Ge Ri-Li, Simonson Tatum S, Gordeuk Victor, Prchal Josef T, McClain Donald A
Research Center for High-Altitude Medicine, Qinghai University Medical School, Xining, Qinghai, People's Republic of China.
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.
Exp Physiol. 2015 Nov;100(11):1247-55. doi: 10.1113/EP085292. Epub 2015 Jul 14.
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.
这篇综述的主题是什么？这篇综述的主题是藏族人如何在基因上适应高海拔环境，特别是与海拔引起的代谢变化相关的方面。它突出了哪些进展？它突出了近期关于藏族人代谢表型分析的研究工作，并表明选定的基因单倍型会影响他们对脂肪和葡萄糖的代谢。近期研究已经确定了藏族人中参与高海拔适应的基因。与生活在高海拔地区的非藏族人相比，其中三个基因（EPAS1、EGLN1和PPARA）与血红蛋白水平降低有关。与这种表型一致，藏族人中的EGLN1有一个功能获得性突变，赋予了对氧气更高的亲和力，因此对缺氧的敏感性较低。考虑到尽管燃料氧化受到限制，但在满足能量需求时对代谢的要求，我们推测其他选定的基因可能会改变代谢，以允许适应高海拔环境，尽管EGLN1突变导致上游缺氧感知脱敏，从而导致无法感知缺氧。以脂肪酸氧化为代价，燃料偏好转向葡萄糖氧化和糖酵解将有助于适应氧气供应减少的情况。对生活在高海拔地区的藏族人的血清代谢物测量结果与这一假设一致；EPAS1单倍型与乳酸水平升高显著相关（表明无氧代谢增加），PPARA单倍型与血清游离脂肪酸呈正相关（表明脂肪氧化减少）。这些数据表明，高海拔适应可能在高海拔地区提供对糖尿病的保护，但在较低海拔和/或采用非传统饮食时会增加患糖尿病的风险。在该领域未来的工作中还应考虑到，由于铁是EGLN1的辅因子，人群中组织铁的显著差异可能与表型有显著关联。
