNOS

Journal Title

Frontiers in Physiology

Conference Name

Journal ISSN

1664-042X

Volume Title

11

Publisher

Frontiers Media S.A.