Metabolite Modulation in Human Plasma in the Early Phase of Acclimatization to Hypobaric Hypoxia - PubMed (original) (raw)

Wen-Ting Liao 1 2 3, Bao Liu 1 2 3, Jian Chen 4 2 3, Yi-Xing Gao 1 2 3, Fu-Yu Liu 1 2 3, Gang Xu 1 2 3, Bing-Da Sun 1 2 3, Er-Long Zhang 1 2 3, Zhi-Bin Yuan 1 2 3, Gang Zhang 6 2 3, Yu-Qi Gao 1 2 3

Affiliations

Metabolite Modulation in Human Plasma in the Early Phase of Acclimatization to Hypobaric Hypoxia

Wen-Ting Liao et al. Sci Rep. 2016.

Abstract

The exposure of healthy subjects to high altitude represents a model to explore the pathophysiology of diseases related to tissue hypoxia. We explored a plasma metabolomics approach to detect alterations induced by the exposure of subjects to high altitude. Plasma samples were collected from 60 subjects both on plain and at high altitude (5300 m). Metabolite profiling was performed by gas chromatography-mass spectrometry (GC-MS) and ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS) in conjunction with univariate and multivariate statistical analyses. ELISA assays were further employed to measure the levels of several relevant enzymes together with perturbed metabolic pathways. The results showed that hypobaric hypoxia caused significant and comprehensive metabolic changes, as represented by significant changes of 44 metabolites and 4 relevant enzymes. Using MetaboAnalyst 3.0, it was found that several key metabolic pathways were acutely perturbed. In addition, 5 differentially expressed metabolites in pre-exposure samples from the acute mountain sickness-susceptible (AMS-S) group compared with those from the AMS-resistant (AMS-R) group are identified, which warrant further validation as potential predictive biomarkers for AMS-S individuals. These results provide new insights for further understanding the pathophysiological mechanism of early acclimatization to hypobaric hypoxia and other diseases correlated to tissue hypoxia.

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Figures

Figure 1

Figure 1. Schematic flow chart of the metabolic profiling strategy used in this study.

AMS-S, acute mountain sickness susceptible subjects; AMS-R, acute mountain sickness resistant subjects; Pre-AMS-S, pre-exposure samples of AMS-S subjects; Pre-AMS-R, pre-exposure samples of AMS-R subjects.

Figure 2

Figure 2

PCA and OPLS-DA scores plots of 60 subjects at high altitude (red diamonds) and on plain (blue boxes) based on plasma spectral data of (A) UPLC-QTOFMS positive ion mode, (B) UPLC-QTOFMS negative ion mode and (C) GC-MS.

Figure 3

Figure 3. Heat map visualization based on the differential metabolites of importance for the plasma of the AMS-S group.

Variable differences marked on the right corresponding to Table 2 are revealed between the AMS-S and AMS-R groups. Rows, differential metabolites; columns, samples; colour key indicates metabolite expression value, green is lowest and red is highest.

Figure 4

Figure 4. Summary of pathway analysis with MetaboAnalyst 3.0.

(A) Altered metabolic pathways between high-altitude post-exposure and pre-exposure groups. a, linoleic acid metabolism; b, arachidonic acid metabolism; c, pyruvate metabolism; d, inositol phosphate metabolism; e, phenylalanine metabolism; f, citrate cycle. (B) Altered metabolic pathways between AMS-S and AMS-R groups. g, alanine, aspartate and glutamate metabolism; h, phenylalanine metabolism; i, pyruvate metabolism; j, sphingolipid metabolism; k, D-Glutamine and D-glutamate metabolism; l, glycerophospholipid metabolism. (C) Altered metabolic pathways between Pre-AMS-S and Pre-AMS-R groups. m, alanine, aspartate and glutamate metabolism; n, glycerophospholipid metabolism.

Figure 5

Figure 5. Schematic overview of the metabolites and major metabolic pathways as well as pathway-related enzyme changes in plasma of the 60 subjects after arriving at high altitude for four days.

The metabolites and enzymes (italic) are shown in color: red represents increased metabolites or enzymes, green represents decreased metabolites or enzymes, yellow represents no change, and the open circles represent no detected metabolites.

Figure 6

Figure 6. The levels of key enzymes involved in the pathways of altered metabolites.

(A) The levels of key enzymes determined by ELISA. The error bars represent the S.D. of the mean. *p < 0.05, compared with plain control. Key: sEH, soluble epoxy hydrolase; CPT-I, carnitine palmitoyltransferase-I; HO-1, heme oxygenase-1. (B) The level of xanthine oxidase (XO) determined by a colorimetric method. The error bars represent the S.D. of the mean. *p < 0.05, compared with plain control.

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