Metabolomic and lipidomic plasma profile changes in human participants ascending to Everest Base Camp

Abstract

At high altitude oxygen delivery to the tissues is impaired leading to oxygen insufficiency (hypoxia). Acclimatisation requires adjustment to tissue metabolism, the details of which remain incompletely understood. Here, metabolic responses to progressive environmental hypoxia were assessed through metabolomic and lipidomic profiling of human plasma taken from 198 human participants before and during an ascent to Everest Base Camp (5,300 m). Aqueous and lipid fractions of plasma were separated and analysed using proton (1H)-nuclear magnetic resonance spectroscopy and direct infusion mass spectrometry, respectively. Bayesian robust hierarchical regression revealed decreasing isoleucine with ascent alongside increasing lactate and decreasing glucose, which may point towards increased glycolytic rate. Changes in the lipid profile with ascent included a decrease in triglycerides (48–50 carbons) associated with de novo lipogenesis, alongside increases in circulating levels of the most abundant free fatty acids (palmitic, linoleic and oleic acids). Together, this may be indicative of fat store mobilisation. This study provides the first broad metabolomic account of progressive exposure to environmental hypobaric hypoxia in healthy humans. Decreased isoleucine is of particular interest as a potential contributor to muscle catabolism observed with exposure to hypoxia at altitude. Substantial changes in lipid metabolism may represent important metabolic responses to sub-acute exposure to environmental hypoxia.

The Effect of Acute Continuous Hypoxia on Triglyceride Levels in Constantly Fed Healthy Men

“…In the present study, however, it could be suspected that the combination of chylomicron remnants delivery and elevated plasma NEFA may have provided enough lipid substrate to drive an increase in hepatic VLDL production. Consistent with this hypothesis, a recent report suggests that journey at altitude may increase the liver output of TG constituted of adipose tissue lipolytic products such as palmitic and oleic acid, supporting the concept that hypoxia may promote lipid recycling and stimulate hepatic TG secretion (O’Brien et al, 2019).…”

Sphingolipids in Obesity and Correlated Co-Morbidities: The Contribution of Gender, Age and Environment

“…Another investigation [253], conducted in human subjects which had developed high-altitude pulmonary edema (HAPE) after high altitude exposure, demonstrated that plasma C8-ceramide, sphingosine and glutamine could be used as diagnostic biomarkers for HAPE, suggesting that S1P levels could be used for monitoring adaptation to hypoxia. Finally, a work from 2019 by O’Brien et al [254] on human subjects ascending to Mount Everest Base Camp, identified a decrease in TG alongside an increase in plasma levels of free fatty acids (palmitic, linoleic and oleic acids) and an increase in SM 34:2. Unfortunately, the work did not mention ceramide levels in subjects; this would have been of interest given the increased levels of circulating free fatty acids (in particular palmitate) that are known to be central in ceramide de-novo biosynthesis [57,105,106].…”

Comparative Analysis of Metabolic Differences of Jersey Cattle in Different High-Altitude Areas

“…Recent studies have found that people from low altitude to high altitude will cause significant remodeling of tissue metabolism, as well as changes in the level of circulating metabolism ( 9 , 10 ). Hypoxia can inhibit the oxidative metabolism of heart ( 11 ) and skeletal muscle ( 12 ), reduce the ability of fatty acid oxidation ( 13 ), and increase glycolysis ( 14 ) in rodents and non-plateau native people. Based on miRNA and proteomics, we found that Jersey cattle adapt to high-altitude hypoxia by regulating inflammatory homeostasis ( 15 ).…”