Ri-Li Ge1, Tatum S Simonson2, Victor Gordeuk3, Josef T Prchal2, Donald A McClain2. 1. Research Center for High-Altitude Medicine, Qinghai University Medical School, Xining, Qinghai, People's Republic of China. 2. Department of Human Genetics and the Divisions of Endocrinology, Metabolism, and Diabetes and Division of Hematology, University of Utah School of Medicine, Salt Lake City, UT, USA. 3. Section of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Abstract
NEW FINDINGS: 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.
NEW FINDINGS: 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.
Authors: Fernando Naya-Català; Juan A Martos-Sitcha; Verónica de Las Heras; Paula Simó-Mirabet; Josep À Calduch-Giner; Jaume Pérez-Sánchez Journal: Biology (Basel) Date: 2021-05-08