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

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.

Mechanisms of intermittent hypoxia‐mediated macrophage activation – potential therapeutic targets for obstructive sleep apnoea

“…Bone‐marrow derived macrophages (BMDMs) were isolated from femurs and tibias obtained from male mice as previously described (Fitzpatrick et al., 2020). Cells were plated in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% heat‐inactivated fetal bovine serum (FBS), 5% penicillin/streptomycin and 30% conditioned media [media isolated from macrophage colony‐stimulating factor (MCSF) producing L929 cells cultured for 7 days].…”

“…RNA was extracted with TRI Reagent (Sigma, USA) and complementary DNA (cDNA) was generated using a Maxima First Strand cDNA synthesis kit (Thermo Scientific, UK), as previously described (Fitzpatrick et al., 2020). TaqMan probes used were: inducible nitric oxide synthase (iNOS) (Mm00440502), IL‐6 (Mm00446190), IL‐1β (Mm01336189), TLR4 (Mm00445273), and 18S ribosomal RNA (rRNA; 4310893E).…”

Metabolic Reprogramming in Cancer Cells: Emerging Molecular Mechanisms and Novel Therapeutic Approaches

“…An IDH mutation leads to major metabolic changes involving increased oxidative stress through the reduction of NADPH [52], lactate dehydrogenase A (LDHA) silencing (suggesting that the carbon source is preferentially derived from alpha-ketoglutarate via glutamine metabolism), and PDH suppression (via elevated PDK3 expression) accompanied by increased activity of PC, an essential enzyme for producing intermediate metabolites in various pathways crucial for gluconeogenesis and lipogenesis [53]. Likewise, an IDH mutation increases 2-hydroxyglutarate, a key metabolite during metabolic reprogramming [54].…”

Urinary 2-Hydroxyglutarate Enantiomers Are Markedly Elevated in a Murine Model of Type 2 Diabetic Kidney Disease

“…Apart from its role in oncogenesis, studies have found a physiological role of 2-HG in regulating T cell fate and function, in which accumulation of L-2HG precedes T cell differentiation and alters both T cell metabolism and epigenetics [ 21 , 22 ]. A recent study found decreased production of L and D-2HG in a murine model of lipopolysaccharide-induced endotoxemia, driven by increases in D-2HGDH and L-2HGDH protein levels [ 23 ]. In conclusion, 2-HG is a metabolite with physiological regulatory roles, and alterations in its levels can lead to significant changes in cellular function.…”