Metabolic aspects of high-altitude adaptation in Tibetans

Exp Physiol. 2015 Nov;100(11):1247-55. doi: 10.1113/EP085292. Epub 2015 Jul 14.

Abstract

What is the topic of this review? The topic of this review is how Tibetans have adapted genetically to high altitude, particularly with reference to altitude-induced changes in metabolism. What advances does it highlight? It highlights recent work on metabolic phenotyping in Tibetans and demonstrates that selected genetic haplotypes influence their metabolism of fats and glucose. Recent studies have identified genes involved in high-altitude adaptation in Tibetans. Three of these genes (EPAS1, EGLN1 and PPARA) are associated with decreased haemoglobin levels compared with non-Tibetans living at altitude. Consistent with the phenotype, EGLN1 in Tibetans has a gain-of-function mutation that confers a higher affinity for oxygen, hence less sensitivity to hypoxia. Considering the demands imposed upon metabolism in meeting energy demands despite limitations on fuel oxidation, we hypothesized that other selected genes might alter metabolism to allow adaptation to altitude despite the desensitization of the upstream hypoxia sensing caused by the EGLN1 mutation that results in the failure to sense hypoxia. A shift in fuel preference to glucose oxidation and glycolysis at the expense of fatty acid oxidation would provide adaptation to decreased oxygen availability. Measurements of serum metabolites from Tibetans living at high altitude are consistent with this hypothesis; the EPAS1 haplotype is significantly associated with increased lactate levels (suggesting increased anaerobic metabolism), and the PPARA haplotype and serum free fatty acids are positively related (suggesting decreased fat oxidation). These data suggest that the high-altitude adaptations may offer protection from diabetes at high altitude but increase the risk of diabetes at lower elevations and/or with adoption of a non-traditional diet. It should also be considered in future work in the field that because iron is a cofactor for EGLN1, there may be significant associations of phenotypes with the significant degrees of variation seen in tissue iron among human populations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Adaptation, Physiological*
  • Altitude*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Energy Metabolism*
  • Ethnic Groups
  • Fatty Acids / blood
  • Haplotypes
  • Humans
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor-Proline Dioxygenases / genetics
  • Lactic Acid / blood
  • Mutation
  • Oxygen / metabolism*
  • PPAR alpha / genetics
  • Phenotype
  • Selection, Genetic
  • Tibet

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Fatty Acids
  • PPAR alpha
  • endothelial PAS domain-containing protein 1
  • Lactic Acid
  • EGLN1 protein, human
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Oxygen